Publications by authors named "Encarna Gomez Garcia"

71 Publications

Long-Term Morbidity and Health After Early Menopause Due to Oophorectomy in Women at Increased Risk of Ovarian Cancer: Protocol for a Nationwide Cross-Sectional Study With Prospective Follow-Up (HARMOny Study).

JMIR Res Protoc 2021 Jan 22;10(1):e24414. Epub 2021 Jan 22.

Department of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Amsterdam, Netherlands.

Background: BRCA1/2 mutation carriers are recommended to undergo risk-reducing salpingo-oophorectomy (RRSO) at 35 to 45 years of age. RRSO substantially decreases ovarian cancer risk, but at the cost of immediate menopause. Knowledge about the potential adverse effects of premenopausal RRSO, such as increased risk of cardiovascular disease, osteoporosis, cognitive dysfunction, and reduced health-related quality of life (HRQoL), is limited.

Objective: The aim of this study is to assess the long-term health effects of premenopausal RRSO on cardiovascular disease, bone health, cognitive functioning, urological complaints, sexual functioning, and HRQoL in women with high familial risk of breast or ovarian cancer.

Methods: We will conduct a multicenter cross-sectional study with prospective follow-up, nested in a nationwide cohort of women at high familial risk of breast or ovarian cancer. A total of 500 women who have undergone RRSO before 45 years of age, with a follow-up period of at least 10 years, will be compared with 250 women (frequency matched on current age) who have not undergone RRSO or who have undergone RRSO at over 55 years of age. Participants will complete an online questionnaire on lifestyle, medical history, cardiovascular risk factors, osteoporosis, cognitive function, urological complaints, and HRQoL. A full cardiovascular assessment and assessment of bone mineral density will be performed. Blood samples will be obtained for marker analysis. Cognitive functioning will be assessed objectively with an online neuropsychological test battery.

Results: This study was approved by the institutional review board in July 2018. In February 2019, we included our first participant. As of November 2020, we had enrolled 364 participants in our study.

Conclusions: Knowledge from this study will contribute to counseling women with a high familial risk of breast/ovarian cancer about the long-term health effects of premenopausal RRSO. The results can also be used to offer health recommendations after RRSO.

Trial Registration: ClinicalTrials.gov NCT03835793; https://clinicaltrials.gov/ct2/show/NCT03835793.

International Registered Report Identifier (irrid): DERR1-10.2196/24414.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2196/24414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864779PMC
January 2021

Oral Contraceptive Use and Breast Cancer Risk: Retrospective and Prospective Analyses From a BRCA1 and BRCA2 Mutation Carrier Cohort Study.

JNCI Cancer Spectr 2018 Apr 28;2(2):pky023. Epub 2018 Jun 28.

Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands.

Background: For BRCA1 and BRCA2 mutation carriers, the association between oral contraceptive preparation (OCP) use and breast cancer (BC) risk is still unclear.

Methods: Breast camcer risk associations were estimated from OCP data on 6030 BRCA1 and 3809 BRCA2 mutation carriers using age-dependent Cox regression, stratified by study and birth cohort. Prospective, left-truncated retrospective and full-cohort retrospective analyses were performed.

Results: For BRCA1 mutation carriers, OCP use was not associated with BC risk in prospective analyses (hazard ratio [HR] = 1.08, 95% confidence interval [CI] = 0.75 to 1.56), but in the left-truncated and full-cohort retrospective analyses, risks were increased by 26% (95% CI = 6% to 51%) and 39% (95% CI = 23% to 58%), respectively. For BRCA2 mutation carriers, OCP use was associated with BC risk in prospective analyses (HR = 1.75, 95% CI = 1.03 to 2.97), but retrospective analyses were inconsistent (left-truncated: HR = 1.06, 95% CI = 0.85 to 1.33; full cohort: HR = 1.52, 95% CI = 1.28 to 1.81). There was evidence of increasing risk with duration of use, especially before the first full-term pregnancy (BRCA1: both retrospective analyses, < .001 and = .001, respectively; BRCA2: full retrospective analysis, = .002).

Conclusions: Prospective analyses did not show that past use of OCP is associated with an increased BC risk for BRCA1 mutation carriers in young middle-aged women (40-50 years). For BRCA2 mutation carriers, a causal association is also not likely at those ages. Findings between retrospective and prospective analyses were inconsistent and could be due to survival bias or a true association for younger women who were underrepresented in the prospective cohort. Given the uncertain safety of long-term OCP use for BRCA1/2 mutation carriers, indications other than contraception should be avoided and nonhormonal contraceptive methods should be discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jncics/pky023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649757PMC
April 2018

Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers.

Authors:
Frank Qian Matti A Rookus Goska Leslie Harvey A Risch Mark H Greene Cora M Aalfs Muriel A Adank Julian Adlard Bjarni A Agnarsson Munaza Ahmed Kristiina Aittomäki Irene L Andrulis Norbert Arnold Banu K Arun Margreet G E M Ausems Jacopo Azzollini Daniel Barrowdale Julian Barwell Javier Benitez Katarzyna Białkowska Valérie Bonadona Julika Borde Ake Borg Angela R Bradbury Joan Brunet Saundra S Buys Trinidad Caldés Maria A Caligo Ian Campbell Jonathan Carter Jocelyne Chiquette Wendy K Chung Kathleen B M Claes J Margriet Collée Marie-Agnès Collonge-Rame Fergus J Couch Mary B Daly Capucine Delnatte Orland Diez Susan M Domchek Cecilia M Dorfling Jacqueline Eason Douglas F Easton Ros Eeles Christoph Engel D Gareth Evans Laurence Faivre Lidia Feliubadaló Lenka Foretova Eitan Friedman Debra Frost Patricia A Ganz Judy Garber Vanesa Garcia-Barberan Andrea Gehrig Gord Glendon Andrew K Godwin Encarna B Gómez Garcia Ute Hamann Jan Hauke John L Hopper Peter J Hulick Evgeny N Imyanitov Claudine Isaacs Louise Izatt Anna Jakubowska Ramunas Janavicius Esther M John Beth Y Karlan Carolien M Kets Yael Laitman Conxi Lázaro Dominique Leroux Jenny Lester Fabienne Lesueur Jennifer T Loud Jan Lubiński Alicja Łukomska Lesley McGuffog Noura Mebirouk Hanne E J Meijers-Heijboer Alfons Meindl Austin Miller Marco Montagna Thea M Mooij Emmanuelle Mouret-Fourme Katherine L Nathanson Bita Nehoray Susan L Neuhausen Heli Nevanlinna Finn C Nielsen Kenneth Offit Edith Olah Kai-Ren Ong Jan C Oosterwijk Laura Ottini Michael T Parsons Paolo Peterlongo Georg Pfeiler Nisha Pradhan Paolo Radice Susan J Ramus Johanna Rantala Gad Rennert Mark Robson Gustavo C Rodriguez Ritu Salani Maren T Scheuner Rita K Schmutzler Payal D Shah Lucy E Side Jacques Simard Christian F Singer Doris Steinemann Dominique Stoppa-Lyonnet Yen Yen Tan Manuel R Teixeira Mary Beth Terry Mads Thomassen Marc Tischkowitz Silvia Tognazzo Amanda E Toland Nadine Tung Christi J van Asperen Klaartje van Engelen Elizabeth J van Rensburg Laurence Venat-Bouvet Jeroen Vierstraete Gabriel Wagner Lisa Walker Jeffrey N Weitzel Drakoulis Yannoukakos Antonis C Antoniou David E Goldgar Olufunmilayo I Olopade Georgia Chenevix-Trench Timothy R Rebbeck Dezheng Huo

Br J Cancer 2019 07 19;121(2):180-192. Epub 2019 Jun 19.

Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA.

Background: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown.

Methods: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models.

Results: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (P < 0.05).

Conclusion: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41416-019-0492-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738050PMC
July 2019

An alternative approach to establishing unbiased colorectal cancer risk estimation in Lynch syndrome.

Genet Med 2019 12 17;21(12):2706-2712. Epub 2019 Jun 17.

Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.

Purpose: Biallelic pathogenic variants in the mismatch repair (MMR) genes cause a recessive childhood cancer predisposition syndrome known as constitutional mismatch repair deficiency (CMMRD). Family members with a heterozygous MMR variant have Lynch syndrome. We aimed at estimating cancer risk in these heterozygous carriers as a novel approach to avoid complicated statistical methods to correct for ascertainment bias.

Methods: Cumulative colorectal cancer incidence was estimated in a cohort of PMS2- and MSH6-associated families, ascertained by the CMMRD phenotype of the index, by using mutation probabilities based on kinship coefficients as analytical weights in a proportional hazard regression on the cause-specific hazards. Confidence intervals (CIs) were obtained by bootstrapping at the family level.

Results: The estimated cumulative colorectal cancer risk at age 70 years for heterozygous PMS2 variant carriers was 8.7% (95% CI 4.3-12.7%) for both sexes combined, and 9.9% (95% CI 4.9-15.3%) for men and 5.9% (95% CI 1.6-11.1%) for women separately. For heterozygous MSH6 variant carriers these estimates are 11.8% (95% CI 4.5-22.7%) for both sexes combined, 10.0% (95% CI 1.83-24.5%) for men and 11.7% (95% CI 2.10-26.5%) for women.

Conclusion: Our findings are consistent with previous reports that used more complex statistical methods to correct for ascertainment bias. These results underline the need for MMR gene-specific surveillance protocols for Lynch syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-019-0577-zDOI Listing
December 2019

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.

Authors:
Michael T Parsons Emma Tudini Hongyan Li Eric Hahnen Barbara Wappenschmidt Lidia Feliubadaló Cora M Aalfs Simona Agata Kristiina Aittomäki Elisa Alducci María Concepción Alonso-Cerezo Norbert Arnold Bernd Auber Rachel Austin Jacopo Azzollini Judith Balmaña Elena Barbieri Claus R Bartram Ana Blanco Britta Blümcke Sandra Bonache Bernardo Bonanni Åke Borg Beatrice Bortesi Joan Brunet Carla Bruzzone Karolin Bucksch Giulia Cagnoli Trinidad Caldés Almuth Caliebe Maria A Caligo Mariarosaria Calvello Gabriele L Capone Sandrine M Caputo Ileana Carnevali Estela Carrasco Virginie Caux-Moncoutier Pietro Cavalli Giulia Cini Edward M Clarke Paola Concolino Elisa J Cops Laura Cortesi Fergus J Couch Esther Darder Miguel de la Hoya Michael Dean Irmgard Debatin Jesús Del Valle Capucine Delnatte Nicolas Derive Orland Diez Nina Ditsch Susan M Domchek Véronique Dutrannoy Diana M Eccles Hans Ehrencrona Ute Enders D Gareth Evans Chantal Farra Ulrike Faust Ute Felbor Irene Feroce Miriam Fine William D Foulkes Henrique C R Galvao Gaetana Gambino Andrea Gehrig Francesca Gensini Anne-Marie Gerdes Aldo Germani Jutta Giesecke Viviana Gismondi Carolina Gómez Encarna B Gómez Garcia Sara González Elia Grau Sabine Grill Eva Gross Aliana Guerrieri-Gonzaga Marine Guillaud-Bataille Sara Gutiérrez-Enríquez Thomas Haaf Karl Hackmann Thomas V O Hansen Marion Harris Jan Hauke Tilman Heinrich Heide Hellebrand Karen N Herold Ellen Honisch Judit Horvath Claude Houdayer Verena Hübbel Silvia Iglesias Angel Izquierdo Paul A James Linda A M Janssen Udo Jeschke Silke Kaulfuß Katharina Keupp Marion Kiechle Alexandra Kölbl Sophie Krieger Torben A Kruse Anders Kvist Fiona Lalloo Mirjam Larsen Vanessa L Lattimore Charlotte Lautrup Susanne Ledig Elena Leinert Alexandra L Lewis Joanna Lim Markus Loeffler Adrià López-Fernández Emanuela Lucci-Cordisco Nicolai Maass Siranoush Manoukian Monica Marabelli Laura Matricardi Alfons Meindl Rodrigo D Michelli Setareh Moghadasi Alejandro Moles-Fernández Marco Montagna Gemma Montalban Alvaro N Monteiro Eva Montes Luigi Mori Lidia Moserle Clemens R Müller Christoph Mundhenke Nadia Naldi Katherine L Nathanson Matilde Navarro Heli Nevanlinna Cassandra B Nichols Dieter Niederacher Henriette R Nielsen Kai-Ren Ong Nicholas Pachter Edenir I Palmero Laura Papi Inge Sokilde Pedersen Bernard Peissel Pedro Perez-Segura Katharina Pfeifer Marta Pineda Esther Pohl-Rescigno Nicola K Poplawski Berardino Porfirio Anne S Quante Juliane Ramser Rui M Reis Françoise Revillion Kerstin Rhiem Barbara Riboli Julia Ritter Daniela Rivera Paula Rofes Andreas Rump Monica Salinas Ana María Sánchez de Abajo Gunnar Schmidt Ulrike Schoenwiese Jochen Seggewiß Ares Solanes Doris Steinemann Mathias Stiller Dominique Stoppa-Lyonnet Kelly J Sullivan Rachel Susman Christian Sutter Sean V Tavtigian Soo H Teo Alex Teulé Mads Thomassen Maria Grazia Tibiletti Marc Tischkowitz Silvia Tognazzo Amanda E Toland Eva Tornero Therese Törngren Sara Torres-Esquius Angela Toss Alison H Trainer Katherine M Tucker Christi J van Asperen Marion T van Mackelenbergh Liliana Varesco Gardenia Vargas-Parra Raymonda Varon Ana Vega Ángela Velasco Anne-Sophie Vesper Alessandra Viel Maaike P G Vreeswijk Sebastian A Wagner Anke Waha Logan C Walker Rhiannon J Walters Shan Wang-Gohrke Bernhard H F Weber Wilko Weichert Kerstin Wieland Lisa Wiesmüller Isabell Witzel Achim Wöckel Emma R Woodward Silke Zachariae Valentina Zampiga Christine Zeder-Göß Conxi Lázaro Arcangela De Nicolo Paolo Radice Christoph Engel Rita K Schmutzler David E Goldgar Amanda B Spurdle

Hum Mutat 2019 09;40(9):1557-1578

Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.23818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6772163PMC
September 2019

The Apparent Genetic Anticipation in PMS2-Associated Lynch Syndrome Families Is Explained by Birth-cohort Effect.

Cancer Epidemiol Biomarkers Prev 2019 06 1;28(6):1010-1014. Epub 2019 Mar 1.

Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.

Background: PMS2-associated Lynch syndrome is characterized by a relatively low colorectal cancer penetrance compared with other Lynch syndromes. However, age at colorectal cancer diagnosis varies widely, and a strong genetic anticipation effect has been suggested for PMS2 families. In this study, we examined proposed genetic anticipation in a sample of 152 European PMS2 families.

Methods: The 152 families (637 family members) that were eligible for analysis were mainly clinically ascertained via clinical genetics centers. We used weighted Cox-type random effects model, adjusted by birth cohort and sex, to estimate the generational effect on the age of onset of colorectal cancer. Probands and young birth cohorts were excluded from the analyses. Weights represented mutation probabilities based on kinship coefficients, thus avoiding testing bias.

Results: Family data across three generations, including 123 colorectal cancers, were analyzed. When compared with the first generation, the crude HR for anticipation was 2.242 [95% confidence interval (CI), 1.162-4.328] for the second generation and 2.644 (95% CI, 1.082-6.464) for the third generation. However, after correction for birth cohort and sex, the effect vanished [HR = 1.302 (95% CI, 0.648-2.619) and HR = 1.074 (95% CI, 0.406-2.842) for second and third generations, respectively].

Conclusions: Our study did not confirm previous reports of genetic anticipation in PMS2-associated Lynch syndrome. Birth-cohort effect seems the most likely explanation for observed younger colorectal cancer diagnosis in subsequent generations, particularly because there is currently no commonly accepted biological mechanism that could explain genetic anticipation in Lynch syndrome.

Impact: This new model for studying genetic anticipation provides a standard for rigorous analysis of families with dominantly inherited cancer predisposition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-18-0576DOI Listing
June 2019

Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study.

Authors:
Frank Qian Shengfeng Wang Jonathan Mitchell Lesley McGuffog Daniel Barrowdale Goska Leslie Jan C Oosterwijk Wendy K Chung D Gareth Evans Christoph Engel Karin Kast Cora M Aalfs Muriel A Adank Julian Adlard Bjarni A Agnarsson Kristiina Aittomäki Elisa Alducci Irene L Andrulis Banu K Arun Margreet G E M Ausems Jacopo Azzollini Emmanuelle Barouk-Simonet Julian Barwell Muriel Belotti Javier Benitez Andreas Berger Ake Borg Angela R Bradbury Joan Brunet Saundra S Buys Trinidad Caldes Maria A Caligo Ian Campbell Sandrine M Caputo Jocelyne Chiquette Kathleen B M Claes J Margriet Collée Fergus J Couch Isabelle Coupier Mary B Daly Rosemarie Davidson Orland Diez Susan M Domchek Alan Donaldson Cecilia M Dorfling Ros Eeles Lidia Feliubadaló Lenka Foretova Jeffrey Fowler Eitan Friedman Debra Frost Patricia A Ganz Judy Garber Vanesa Garcia-Barberan Gord Glendon Andrew K Godwin Encarna B Gómez Garcia Jacek Gronwald Eric Hahnen Ute Hamann Alex Henderson Carolyn B Hendricks John L Hopper Peter J Hulick Evgeny N Imyanitov Claudine Isaacs Louise Izatt Ángel Izquierdo Anna Jakubowska Katarzyna Kaczmarek Eunyoung Kang Beth Y Karlan Carolien M Kets Sung-Won Kim Zisun Kim Ava Kwong Yael Laitman Christine Lasset Min Hyuk Lee Jong Won Lee Jihyoun Lee Jenny Lester Fabienne Lesueur Jennifer T Loud Jan Lubinski Noura Mebirouk Hanne E J Meijers-Heijboer Alfons Meindl Austin Miller Marco Montagna Thea M Mooij Patrick J Morrison Emmanuelle Mouret-Fourme Katherine L Nathanson Susan L Neuhausen Heli Nevanlinna Dieter Niederacher Finn C Nielsen Robert L Nussbaum Kenneth Offit Edith Olah Kai-Ren Ong Laura Ottini Sue K Park Paolo Peterlongo Georg Pfeiler Catherine M Phelan Bruce Poppe Nisha Pradhan Paolo Radice Susan J Ramus Johanna Rantala Mark Robson Gustavo C Rodriguez Rita K Schmutzler Christina G Hutten Selkirk Payal D Shah Jacques Simard Christian F Singer Johanna Sokolowska Dominique Stoppa-Lyonnet Christian Sutter Yen Yen Tan R Manuel Teixeira Soo H Teo Mary Beth Terry Mads Thomassen Marc Tischkowitz Amanda E Toland Katherine M Tucker Nadine Tung Christi J van Asperen Klaartje van Engelen Elizabeth J van Rensburg Shan Wang-Gohrke Barbara Wappenschmidt Jeffrey N Weitzel Drakoulis Yannoukakos Mark H Greene Matti A Rookus Douglas F Easton Georgia Chenevix-Trench Antonis C Antoniou David E Goldgar Olufunmilayo I Olopade Timothy R Rebbeck Dezheng Huo

J Natl Cancer Inst 2019 04;111(4):350-364

Department of Medicine, The University of Chicago, Chicago, IL.

Background: BRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 mutation carriers remains unclear.

Methods: We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants. We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided.

Results: Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m2 increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer.

Conclusion: Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djy132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449171PMC
April 2019

Cancer Risks for PMS2-Associated Lynch Syndrome.

J Clin Oncol 2018 10 30;36(29):2961-2968. Epub 2018 Aug 30.

Sanne W. ten Broeke, Heleen M. van der Klift, Carli M.J. Tops, Manon Suerink, Frederik J. Hes, Hans F.A. Vasen, Juul T. Wijnen, and Maartje Nielsen, Leiden University Medical Center, Leiden; Encarna Gomez Garcia, Maastricht University Medical Center, Maastricht; Nicoline Hoogerbrugge, Arjen R. Mensenkamp, and Liesbeth Spruijt, Radboud University Medical Center, Nijmegen; Tom G.W. Letteboer, University Medical Center, Utrecht; Theo A.M. van Os and Egbert J.W. Redeker, Academic Medical Center, Amsterdam; Maran J.W. Olderode-Berends and Yvonne J. Vos, University of Groningen; University Medical Center Groningen, Groningen; Anja Wagner, Erasmus Medical Center, Rotterdam, the Netherlands; Stefan Aretz, University of Bonn; University Hospital Bonn, Bonn; Christoph Engel, Leipzig University; Medizinisch Genetisches Zentrum Bayerstr, Leipzig; Magnus von Knebel Doeberitz, University of Heidelberg; German Cancer Research Center, Heidelberg; Pål Møller, University of Witten-Herdecke, Wuppertal; Nils Rahner, Heinrich-Heine-University, Düsseldorf; Hans K. Schackert, Technische Universität Dresden, Dresden; Verena Steinke-Lange, Medizinische Klinik und Poliklinik IV Campus Innenstadt, Klinikum der Universität München, Munich, Germany; Pål Møller, The Norwegian Radium Hospital; Oslo University Hospital, Oslo, Norway; Inge Bernstein, Hvidovre Hospital, Hvidovre, and Aalborg University Hospital, Aalborg, Denmark; Daniel D. Buchanan, Mark Clendenning, John L. Hopper, Mark A. Jenkins, Christophe Rosty, Ingrid Winship, and Aung Ko Win, The University of Melbourne; Daniel D. Buchanan, Ingrid Winship, and Aung Ko Win, Royal Melbourne Hospital, Parkville, Melbourne, Victoria; Rodney Scott, University of Newcastle, Newcastle, New South Wales, Australia; Albert de la Chapelle, Heather L. Hampel, Rachel Pearlman, and Leigha Senter, The Ohio State University Comprehensive Cancer Center, Columbus, OH; Gabriel Capella and Marta Pineda, Institut d'Investigació Biomédica de Bellvitge, Barcelona, Spain; Steven Gallinger, Mount Sinai Hospital, Toronto, Ontario, Canada; Jane C. Figueiredo and Robert Haile, Cedars-Sinai Medical Center, Los Angeles, CA; Loic Le Marchand, University of Hawaii Cancer Center, Honolulu, HI; Annika Lindblom, Karolinska Institutet; Karolinska University Hospital, Stockholm, Sweden; Noralane M. Lindor, Mayo Clinic Arizona, Scottsdale, AZ; Polly A. Newcomb, Fred Hutchinson Cancer Research Center; University of Washington, Seattle, WA; and Stephen Thibodeau, Mayo Clinic, Rochester, MN.

Purpose: Lynch syndrome due to pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, and MSH6 is predominantly associated with colorectal and endometrial cancer, although extracolonic cancers have been described within the Lynch tumor spectrum. However, the age-specific cumulative risk (penetrance) of these cancers is still poorly defined for PMS2-associated Lynch syndrome. Using a large data set from a worldwide collaboration, our aim was to determine accurate penetrance measures of cancers for carriers of heterozygous pathogenic PMS2 variants.

Methods: A modified segregation analysis was conducted that incorporated both genotyped and nongenotyped relatives, with conditioning for ascertainment to estimates corrected for bias. Hazard ratios (HRs) and corresponding 95% CIs were estimated for each cancer site for mutation carriers compared with the general population, followed by estimation of penetrance.

Results: In total, 284 families consisting of 4,878 first- and second-degree family members were included in the analysis. PMS2 mutation carriers were at increased risk for colorectal cancer (cumulative risk to age 80 years of 13% [95% CI, 7.9% to 22%] for males and 12% [95% CI, 6.7% to 21%] for females) and endometrial cancer (13% [95% CI, 7.0%-24%]), compared with the general population (6.6%, 4.7%, and 2.4%, respectively). There was no clear evidence of an increased risk of ovarian, gastric, hepatobiliary, bladder, renal, brain, breast, prostate, or small bowel cancer.

Conclusion: Heterozygous PMS2 mutation carriers were at small increased risk for colorectal and endometrial cancer but not for any other Lynch syndrome-associated cancer. This finding justifies that PMS2-specific screening protocols could be restricted to colonoscopies. The role of risk-reducing hysterectomy and bilateral salpingo-oophorectomy for PMS2 mutation carriers needs further discussion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2018.78.4777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349460PMC
October 2018

Ovarian stimulation for IVF and risk of primary breast cancer in BRCA1/2 mutation carriers.

Br J Cancer 2018 05 1;119:357-363. Epub 2018 May 1.

Department of Clinical Genetics, Maastricht University Medical Centre+, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands.

Background: The effect of in vitro fertilisation (IVF) on breast cancer risk for BRCA1/2 mutation carriers is rarely examined. As carriers may increasingly undergo IVF as part of preimplantation genetic diagnosis (PGD), we examined the impact of ovarian stimulation for IVF on breast cancer risk in BRCA1/2 mutation carriers.

Methods: The study population consisted of 1550 BRCA1 and 964 BRCA2 mutation carriers, derived from the nationwide HEBON study and the nationwide PGD registry. Questionnaires, clinical records and linkages with the Netherlands Cancer Registry were used to collect data on IVF exposure, risk-reducing surgeries and cancer diagnosis, respectively. Time-dependent Cox regression analyses were conducted, stratified for birth cohort and adjusted for subfertility.

Results: Of the 2514 BRCA1/2 mutation carriers, 3% (n = 76) were exposed to ovarian stimulation for IVF. In total, 938 BRCA1/2 mutation carriers (37.3%) were diagnosed with breast cancer. IVF exposure was not associated with risk of breast cancer (HR: 0.79, 95% CI: 0.46-1.36). Similar results were found for the subgroups of subfertile women (n = 232; HR: 0.73, 95% CI: 0.39-1.37) and BRCA1 mutation carriers (HR: 1.12, 95% CI: 0.60-2.09). In addition, age at and recency of first IVF treatment were not associated with breast cancer risk.

Conclusion: No evidence was found for an association between ovarian stimulation for IVF and breast cancer risk in BRCA1/2 mutation carriers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41416-018-0139-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068188PMC
May 2018

Role of germline aberrations affecting , and in gastric cancer susceptibility.

J Med Genet 2018 10 12;55(10):669-674. Epub 2018 Jan 12.

Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.

Background: In approximately 10% of all gastric cancer (GC) cases, a heritable cause is suspected. A subset of these cases have a causative germline mutation; however, in most cases the cause remains unknown. Our objective was to assess to what extent these remaining cases may be explained by germline mutations in the novel candidate GC predisposing genes , or .

Methods: We sequenced a large cohort of unexplained young and/or familial patients with GC (n=286) without a germline mutation for germline variants affecting , and using a targeted next-generation sequencing approach based on single-molecule molecular inversion probes.

Results: Predicted deleterious germline variants were not encountered in , but recurrently observed in (n=2) and (n=3) in our cohort of patients with GC. In contrast to deleterious variants in , deleterious variants in also occur frequently in the general population.

Conclusions: Based on our results should no longer be considered a GC predisposition gene, whereas deleterious variants are confirmed as an infrequent cause of GC susceptibility. Biallelic germline mutations are at most a very rare cause of GC susceptibility as no additional cases were identified.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2017-104962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161648PMC
October 2018

Genetic Testing and Clinical Management Practices for Variants in Non-BRCA1/2 Breast (and Breast/Ovarian) Cancer Susceptibility Genes: An International Survey by the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Clinical Working Group.

JCO Precis Oncol 2018 26;2. Epub 2018 Oct 26.

Maastricht University Medical Center, Maastricht.

Purpose: To describe a snapshot of international genetic testing practices, specifically regarding the use of multigene panels, for hereditary breast/ovarian cancers. We conducted a survey through the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium, covering questions about 16 non-/ genes.

Methods: Data were collected via in-person and paper/electronic surveys. ENIGMA members from around the world were invited to participate. Additional information was collected via country networks in the United Kingdom and in Italy.

Results: Responses from 61 cancer genetics practices across 20 countries showed that 16 genes were tested by > 50% of the centers, but only six (, , , , , and ) were tested regularly. US centers tested the genes most often, whereas United Kingdom and Italian centers with no direct ENIGMA affiliation at the time of the survey were the least likely to regularly test them. Most centers tested the 16 genes through multigene panels; some centers tested , , and other cancer syndrome-associated genes individually. Most centers reported (likely) pathogenic variants to patients and would test family members for such variants. Gene-specific guidelines for breast and ovarian cancer risk management were limited and differed among countries, especially with regard to starting age and type of imaging and risk-reducing surgery recommendations.

Conclusion: Currently, a small number of genes beyond / are routinely analyzed worldwide, and management guidelines are limited and largely based on expert opinion. To attain clinical implementation of multigene panel testing through evidence-based management practices, it is paramount that clinicians (and patients) participate in international initiatives that share panel testing data, interpret sequence variants, and collect prospective data to underpin risk estimates and evaluate the outcome of risk intervention strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/PO.18.00091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742430PMC
October 2018

SNP association study in PMS2-associated Lynch syndrome.

Fam Cancer 2018 10;17(4):507-515

Department of Clinical Genetics, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.

Lynch syndrome (LS) patients are at high risk of developing colorectal cancer (CRC). Phenotypic variability might in part be explained by common susceptibility loci identified in Genome Wide Association Studies (GWAS). Previous studies focused mostly on MLH1, MSH2 and MSH6 carriers, with conflicting results. We aimed to determine the role of GWAS SNPs in PMS2 mutation carriers. A cohort study was performed in 507 PMS2 carriers (124 CRC cases), genotyped for 24 GWAS SNPs, including SNPs at 11q23.1 and 8q23.3. Hazard ratios (HRs) were calculated using a weighted Cox regression analysis to correct for ascertainment bias. Discrimination was assessed with a concordance statistic in a bootstrap cross-validation procedure. Individual SNPs only had non-significant associations with CRC occurrence with HRs lower than 2, although male carriers of allele A at rs1321311 (6p21.31) may have increased risk of CRC (HR = 2.1, 95% CI 1.2-3.0). A polygenic risk score (PRS) based on 24 HRs had an HR of 2.6 (95% CI 1.5-4.6) for the highest compared to the lowest quartile, but had no discriminative ability (c statistic 0.52). Previously suggested SNPs do not modify CRC risk in PMS2 carriers. Future large studies are needed for improved risk stratification among Lynch syndrome patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10689-017-0061-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182583PMC
October 2018

Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing.

Eur J Hum Genet 2017 11 6;25(11):1246-1252. Epub 2017 Sep 6.

Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.

Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ejhg.2017.138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5643972PMC
November 2017

The c. 5096G>A p.Arg1699Gln (R1699Q) intermediate risk variant: breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium.

J Med Genet 2018 01 10;55(1):15-20. Epub 2017 May 10.

Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.

Background: We previously showed that the variant c.5096G>A p.Arg1699Gln (R1699Q) was associated with an intermediate risk of breast cancer (BC) and ovarian cancer (OC). This study aimed to assess these cancer risks for R1699Q carriers in a larger cohort, including follow-up of previously studied families, to further define cancer risks and to propose adjusted clinical management of female *R1699Q carriers.

Methods: Data were collected from 129 *R1699Q families ascertained internationally by ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium members. A modified segregation analysis was used to calculate BC and OC risks. Relative risks were calculated under both monogenic model and major gene plus polygenic model assumptions.

Results: In this cohort the cumulative risk of BC and OC by age 70 years was 20% and 6%, respectively. The relative risk for developing cancer was higher when using a model that included the effects of both the R1699Q variant and a residual polygenic component compared with monogenic model (for BC 3.67 vs 2.83, and for OC 6.41 vs 5.83).

Conclusion: Our results confirm that *R1699Q confers an intermediate risk for BC and OC. Breast surveillance for female carriers based on mammogram annually from age 40 is advised. Bilateral salpingo-oophorectomy should be considered based on family history.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2017-104560DOI Listing
January 2018

Novel BRCA1 and BRCA2 Tumor Test as Basis for Treatment Decisions and Referral for Genetic Counselling of Patients with Ovarian Carcinomas.

Hum Mutat 2017 02 9;38(2):226-235. Epub 2016 Nov 9.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

With the recent introduction of Poly(ADP-ribose) polymerase inhibitors, a promising novel therapy has become available for ovarian carcinoma (OC) patients with inactivating BRCA1 or BRCA2 mutations in their tumor. To select patients who may benefit from these treatments, assessment of the mutation status of BRCA1 and BRCA2 in the tumor is required. For reliable evaluation of germline and somatic mutations in these genes in DNA derived from formalin-fixed, paraffin-embedded (FFPE) tissue, we have developed a single-molecule molecular inversion probe (smMIP)-based targeted next-generation sequencing (NGS) approach. Our smMIP-based NGS approach provides analysis of both strands of the open reading frame of BRCA1 and BRCA2, enabling the discrimination between real variants and formalin-induced artefacts. The single molecule tag enables compilation of unique reads leading to a high analytical sensitivity and enabling assessment of the reliability of mutation-negative results. Multiplex ligation-dependent probe amplification (MLPA) and Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) were used to detect exon deletions of BRCA1 and methylation of the BRCA1 promoter, respectively. Here, we show that this combined approach allows the rapid and reliable detection of both germline and somatic aberrations affecting BRCA1 and BRCA2 in DNA derived from FFPE OCs, enabling improved hereditary cancer risk assessment and clinical treatment of ovarian cancer patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.23137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5248611PMC
February 2017

Comprehensive Mutation Analysis of PMS2 in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency Syndrome.

Hum Mutat 2016 11 21;37(11):1162-1179. Epub 2016 Aug 21.

Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.

Monoallelic PMS2 germline mutations cause 5%-15% of Lynch syndrome, a midlife cancer predisposition, whereas biallelic PMS2 mutations cause approximately 60% of constitutional mismatch repair deficiency (CMMRD), a rare childhood cancer syndrome. Recently improved DNA- and RNA-based strategies are applied to overcome problematic PMS2 mutation analysis due to the presence of pseudogenes and frequent gene conversion events. Here, we determined PMS2 mutation detection yield and mutation spectrum in a nationwide cohort of 396 probands. Furthermore, we studied concordance between tumor IHC/MSI (immunohistochemistry/microsatellite instability) profile and mutation carrier state. Overall, we found 52 different pathogenic PMS2 variants explaining 121 Lynch syndrome and nine CMMRD patients. In vitro mismatch repair assays suggested pathogenicity for three missense variants. Ninety-one PMS2 mutation carriers (70%) showed isolated loss of PMS2 in their tumors, for 31 (24%) no or inconclusive IHC was available, and eight carriers (6%) showed discordant IHC (presence of PMS2 or loss of both MLH1 and PMS2). Ten cases with isolated PMS2 loss (10%; 10/97) harbored MLH1 mutations. We confirmed that recently improved mutation analysis provides a high yield of PMS2 mutations in patients with isolated loss of PMS2 expression. Application of universal tumor prescreening methods will however miss some PMS2 germline mutation carriers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.23052DOI Listing
November 2016

Do BRCA1/2 mutation carriers have an earlier onset of natural menopause?

Menopause 2016 08;23(8):903-10

1Department of Reproductive Medicine 2Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands 3Department of Epidemiology 4Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands 5Department of Genetics, Groningen University, University Medical Center, Groningen, The Netherlands 6Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands 7GROW, School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands 8Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands 9Department of Clinical Genetics, VU University Medical Centre, Amsterdam, The Netherlands 10Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands 11Department of Obstetrics and Gynaecology, Division of Gynaecology Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands 12Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.

Objective: It has been hypothesized that BRCA1/2 mutation carriers have an earlier age at natural menopause (ANM), although to date findings are inconclusive. This study assessed the influence of BRCA mutation status on ANM, and aimed to explore the reasons of inconsistency in the literature.

Methods: Cross-sectional assessment from an ongoing nationwide cohort study among members of BRCA1/2 mutated families. Information was obtained by a standardized questionnaire. Kaplan-Meier curves were constructed, and Cox regression was used to assess the association between BRCA1/2 mutation status and ANM. Adjustments were made for birth cohort, family, smoking, use of hormonal contraceptives, and parity.

Results: A total of 1,208 BRCA1/2 mutation carriers and 2,211 proven noncarriers were included. Overall, no association was found between BRCA1/2 mutation status and ANM (adjusted hazard ratio [HR] = 1.06 [95% CI, 0.87-1.30]). We examined if the null finding was due to informative censoring by uptake of risk-reducing salpingo-oophorectomy. Indeed, within the oldest birth cohort, in which the percentage of surgical menopause events was lowest and comparable between carriers and noncarriers, the HR for earlier natural menopause in carriers was 1.45 (95% CI, 1.09-1.94). The second oldest birth cohort, however, demonstrated a decreased HR (0.67 [95% CI, 0.46-0.98]), and thus no trend over birth cohorts was found.

Conclusions: Various types of selection bias hamper the comparison of ANM between BRCA1/2 mutation carriers and noncarriers, genetically tested in the clinic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/GME.0000000000000633DOI Listing
August 2016

Whole Gene Capture Analysis of 15 CRC Susceptibility Genes in Suspected Lynch Syndrome Patients.

PLoS One 2016 14;11(6):e0157381. Epub 2016 Jun 14.

Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.

Background And Aims: Lynch Syndrome (LS) is caused by pathogenic germline variants in one of the mismatch repair (MMR) genes. However, up to 60% of MMR-deficient colorectal cancer cases are categorized as suspected Lynch Syndrome (sLS) because no pathogenic MMR germline variant can be identified, which leads to difficulties in clinical management. We therefore analyzed the genomic regions of 15 CRC susceptibility genes in leukocyte DNA of 34 unrelated sLS patients and 11 patients with MLH1 hypermethylated tumors with a clear family history.

Methods: Using targeted next-generation sequencing, we analyzed the entire non-repetitive genomic sequence, including intronic and regulatory sequences, of 15 CRC susceptibility genes. In addition, tumor DNA from 28 sLS patients was analyzed for somatic MMR variants.

Results: Of 1979 germline variants found in the leukocyte DNA of 34 sLS patients, one was a pathogenic variant (MLH1 c.1667+1delG). Leukocyte DNA of 11 patients with MLH1 hypermethylated tumors was negative for pathogenic germline variants in the tested CRC susceptibility genes and for germline MLH1 hypermethylation. Somatic DNA analysis of 28 sLS tumors identified eight (29%) cases with two pathogenic somatic variants, one with a VUS predicted to pathogenic and LOH, and nine cases (32%) with one pathogenic somatic variant (n = 8) or one VUS predicted to be pathogenic (n = 1).

Conclusions: This is the first study in sLS patients to include the entire genomic sequence of CRC susceptibility genes. An underlying somatic or germline MMR gene defect was identified in ten of 34 sLS patients (29%). In the remaining sLS patients, the underlying genetic defect explaining the MMRdeficiency in their tumors might be found outside the genomic regions harboring the MMR and other known CRC susceptibility genes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157381PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4907507PMC
July 2017

Bias Explains Most of the Parent-of-Origin Effect on Breast Cancer Risk in BRCA1/2 Mutation Carriers.

Cancer Epidemiol Biomarkers Prev 2016 08 8;25(8):1251-8. Epub 2016 Jun 8.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Background: Paternal transmission of a BRCA mutation has been reported to increase the risk of breast cancer in offspring more than when the mutation is maternally inherited. As this effect might be caused by referral bias, the aim of this study was to assess the parent-of-origin effect of the BRCA1/2 mutation on the breast cancer lifetime risk, when adjusted for referral bias.

Methods: A Dutch national cohort including 1,314 proven BRCA1/2 mutation carriers and covering 54,752 person years. Data were collected by family cancer clinics, via questionnaires and from the national Dutch Cancer Registry. The parent-of-origin effect was assessed using Cox regression analyses, both unadjusted and adjusted for referral bias. Referral bias was operationalized by number of relatives with cancer and by personal cancer history.

Results: The mutation was of paternal origin in 330 (42%, P < 0.001) BRCA1 and 222 (42%, P < 0.001) BRCA2 carriers. Paternal origin increased the risk of prevalent breast cancer for BRCA1 [HR, 1.54; 95% confidence interval (CI), 1.19-2.00] and BRCA2 carriers (HR, 1.40; 95% CI, 0.95-2.06). Adjusted for referral bias by several family history factors, these HRs ranged from 1.41 to 1.83 in BRCA1 carriers and 1.27 to 1.62 in BRCA2 carriers. Adjusted for referral bias by personal history, these HRs were 0.66 (95% CI, 0.25-1.71) and 1.14 (95% CI, 0.42-3.15), respectively.

Conclusion: A parent-of-origin effect is present after correction for referral bias by family history, but correction for the personal cancer history made the effect disappear.

Impact: There is no conclusive evidence regarding incorporating a BRCA1/2 parent-of-origin effect in breast cancer risk prediction models. Cancer Epidemiol Biomarkers Prev; 25(8); 1251-8. ©2016 AACR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-16-0182DOI Listing
August 2016

Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers.

Eur J Hum Genet 2016 07 9;24(7):1089-92. Epub 2015 Dec 9.

Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands.

Many suspected Lynch Syndrome (sLS) patients who lack mismatch repair (MMR) germline gene variants and MLH1 or MSH2 hypermethylation are currently explained by somatic MMR gene variants or, occasionally, by germline POLE variants. To further investigate unexplained sLS patients, we analyzed leukocyte and tumor DNA of 62 sLS patients using gene panel sequencing including the POLE, POLD1 and MMR genes. Forty tumors showed either one, two or more somatic MMR variants predicted to affect function. Nine sLS tumors showed a likely ultramutated phenotype and were found to carry germline (n=2) or somatic variants (n=7) in the POLE/POLD1 exonuclease domain (EDM). Six of these POLE/POLD1-EDM mutated tumors also carried somatic MMR variants. Our findings suggest that faulty proofreading may result in loss of MMR and thereby in microsatellite instability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ejhg.2015.252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070903PMC
July 2016

Germ-line variants identified by next generation sequencing in a panel of estrogen and cancer associated genes correlate with poor clinical outcome in Lynch syndrome patients.

Oncotarget 2015 Dec;6(38):41108-22

Department of Gynecology and Obstetrics, GROW - School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.

Background: The risk to develop colorectal and endometrial cancers among subjects testing positive for a pathogenic Lynch syndrome mutation varies, making the risk prediction difficult. Genetic risk modifiers alter the risk conferred by inherited Lynch syndrome mutations, and their identification can improve genetic counseling. We aimed at identifying rare genetic modifiers of the risk of Lynch syndrome endometrial cancer.

Methods: A family based approach was used to assess the presence of genetic risk modifiers among 35 Lynch syndrome mutation carriers having either a poor clinical phenotype (early age of endometrial cancer diagnosis or multiple cancers) or a neutral clinical phenotype. Putative genetic risk modifiers were identified by Next Generation Sequencing among a panel of 154 genes involved in endometrial physiology and carcinogenesis.

Results: A simple pipeline, based on an allele frequency lower than 0.001 and on predicted non-conservative amino-acid substitutions returned 54 variants that were considered putative risk modifiers. The presence of two or more risk modifying variants in women carrying a pathogenic Lynch syndrome mutation was associated with a poor clinical phenotype.

Conclusion: A gene-panel is proposed that comprehends genes that can carry variants with putative modifying effects on the risk of Lynch syndrome endometrial cancer. Validation in further studies is warranted before considering the possible use of this tool in genetic counseling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.5694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747393PMC
December 2015

The effect of genotypes and parent of origin on cancer risk and age of cancer development in PMS2 mutation carriers.

Genet Med 2016 Apr 25;18(4):405-9. Epub 2015 Jun 25.

Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Purpose: Lynch syndrome (LS), a heritable disorder with an increased risk of primarily colorectal cancer (CRC) and endometrial cancer (EC), can be caused by mutations in the PMS2 gene. We wished to establish whether genotype and/or parent-of-origin effects (POE) explain (part of) the reported variability in severity of the phenotype.

Methods: European PMS2 mutation carriers (n = 381) were grouped and compared based on RNA expression and whether the mutation was inherited paternally or maternally.

Results: Mutation carriers with loss of RNA expression (group 1) had a significantly lower age at CRC diagnosis (51.1 years vs. 60.0 years, P = 0.035) and a lower age at EC diagnosis (55.8 years vs. 61.0 years, P = 0.2, nonsignificant) compared with group 2 (retention of RNA expression). Furthermore, group 1 showed slightly higher, but nonsignificant, hazard ratios (HRs) for both CRC (HR: 1.31, P = 0.38) and EC (HR: 1.22, P = 0.72). No evidence for a significant parent-of-origin effect was found for either CRC or EC.

Conclusions: PMS2 mutation carriers with retention of RNA expression developed CRC 9 years later than those with loss of RNA expression. If confirmed, this finding would justify a delay in surveillance for these cases. Cancer risk was not influenced by a parent-of-origin effect.Genet Med 18 4, 405-409.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/gim.2015.83DOI Listing
April 2016

Accuracy of Hereditary Diffuse Gastric Cancer Testing Criteria and Outcomes in Patients With a Germline Mutation in CDH1.

Gastroenterology 2015 Oct 11;149(4):897-906.e19. Epub 2015 Jun 11.

Department of Pathology, Radboud university medical center, Nijmegen, The Netherlands; Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands. Electronic address:

Background & Aims: Germline mutations in the cadherin 1, type 1, E-cadherin gene (CDH1) cause a predisposition to gastric cancer. We evaluated the ability of the internationally accepted hereditary diffuse gastric cancer (HDGC) criteria to identify individuals with pathogenic mutations in CDH1, and assessed their outcomes. The criteria were as follows: families with 2 or more cases of gastric cancer, with at least 1 patient diagnosed with diffuse gastric cancer (DGC) before age 50; families with 3 or more cases of DGC; families with 1 DGC before the age of 40; and families with a history of DGC and lobular breast cancer, with 1 diagnosis before the age of 50.

Methods: We collected results of a CDH1 mutation analysis of 578 individuals from 499 families tested in The Netherlands between 1999 and 2014 (118 families met the HDGC criteria for testing and 236 did not; there were 145 families with incomplete data and/or availability of only first-degree relatives). Data were linked with family histories and findings from clinical and pathology analyses. The Kaplan-Meier method and Cox regression analysis were used to evaluate the overall survival of patients with and without CDH1 mutations.

Results: In a cohort study in The Netherlands, the HDGC criteria identified individuals with a germline CDH1 mutation with a positive predictive value of 14% and 89% sensitivity. There were 18 pathogenic CDH1 mutations in 499 families (4%); 16 of these mutations were detected in the 118 families who met the HDGC criteria for testing. One pathogenic CDH1 mutation was detected in the 236 families who did not meet HDGC criteria and 1 in the 145 families with incomplete data and/or availability of only first-degree relatives. No CDH1 mutations were found in the 67 families whose members developed intestinal-type gastric cancer, or in the 22 families whose families developed lobular breast cancer. Among patients who fulfilled the HDGC criteria and had pathogenic CDH1 mutations, 36% survived for 1 year and 4% survived for 5 years; among patients who fulfilled the HDGC criteria but did not carry pathogenic CDH1 mutations, 48% survived for 1 year and 13% survived for 5 years (P = .014 for comparative survival analysis between patients with and without a CDH1 mutation).

Conclusions: All individuals with a CDH1 mutation had a personal or family history of diffuse gastric cancer. Patients with gastric cancer and germline CDH1 mutations had shorter survival times than patients who met the HDGC criteria but did not have CDH1 mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.gastro.2015.06.003DOI Listing
October 2015

Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.

Authors:
Timothy R Rebbeck Nandita Mitra Fei Wan Olga M Sinilnikova Sue Healey Lesley McGuffog Sylvie Mazoyer Georgia Chenevix-Trench Douglas F Easton Antonis C Antoniou Katherine L Nathanson Yael Laitman Anya Kushnir Shani Paluch-Shimon Raanan Berger Jamal Zidan Eitan Friedman Hans Ehrencrona Marie Stenmark-Askmalm Zakaria Einbeigi Niklas Loman Katja Harbst Johanna Rantala Beatrice Melin Dezheng Huo Olufunmilayo I Olopade Joyce Seldon Patricia A Ganz Robert L Nussbaum Salina B Chan Kunle Odunsi Simon A Gayther Susan M Domchek Banu K Arun Karen H Lu Gillian Mitchell Beth Y Karlan Christine Walsh Jenny Lester Andrew K Godwin Harsh Pathak Eric Ross Mary B Daly Alice S Whittemore Esther M John Alexander Miron Mary Beth Terry Wendy K Chung David E Goldgar Saundra S Buys Ramunas Janavicius Laima Tihomirova Nadine Tung Cecilia M Dorfling Elizabeth J van Rensburg Linda Steele Susan L Neuhausen Yuan Chun Ding Bent Ejlertsen Anne-Marie Gerdes Thomas v O Hansen Teresa Ramón y Cajal Ana Osorio Javier Benitez Javier Godino Maria-Isabel Tejada Mercedes Duran Jeffrey N Weitzel Kristie A Bobolis Sharon R Sand Annette Fontaine Antonella Savarese Barbara Pasini Bernard Peissel Bernardo Bonanni Daniela Zaffaroni Francesca Vignolo-Lutati Giulietta Scuvera Giuseppe Giannini Loris Bernard Maurizio Genuardi Paolo Radice Riccardo Dolcetti Siranoush Manoukian Valeria Pensotti Viviana Gismondi Drakoulis Yannoukakos Florentia Fostira Judy Garber Diana Torres Muhammad Usman Rashid Ute Hamann Susan Peock Debra Frost Radka Platte D Gareth Evans Rosalind Eeles Rosemarie Davidson Diana Eccles Trevor Cole Jackie Cook Carole Brewer Shirley Hodgson Patrick J Morrison Lisa Walker Mary E Porteous M John Kennedy Louise Izatt Julian Adlard Alan Donaldson Steve Ellis Priyanka Sharma Rita Katharina Schmutzler Barbara Wappenschmidt Alexandra Becker Kerstin Rhiem Eric Hahnen Christoph Engel Alfons Meindl Stefanie Engert Nina Ditsch Norbert Arnold Hans Jörg Plendl Christoph Mundhenke Dieter Niederacher Markus Fleisch Christian Sutter C R Bartram Nicola Dikow Shan Wang-Gohrke Dorothea Gadzicki Doris Steinemann Karin Kast Marit Beer Raymonda Varon-Mateeva Andrea Gehrig Bernhard H Weber Dominique Stoppa-Lyonnet Olga M Sinilnikova Sylvie Mazoyer Claude Houdayer Muriel Belotti Marion Gauthier-Villars Francesca Damiola Nadia Boutry-Kryza Christine Lasset Hagay Sobol Jean-Philippe Peyrat Danièle Muller Jean-Pierre Fricker Marie-Agnès Collonge-Rame Isabelle Mortemousque Catherine Nogues Etienne Rouleau Claudine Isaacs Anne De Paepe Bruce Poppe Kathleen Claes Kim De Leeneer Marion Piedmonte Gustavo Rodriguez Katie Wakely John Boggess Stephanie V Blank Jack Basil Masoud Azodi Kelly-Anne Phillips Trinidad Caldes Miguel de la Hoya Atocha Romero Heli Nevanlinna Kristiina Aittomäki Annemarie H van der Hout Frans B L Hogervorst Senno Verhoef J Margriet Collée Caroline Seynaeve Jan C Oosterwijk Johannes J P Gille Juul T Wijnen Encarna B Gómez Garcia Carolien M Kets Margreet G E M Ausems Cora M Aalfs Peter Devilee Arjen R Mensenkamp Ava Kwong Edith Olah Janos Papp Orland Diez Conxi Lazaro Esther Darder Ignacio Blanco Mónica Salinas Anna Jakubowska Jan Lubinski Jacek Gronwald Katarzyna Jaworska-Bieniek Katarzyna Durda Grzegorz Sukiennicki Tomasz Huzarski Tomasz Byrski Cezary Cybulski Aleksandra Toloczko-Grabarek Elżbieta Złowocka-Perłowska Janusz Menkiszak Adalgeir Arason Rosa B Barkardottir Jacques Simard Rachel Laframboise Marco Montagna Simona Agata Elisa Alducci Ana Peixoto Manuel R Teixeira Amanda B Spurdle Min Hyuk Lee Sue K Park Sung-Won Kim Tara M Friebel Fergus J Couch Noralane M Lindor Vernon S Pankratz Lucia Guidugli Xianshu Wang Marc Tischkowitz Lenka Foretova Joseph Vijai Kenneth Offit Mark Robson Rohini Rau-Murthy Noah Kauff Anneliese Fink-Retter Christian F Singer Christine Rappaport Daphne Gschwantler-Kaulich Georg Pfeiler Muy-Kheng Tea Andreas Berger Mark H Greene Phuong L Mai Evgeny N Imyanitov Amanda Ewart Toland Leigha Senter Anders Bojesen Inge Sokilde Pedersen Anne-Bine Skytte Lone Sunde Mads Thomassen Sanne Traasdahl Moeller Torben A Kruse Uffe Birk Jensen Maria Adelaide Caligo Paolo Aretini Soo-Hwang Teo Christina G Selkirk Peter J Hulick Irene Andrulis

JAMA 2015 Apr;313(13):1347-61

Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada.

Importance: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.

Objective: To identify mutation-specific cancer risks for carriers of BRCA1/2.

Design, Setting, And Participants: Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk.

Exposures: Mutations of BRCA1 or BRCA2.

Main Outcomes And Measures: Breast and ovarian cancer risks.

Results: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers.

Conclusions And Relevance: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jama.2014.5985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537700PMC
April 2015

Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk.

J Clin Oncol 2015 Feb 15;33(4):319-25. Epub 2014 Dec 15.

Sanne W. ten Broeke, Carli M. Tops, Heleen M. van der Klift, Manon Suerink, Frederik J. Hes, Hans F. Vasen, Maartje Nielsen, and Juul T. Wijnen, Leiden University Medical Center; Hans F. Vasen, The Netherlands Foundation for the Detection of Hereditary Tumors, Leiden; Richard M. Brohet, Research Center Linnaeus Institute, Spaarne Hospital, Hoofddorp; Mary E. Velthuizen and Tom G.W. Letteboer, University Medical Center Utrecht, Utrecht; Encarna Gomez Garcia, Maastricht University Medical Center, Maastricht; Nicoline Hoogerbrugge, Arjen R. Mensenkamp, and Liesbeth Spruijt, Radboud University Medical Center, Nijmegen; Fred H. Menko, Vrije Universiteit, University Medical Center; Theo A. van Os and Bert J.W. Redeker, Academic Medical Center, Amsterdam; Rolf H. Sijmons and Yvonne J. Vos, University of Groningen, University Medical Center Groningen, Groningen; Anja Wagner, Erasmus University Medical Center, Rotterdam, the Netherlands; Inge Bernstein, Aalborg University Hospital, Aalborg; Inge Bernstein, Danish Hereditary Nonpolyposis Colorectal Cancer Registry, Hvidovre University Hospital Copenhagen, Denmark; Gabriel Capellá Munar, Hereditary Cancer Program, Catalan Institute of Oncology-Institut D'Investigació Biomèdica de Bellvitge, l'Hospitalet de Llobregat, Spain; Annika Lindblom, Karolinska Institutet, Karolinska University Hospital, Solna; Pal Moller, Research Group Inherited Cancer, Oslo University Hospital, Oslo, Norway; and Nils Rahner, Institute of Human Genetics, University of Dusseldorf, Dusseldorf, Germany.

Purpose: The clinical consequences of PMS2 germline mutations are poorly understood compared with other Lynch-associated mismatch repair gene (MMR) mutations. The aim of this European cohort study was to define the cancer risk faced by PMS2 mutation carriers.

Methods: Data were collected from 98 PMS2 families ascertained from family cancer clinics that included a total of 2,548 family members and 377 proven mutation carriers. To adjust for potential ascertainment bias, a modified segregation analysis model was used to calculate colorectal cancer (CRC) and endometrial cancer (EC) risks. Standardized incidence ratios (SIRs) were calculated to estimate risks for other Lynch syndrome-associated cancers.

Results: The cumulative risk (CR) of CRC for male mutation carriers by age 70 years was 19%. The CR among female carriers was 11% for CRC and 12% for EC. The mean age of CRC development was 52 years, and there was a significant difference in mean age of CRC between the probands (mean, 47 years; range, 26 to 68 years) and other family members with a PMS2 mutation (mean, 58 years; range, 31 to 86 years; P < .001). Significant SIRs were observed for cancers of the small bowel, ovaries, breast, and renal pelvis.

Conclusion: CRC and EC risks were found to be markedly lower than those previously reported for the other MMR. However, these risks embody the isolated risk of carrying a PMS2 mutation, and it should be noted that we observed a substantial variation in cancer phenotype within and between families, suggesting the influence of genetic modifiers and lifestyle factors on cancer risks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2014.57.8088DOI Listing
February 2015

Gastric cancer in three relatives of a patient with a biallelic IL12RB1 mutation.

Fam Cancer 2015 Mar;14(1):89-94

Department of Human Genetics, Radboud university medical center, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands,

IL-12Rβ1 deficiency, also known as immunodeficiency 30 (IMD30, OMIM 614891), is a rare immunodeficiency syndrome caused by biallelic mutations in IL12RB1. Three second-degree relatives of a patient with this syndrome, all women, developed intestinal-type gastric cancer (GC). In the Netherlands the incidence of non-cardia GC in women is only 7 per 100,000 person years. Both relatives that were available for testing proved to be heterozygous for the familial IL12RB1 mutation, suggesting there might be a causal relation. Testing 29 index patients from families with early onset and/or a familial history of GC for germline mutations in both IL12RB1 and IL12RB2, that encodes the binding partner of IL-12Rβ1, did not reveal other germline mutations in these genes. Therefore heterozygous inactivating mutations in IL12RB1 and IL12RB2 are unlikely to be frequently involved in GC predisposition. Additional research in families with IL12RB1 mutations is required to determine whether carriers of IL12RB1 mutations have an increased (gastric) cancer risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10689-014-9764-xDOI Listing
March 2015

Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.

Authors:
Paolo Peterlongo Jenny Chang-Claude Kirsten B Moysich Anja Rudolph Rita K Schmutzler Jacques Simard Penny Soucy Rosalind A Eeles Douglas F Easton Ute Hamann Stefan Wilkening Bowang Chen Matti A Rookus Marjanka K Schmidt Frederieke H van der Baan Amanda B Spurdle Logan C Walker Felicity Lose Ana-Teresa Maia Marco Montagna Laura Matricardi Jan Lubinski Anna Jakubowska Encarna B Gómez Garcia Olufunmilayo I Olopade Robert L Nussbaum Katherine L Nathanson Susan M Domchek Timothy R Rebbeck Banu K Arun Beth Y Karlan Sandra Orsulic Jenny Lester Wendy K Chung Alex Miron Melissa C Southey David E Goldgar Saundra S Buys Ramunas Janavicius Cecilia M Dorfling Elizabeth J van Rensburg Yuan Chun Ding Susan L Neuhausen Thomas V O Hansen Anne-Marie Gerdes Bent Ejlertsen Lars Jønson Ana Osorio Cristina Martínez-Bouzas Javier Benitez Edye E Conway Kathleen R Blazer Jeffrey N Weitzel Siranoush Manoukian Bernard Peissel Daniela Zaffaroni Giulietta Scuvera Monica Barile Filomena Ficarazzi Frederique Mariette Stefano Fortuzzi Alessandra Viel Giuseppe Giannini Laura Papi Aline Martayan Maria Grazia Tibiletti Paolo Radice Athanassios Vratimos Florentia Fostira Judy E Garber Alan Donaldson Carole Brewer Claire Foo D Gareth R Evans Debra Frost Diana Eccles Angela Brady Jackie Cook Marc Tischkowitz Julian Adlard Julian Barwell Lisa Walker Louise Izatt Lucy E Side M John Kennedy Mark T Rogers Mary E Porteous Patrick J Morrison Radka Platte Rosemarie Davidson Shirley V Hodgson Steve Ellis Trevor Cole Andrew K Godwin Kathleen Claes Tom Van Maerken Alfons Meindl Andrea Gehrig Christian Sutter Christoph Engel Dieter Niederacher Doris Steinemann Hansjoerg Plendl Karin Kast Kerstin Rhiem Nina Ditsch Norbert Arnold Raymonda Varon-Mateeva Barbara Wappenschmidt Shan Wang-Gohrke Brigitte Bressac-de Paillerets Bruno Buecher Capucine Delnatte Claude Houdayer Dominique Stoppa-Lyonnet Francesca Damiola Isabelle Coupier Laure Barjhoux Laurence Venat-Bouvet Lisa Golmard Nadia Boutry-Kryza Olga M Sinilnikova Olivier Caron Pascal Pujol Sylvie Mazoyer Muriel Belotti Marion Piedmonte Michael L Friedlander Gustavo C Rodriguez Larry J Copeland Miguel de la Hoya Pedro Perez Segura Heli Nevanlinna Kristiina Aittomäki Theo A M van Os Hanne E J Meijers-Heijboer Annemarie H van der Hout Maaike P G Vreeswijk Nicoline Hoogerbrugge Margreet G E M Ausems Helena C van Doorn J Margriet Collée Edith Olah Orland Diez Ignacio Blanco Conxi Lazaro Joan Brunet Lidia Feliubadalo Cezary Cybulski Jacek Gronwald Katarzyna Durda Katarzyna Jaworska-Bieniek Grzegorz Sukiennicki Adalgeir Arason Jocelyne Chiquette Manuel R Teixeira Curtis Olswold Fergus J Couch Noralane M Lindor Xianshu Wang Csilla I Szabo Kenneth Offit Marina Corines Lauren Jacobs Mark E Robson Liying Zhang Vijai Joseph Andreas Berger Christian F Singer Christine Rappaport Daphne Geschwantler Kaulich Georg Pfeiler Muy-Kheng M Tea Catherine M Phelan Mark H Greene Phuong L Mai Gad Rennert Anna Marie Mulligan Gord Glendon Sandrine Tchatchou Irene L Andrulis Amanda Ewart Toland Anders Bojesen Inge Sokilde Pedersen Mads Thomassen Uffe Birk Jensen Yael Laitman Johanna Rantala Anna von Wachenfeldt Hans Ehrencrona Marie Stenmark Askmalm Åke Borg Karoline B Kuchenbaecker Lesley McGuffog Daniel Barrowdale Sue Healey Andrew Lee Paul D P Pharoah Georgia Chenevix-Trench Antonis C Antoniou Eitan Friedman

Cancer Epidemiol Biomarkers Prev 2015 Jan 21;24(1):308-16. Epub 2014 Oct 21.

Sheba Medical Center, Tel Aviv, Israel.

Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes.

Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach.

Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments.

Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.

Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-14-0532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294951PMC
January 2015

Variation in mutation spectrum partly explains regional differences in the breast cancer risk of female BRCA mutation carriers in the Netherlands.

Cancer Epidemiol Biomarkers Prev 2014 Nov 7;23(11):2482-91. Epub 2014 Aug 7.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Background: We aimed to quantify previously observed relatively high cancer risks in BRCA2 mutation carriers (BRCA2 carriers) older than 60 in the Northern Netherlands, and to analyze whether these could be explained by mutation spectrum or population background risk.

Methods: This consecutive cohort study included all known pathogenic BRCA1/2 carriers in the Northern Netherlands (N = 1,050). Carrier and general reference populations were: BRCA1/2 carriers in the rest of the Netherlands (N = 2,013) and the general population in both regions. Regional differences were assessed with HRs and ORs. HRs were adjusted for birth year and mutation spectrum.

Results: All BRCA1 carriers and BRCA2 carriers younger than 60 had a significantly lower breast cancer risk in the Northern Netherlands; HRs were 0.66 and 0.64, respectively. Above age 60, the breast cancer risk in BRCA2 carriers in the Northern Netherlands was higher than in the rest of the Netherlands [HR, 3.99; 95% confidence interval (CI), 1.11-14.35]. Adjustment for mutational spectrum changed the HRs for BRCA1, BRCA2 <60, and BRCA2 ≥60 years by -3%, +32%, and +11% to 0.75, 0.50, and 2.61, respectively. There was no difference in background breast cancer incidence between the two regions (OR, 1.03; 95% CI, 0.97-1.09).

Conclusions: Differences in mutation spectrum only partly explain the regional differences in breast cancer risk in BRCA2 carriers, and for an even smaller part in BRCA1 carriers.

Impact: The increased risk in BRCA2 carriers older than 60 may warrant extension of intensive breast screening beyond age 60.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-13-1279DOI Listing
November 2014

Relevance and efficacy of breast cancer screening in BRCA1 and BRCA2 mutation carriers above 60 years: a national cohort study.

Int J Cancer 2014 Dec 20;135(12):2940-9. Epub 2014 May 20.

Department of Surgery, Erasmus University Medical Centre, Rotterdam, The Netherlands.

Annual MRI and mammography is recommended for BRCA1/2 mutation carriers to reduce breast cancer mortality. Less intensive screening is advised ≥60 years, although effectiveness is unknown. We identified BRCA1/2 mutation carriers without bilateral mastectomy before age 60 to determine for whom screening ≥60 is relevant, in the Rotterdam Family Cancer Clinic and HEBON: a nationwide prospective cohort study. Furthermore, we compared tumour stage at breast cancer diagnosis between different screening strategies in BRCA1/2 mutation carriers ≥60. Tumours >2 cm, positive lymph nodes, or distant metastases at detection were defined as "unfavourable." Of 548 BRCA1/2 mutation carriers ≥60 years in 2012, 395 (72%) did not have bilateral mastectomy before the age of 60. Of these 395, 224 (57%) had a history of breast or other invasive carcinoma. In 136 BRCA1/2 mutation carriers, we compared 148 breast cancers (including interval cancers) detected ≥60, of which 84 (57%) were first breast cancers. With biennial mammography 53% (30/57) of carcinomas were detected in unfavourable stage, compared to 21% (12/56) with annual mammography (adjusted odds ratio: 4·07, 95% confidence interval [1.79-9.28], p = 0.001). With biennial screening 40% of breast cancers were interval cancers, compared to 20% with annual screening (p = 0.016). Results remained significant for BRCA1 and BRCA2 mutation carriers, and first breast cancers separately. Over 70% of 60-year old BRCA1/2 mutation carriers remain at risk for breast cancer, of which half has prior cancers. When life expectancy is good, continuation of annual breast cancer screening of BRCA1/2 mutation carriers ≥60 is worthwhile.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.28941DOI Listing
December 2014

DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers.

Authors:
Ana Osorio Roger L Milne Karoline Kuchenbaecker Tereza Vaclová Guillermo Pita Rosario Alonso Paolo Peterlongo Ignacio Blanco Miguel de la Hoya Mercedes Duran Orland Díez Teresa Ramón Y Cajal Irene Konstantopoulou Cristina Martínez-Bouzas Raquel Andrés Conejero Penny Soucy Lesley McGuffog Daniel Barrowdale Andrew Lee Brita Arver Johanna Rantala Niklas Loman Hans Ehrencrona Olufunmilayo I Olopade Mary S Beattie Susan M Domchek Katherine Nathanson Timothy R Rebbeck Banu K Arun Beth Y Karlan Christine Walsh Jenny Lester Esther M John Alice S Whittemore Mary B Daly Melissa Southey John Hopper Mary B Terry Saundra S Buys Ramunas Janavicius Cecilia M Dorfling Elizabeth J van Rensburg Linda Steele Susan L Neuhausen Yuan Chun Ding Thomas V O Hansen Lars Jønson Bent Ejlertsen Anne-Marie Gerdes Mar Infante Belén Herráez Leticia Thais Moreno Jeffrey N Weitzel Josef Herzog Kisa Weeman Siranoush Manoukian Bernard Peissel Daniela Zaffaroni Giulietta Scuvera Bernardo Bonanni Frederique Mariette Sara Volorio Alessandra Viel Liliana Varesco Laura Papi Laura Ottini Maria Grazia Tibiletti Paolo Radice Drakoulis Yannoukakos Judy Garber Steve Ellis Debra Frost Radka Platte Elena Fineberg Gareth Evans Fiona Lalloo Louise Izatt Ros Eeles Julian Adlard Rosemarie Davidson Trevor Cole Diana Eccles Jackie Cook Shirley Hodgson Carole Brewer Marc Tischkowitz Fiona Douglas Mary Porteous Lucy Side Lisa Walker Patrick Morrison Alan Donaldson John Kennedy Claire Foo Andrew K Godwin Rita Katharina Schmutzler Barbara Wappenschmidt Kerstin Rhiem Christoph Engel Alfons Meindl Nina Ditsch Norbert Arnold Hans Jörg Plendl Dieter Niederacher Christian Sutter Shan Wang-Gohrke Doris Steinemann Sabine Preisler-Adams Karin Kast Raymonda Varon-Mateeva Andrea Gehrig Dominique Stoppa-Lyonnet Olga M Sinilnikova Sylvie Mazoyer Francesca Damiola Bruce Poppe Kathleen Claes Marion Piedmonte Kathy Tucker Floor Backes Gustavo Rodríguez Wendy Brewster Katie Wakeley Thomas Rutherford Trinidad Caldés Heli Nevanlinna Kristiina Aittomäki Matti A Rookus Theo A M van Os Lizet van der Kolk J L de Lange Hanne E J Meijers-Heijboer A H van der Hout Christi J van Asperen Encarna B Gómez Garcia Nicoline Hoogerbrugge J Margriet Collée Carolien H M van Deurzen Rob B van der Luijt Peter Devilee Edith Olah Conxi Lázaro Alex Teulé Mireia Menéndez Anna Jakubowska Cezary Cybulski Jacek Gronwald Jan Lubinski Katarzyna Durda Katarzyna Jaworska-Bieniek Oskar Th Johannsson Christine Maugard Marco Montagna Silvia Tognazzo Manuel R Teixeira Sue Healey Curtis Olswold Lucia Guidugli Noralane Lindor Susan Slager Csilla I Szabo Joseph Vijai Mark Robson Noah Kauff Liying Zhang Rohini Rau-Murthy Anneliese Fink-Retter Christian F Singer Christine Rappaport Daphne Geschwantler Kaulich Georg Pfeiler Muy-Kheng Tea Andreas Berger Catherine M Phelan Mark H Greene Phuong L Mai Flavio Lejbkowicz Irene Andrulis Anna Marie Mulligan Gord Glendon Amanda Ewart Toland Anders Bojesen Inge Sokilde Pedersen Lone Sunde Mads Thomassen Torben A Kruse Uffe Birk Jensen Eitan Friedman Yael Laitman Shani Paluch Shimon Jacques Simard Douglas F Easton Kenneth Offit Fergus J Couch Georgia Chenevix-Trench Antonis C Antoniou Javier Benitez

PLoS Genet 2014 04 3;10(4):e1004256. Epub 2014 Apr 3.

Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain; Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain; Genotyping Unit (CeGen), Spanish National Cancer Centre (CNIO), Madrid, Spain.

Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7 × 10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8 × 10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1004256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3974638PMC
April 2014