Publications by authors named "John Hopper"

882 Publications

Population-Based Estimates of the Age-Specific Cumulative Risk of Breast Cancer for Pathogenic Variants in : Findings from the Australian Breast Cancer Family Registry.

Cancers (Basel) 2021 Mar 18;13(6). Epub 2021 Mar 18.

Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Victoria 3168, Australia.

Case-control studies of breast cancer have consistently shown that pathogenic variants in are associated with about a 3-fold increased risk of breast cancer. Information about the recurrent protein-truncating variant c.1100delC dominates this estimate. There have been no formal estimates of age-specific cumulative risk of breast cancer for all pathogenic (including likely pathogenic) variants combined. We conducted a population-based case-control-family study of pathogenic variants (26 families, 1071 relatives) and estimated the age-specific cumulative risk of breast cancer using segregation analysis. The estimated hazard ratio for carriers of pathogenic variants (combined) was 4.9 (95% CI 2.5-9.5) relative to non-carriers. The HR for carriers of the c.1100delC variant was estimated to be 3.5 (95% CI 1.02-11.6) and the HR for carriers of all other variants combined was estimated to be 5.7 (95% CI 2.5-12.9). The age-specific cumulative risk of breast cancer was estimated to be 18% (95% CI 11-30%) and 33% (95% CI 21-48%) to age 60 and 80 years, respectively. These findings provide important information for the clinical management of breast cancer risk for women carrying pathogenic variants in .
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http://dx.doi.org/10.3390/cancers13061378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003064PMC
March 2021

: Genetic Variation, Heritable Methylation and Disease Association.

Int J Mol Sci 2021 Mar 3;22(5). Epub 2021 Mar 3.

Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia.

is a metastable epiallele with accumulating evidence that methylation at this region is heritable, modifiable and associated with disease including risk and progression of cancer. This study investigated the influence of genetic variation and other factors such as age and adult lifestyle on blood DNA methylation in this region. We first sequenced the gene region in multiple-case breast cancer families in which methylation was identified as heritable and associated with breast cancer risk. Methylation quantitative trait loci (mQTL) were investigated using a prospective cohort study (4500 participants with genotyping and methylation data). The -mQTL analysis (334 variants ± 50 kb of the most heritable CpG site) identified 43 variants associated with methylation ( < 1.5 × 10); however, these explained little of the methylation variation (R < 0.5% for each of these variants). No genetic variants elsewhere in the genome were found to strongly influence methylation. SNP-based heritability estimates were consistent with the mQTL findings (h = 0, 95%CI: -0.14 to 0.14). We found no evidence that age, sex, country of birth, smoking, body mass index, alcohol consumption or diet influenced blood DNA methylation at . Genetic factors and adult lifestyle play a minimal role in explaining methylation variability at the heritable cluster.
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http://dx.doi.org/10.3390/ijms22052535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961504PMC
March 2021

Uptake of hysterectomy and bilateral salpingo-oophorectomy in carriers of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report.

Eur J Cancer 2021 Mar 17;148:124-133. Epub 2021 Mar 17.

Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo, Norway; The International Society for Gastrointestinal Hereditary Tumours (InSiGHT), The Polyposis Registry, St Mark's Hospital, Watford Road, Harrow, Middlesex, HA1 3UJ, UK; European Hereditary Tumour Group (EHTG), C/o Lindsays, Caledonian Exchange, 19A Canning Street, Edinburgh, EH3 8HE, United Kingdom.

Purpose: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants.

Methods: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years.

Results: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery.

Conclusion: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene- and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syndrome to improve outcomes.
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http://dx.doi.org/10.1016/j.ejca.2021.02.022DOI Listing
March 2021

Age dependency of the polygenic risk score for colorectal cancer.

Am J Hum Genet 2021 03;108(3):525-526

Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.ajhg.2021.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008484PMC
March 2021

Genetic architectures of proximal and distal colorectal cancer are partly distinct.

Authors:
Jeroen R Huyghe Tabitha A Harrison Stephanie A Bien Heather Hampel Jane C Figueiredo Stephanie L Schmit David V Conti Sai Chen Conghui Qu Yi Lin Richard Barfield John A Baron Amanda J Cross Brenda Diergaarde David Duggan Sophia Harlid Liher Imaz Hyun Min Kang David M Levine Vittorio Perduca Aurora Perez-Cornago Lori C Sakoda Fredrick R Schumacher Martha L Slattery Amanda E Toland Fränzel J B van Duijnhoven Bethany Van Guelpen Antonio Agudo Demetrius Albanes M Henar Alonso Kristin Anderson Coral Arnau-Collell Volker Arndt Barbara L Banbury Michael C Bassik Sonja I Berndt Stéphane Bézieau D Timothy Bishop Juergen Boehm Heiner Boeing Marie-Christine Boutron-Ruault Hermann Brenner Stefanie Brezina Stephan Buch Daniel D Buchanan Andrea Burnett-Hartman Bette J Caan Peter T Campbell Prudence R Carr Antoni Castells Sergi Castellví-Bel Andrew T Chan Jenny Chang-Claude Stephen J Chanock Keith R Curtis Albert de la Chapelle Douglas F Easton Dallas R English Edith J M Feskens Manish Gala Steven J Gallinger W James Gauderman Graham G Giles Phyllis J Goodman William M Grady John S Grove Andrea Gsur Marc J Gunter Robert W Haile Jochen Hampe Michael Hoffmeister John L Hopper Wan-Ling Hsu Wen-Yi Huang Thomas J Hudson Mazda Jenab Mark A Jenkins Amit D Joshi Temitope O Keku Charles Kooperberg Tilman Kühn Sébastien Küry Loic Le Marchand Flavio Lejbkowicz Christopher I Li Li Li Wolfgang Lieb Annika Lindblom Noralane M Lindor Satu Männistö Sanford D Markowitz Roger L Milne Lorena Moreno Neil Murphy Rami Nassir Kenneth Offit Shuji Ogino Salvatore Panico Patrick S Parfrey Rachel Pearlman Paul D P Pharoah Amanda I Phipps Elizabeth A Platz John D Potter Ross L Prentice Lihong Qi Leon Raskin Gad Rennert Hedy S Rennert Elio Riboli Clemens Schafmayer Robert E Schoen Daniela Seminara Mingyang Song Yu-Ru Su Catherine M Tangen Stephen N Thibodeau Duncan C Thomas Antonia Trichopoulou Cornelia M Ulrich Kala Visvanathan Pavel Vodicka Ludmila Vodickova Veronika Vymetalkova Korbinian Weigl Stephanie J Weinstein Emily White Alicja Wolk Michael O Woods Anna H Wu Goncalo R Abecasis Deborah A Nickerson Peter C Scacheri Anshul Kundaje Graham Casey Stephen B Gruber Li Hsu Victor Moreno Richard B Hayes Polly A Newcomb Ulrike Peters

Gut 2021 Feb 25. Epub 2021 Feb 25.

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

Objective: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined.

Design: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling.

Results: We identified 13 loci that reached genome-wide significance (p<5×10) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.

Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
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http://dx.doi.org/10.1136/gutjnl-2020-321534DOI Listing
February 2021

Association of Risk-Reducing Salpingo-Oophorectomy With Breast Cancer Risk in Women With BRCA1 and BRCA2 Pathogenic Variants.

JAMA Oncol 2021 Feb 25. Epub 2021 Feb 25.

Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.

Importance: Women with pathogenic variants in BRCA1 and BRCA2 are at high risk of developing breast and ovarian cancers. They usually undergo intensive cancer surveillance and may also consider surgical interventions, such as risk-reducing mastectomy or risk-reducing salpingo-oophorectomy (RRSO). Risk-reducing salpingo-oophorectomy has been shown to reduce ovarian cancer risk, but its association with breast cancer risk is less clear.

Objective: To assess the association of RRSO with the risk of breast cancer in women with BRCA1 and BRCA2 pathogenic variants.

Design, Setting, And Participants: This case series included families enrolled in the Breast Cancer Family Registry between 1996 and 2000 that carried an inherited pathogenic variant in BRCA1 (498 families) or BRCA2 (378 families). A survival analysis approach was used that was designed specifically to assess the time-varying association of RRSO with breast cancer risk and accounting for other potential biases. Data were analyzed from August 2019 to November 2020.

Exposure: Risk-reducing salpingo-oophorectomy.

Main Outcomes And Measures: In all analyses, the primary end point was the time to a first primary breast cancer.

Results: A total of 876 families were evaluated, including 498 with BRCA1 (2650 individuals; mean [SD] event age, 55.8 [19.1] years; 437 White probands [87.8%]) and 378 with BRCA2 (1925 individuals; mean [SD] event age, 57.0 [18.6] years; 299 White probands [79.1%]). Risk-reducing salpingo-oophorectomy was associated with a reduced risk of breast cancer for BRCA1 and BRCA2 pathogenic variant carriers within 5 years after surgery (hazard ratios [HRs], 0.28 [95% CI, 0.10-0.63] and 0.19 [95% CI, 0.06-0.71], respectively), whereas the corresponding HRs were weaker after 5 years postsurgery (HRs, 0.64 [95% CI, 0.38-0.97] and 0.99 [95% CI; 0.84-1.00], respectively). For BRCA1 and BRCA2 pathogenic variant carriers who underwent RRSO at age 40 years, the cause-specific cumulative risk of breast cancer was 49.7% (95% CI, 40.0-60.3) and 52.7% (95% CI, 47.9-58.7) by age 70 years, respectively, compared with 61.0% (95% CI, 56.7-66.0) and 54.0% (95% CI, 49.3-60.1), respectively, for women without RRSO.

Conclusions And Relevance: Although the primary indication for RRSO is the prevention of ovarian cancer, it is also critical to assess its association with breast cancer risk in order to guide clinical decision-making about RRSO use and timing. The results of this case series suggest a reduced risk of breast cancer associated with RRSO in the immediate 5 years after surgery in women carrying BRCA1 and BRCA2 pathogenic variants, and a longer-term association with cumulative breast cancer risk in women carrying BRCA1 pathogenic variants.
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http://dx.doi.org/10.1001/jamaoncol.2020.7995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907985PMC
February 2021

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

Authors:
Juliette Coignard Michael Lush Jonathan Beesley Tracy A O'Mara Joe Dennis Jonathan P Tyrer Daniel R Barnes Lesley McGuffog Goska Leslie Manjeet K Bolla Muriel A Adank Simona Agata Thomas Ahearn Kristiina Aittomäki Irene L Andrulis Hoda Anton-Culver Volker Arndt Norbert Arnold Kristan J Aronson Banu K Arun Annelie Augustinsson Jacopo Azzollini Daniel Barrowdale Caroline Baynes Heko Becher Marina Bermisheva Leslie Bernstein Katarzyna Białkowska Carl Blomqvist Stig E Bojesen Bernardo Bonanni Ake Borg Hiltrud Brauch Hermann Brenner Barbara Burwinkel Saundra S Buys Trinidad Caldés Maria A Caligo Daniele Campa Brian D Carter Jose E Castelao Jenny Chang-Claude Stephen J Chanock Wendy K Chung Kathleen B M Claes Christine L Clarke J Margriet Collée Don M Conroy Kamila Czene Mary B Daly Peter Devilee Orland Diez Yuan Chun Ding Susan M Domchek Thilo Dörk Isabel Dos-Santos-Silva Alison M Dunning Miriam Dwek Diana M Eccles A Heather Eliassen Christoph Engel Mikael Eriksson D Gareth Evans Peter A Fasching Henrik Flyger Florentia Fostira Eitan Friedman Lin Fritschi Debra Frost Manuela Gago-Dominguez Susan M Gapstur Judy Garber Vanesa Garcia-Barberan Montserrat García-Closas José A García-Sáenz Mia M Gaudet Simon A Gayther Andrea Gehrig Vassilios Georgoulias Graham G Giles Andrew K Godwin Mark S Goldberg David E Goldgar Anna González-Neira Mark H Greene Pascal Guénel Lothar Haeberle Eric Hahnen Christopher A Haiman Niclas Håkansson Per Hall Ute Hamann Patricia A Harrington Steven N Hart Wei He Frans B L Hogervorst Antoinette Hollestelle John L Hopper Darling J Horcasitas Peter J Hulick David J Hunter Evgeny N Imyanitov Agnes Jager Anna Jakubowska Paul A James Uffe Birk Jensen Esther M John Michael E Jones Rudolf Kaaks Pooja Middha Kapoor Beth Y Karlan Renske Keeman Elza Khusnutdinova Johanna I Kiiski Yon-Dschun Ko Veli-Matti Kosma Peter Kraft Allison W Kurian Yael Laitman Diether Lambrechts Loic Le Marchand Jenny Lester Fabienne Lesueur Tricia Lindstrom Adria Lopez-Fernández Jennifer T Loud Craig Luccarini Arto Mannermaa Siranoush Manoukian Sara Margolin John W M Martens Noura Mebirouk Alfons Meindl Austin Miller Roger L Milne Marco Montagna Katherine L Nathanson Susan L Neuhausen Heli Nevanlinna Finn C Nielsen Katie M O'Brien Olufunmilayo I Olopade Janet E Olson Håkan Olsson Ana Osorio Laura Ottini Tjoung-Won Park-Simon Michael T Parsons Inge Sokilde Pedersen Beth Peshkin Paolo Peterlongo Julian Peto Paul D P Pharoah Kelly-Anne Phillips Eric C Polley Bruce Poppe Nadege Presneau Miquel Angel Pujana Kevin Punie Paolo Radice Johanna Rantala Muhammad U Rashid Gad Rennert Hedy S Rennert Mark Robson Atocha Romero Maria Rossing Emmanouil Saloustros Dale P Sandler Regina Santella Maren T Scheuner Marjanka K Schmidt Gunnar Schmidt Christopher Scott Priyanka Sharma Penny Soucy Melissa C Southey John J Spinelli Zoe Steinsnyder Jennifer Stone Dominique Stoppa-Lyonnet Anthony Swerdlow Rulla M Tamimi William J Tapper Jack A Taylor Mary Beth Terry Alex Teulé Darcy L Thull Marc Tischkowitz Amanda E Toland Diana Torres Alison H Trainer Thérèse Truong Nadine Tung Celine M Vachon Ana Vega Joseph Vijai Qin Wang Barbara Wappenschmidt Clarice R Weinberg Jeffrey N Weitzel Camilla Wendt Alicja Wolk Siddhartha Yadav Xiaohong R Yang Drakoulis Yannoukakos Wei Zheng Argyrios Ziogas Kristin K Zorn Sue K Park Mads Thomassen Kenneth Offit Rita K Schmutzler Fergus J Couch Jacques Simard Georgia Chenevix-Trench Douglas F Easton Nadine Andrieu Antonis C Antoniou

Nat Commun 2021 02 17;12(1):1078. Epub 2021 Feb 17.

Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
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http://dx.doi.org/10.1038/s41467-020-20496-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890067PMC
February 2021

Lifetime alcohol intake, drinking patterns over time and risk of stomach cancer: A pooled analysis of data from two prospective cohort studies.

Int J Cancer 2021 Jun 22;148(11):2759-2773. Epub 2021 Feb 22.

Nutritional Methodology and Biostatistics Group, International Agency for Research on Cancer, World Health Organization, Lyon, France.

Alcohol consumption is causally linked to several cancers but the evidence for stomach cancer is inconclusive. In our study, the association between long-term alcohol intake and risk of stomach cancer and its subtypes was evaluated. We performed a pooled analysis of data collected at baseline from 491 714 participants in the European Prospective Investigation into Cancer and Nutrition and the Melbourne Collaborative Cohort Study. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for incident stomach cancer in relation to lifetime alcohol intake and group-based life course intake trajectories, adjusted for potential confounders including Helicobacter pylori infection. In all, 1225 incident stomach cancers (78% noncardia) were diagnosed over 7 094 637 person-years; 984 in 382 957 study participants with lifetime alcohol intake data (5 455 507 person-years). Although lifetime alcohol intake was not associated with overall stomach cancer risk, we observed a weak positive association with noncardia cancer (HR = 1.03, 95% CI: 1.00-1.06 per 10 g/d increment), with a HR of 1.50 (95% CI: 1.08-2.09) for ≥60 g/d compared to 0.1 to 4.9 g/d. A weak inverse association with cardia cancer (HR = 0.93, 95% CI: 0.87-1.00) was also observed. HRs of 1.48 (95% CI: 1.10-1.99) for noncardia and 0.51 (95% CI: 0.26-1.03) for cardia cancer were observed for a life course trajectory characterized by heavy decreasing intake compared to light stable intake (P = .02). These associations did not differ appreciably by smoking or H pylori infection status. Limiting alcohol use during lifetime, particularly avoiding heavy use during early adulthood, might help prevent noncardia stomach cancer. Heterogeneous associations observed for cardia and noncardia cancers may indicate etiologic differences.
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http://dx.doi.org/10.1002/ijc.33504DOI Listing
June 2021

Motivators of Inappropriate Ovarian Cancer Screening: A Survey of Women and Their Clinicians.

JNCI Cancer Spectr 2021 Feb 8;5(1):pkaa110. Epub 2020 Dec 8.

Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Background: This study examined why women and doctors screen for ovarian cancer (OC) contrary to guidelines.

Methods: Surveys, based on the Theoretical Domains Framework, were sent to women in the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer and family physicians and gynecologists who organized their screening.

Results: Of 1264 Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer women, 832 (65.8%) responded. In the past 2 years, 126 (15.1%) had screened. Most of these (n = 101, 80.2%) would continue even if their doctor told them it is ineffective. For women, key OC screening motivators operated in the domains of social role and goals (staying healthy for family, 93.9%), emotion and reinforcement (peace of mind, 93.1%), and beliefs about capabilities (tests are easy to have, 91.9%). Of 531 clinicians 252 (47.5%) responded; a minority (family physicians 45.8%, gynecologists 16.7%) thought OC screening was useful. For gynecologists, the main motivators of OC screening operated in the domains of environmental context (lack of other screening options, 27.6%), and emotion (patient peace of mind, 17.2%; difficulty discontinuing screening, 13.8%). For family physicians,, the strongest motivators were in the domains of social influence (women ask for these tests, 20.7%), goals (a chance these tests will detect cancer early, 16.4%), emotion (patient peace of mind, 13.8%), and environmental context (no other OC screening options, 11.2%).

Conclusion: Reasons for OC screening are mostly patient driven. Clinician knowledge and practice are discordant. Motivators of OC screening encompass several domains, which could be targeted in interventions to reduce inappropriate OC screening.
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http://dx.doi.org/10.1093/jncics/pkaa110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853181PMC
February 2021

Familial and Genetic Influences on the Common Pediatric Primary Pain Disorders: A Twin Family Study.

Children (Basel) 2021 Jan 28;8(2). Epub 2021 Jan 28.

Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, VIC 3010, Australia.

The primary pain disorders of childhood are highly prevalent but have infrequently been studied collectively. Genetic influences have been suggested to be causally implicated. Surveys were sent to 3909 Australian twin families, assessing the lifetime prevalence of growing pains, migraine, headache, recurrent abdominal pain, low back pain, and persistent pain (not otherwise specified) in pediatric twins and their immediate family members. Comparisons between monozygous (MZ) and dizygous (DZ) twin pair correlations, concordances and odds ratios were performed to assess the contribution of additive genetic influences. Random-effects logistic regression modelling was used to evaluate relationships between twin individuals and their co-twins, mothers, fathers and oldest siblings with the subject conditions. Twin analyses of responses from 1016 families revealed significant influence of additive genetic effects on the presence of growing pains, migraine, and recurrent abdominal pain. The analyses for headache, low back pain, and persistent pain overall did not conclusively demonstrate that genetic influences were implicated more than shared environmental factors. Regression analyses demonstrated varying levels of significance in relationships between family members and twin individuals for the tested conditions, with strongest support for genetic influences in growing pains and migraine. These data, together with previously published association analyses, suggest common causal influences including genes.
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http://dx.doi.org/10.3390/children8020089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911833PMC
January 2021

Associations of Height With the Risks of Colorectal and Endometrial Cancer in Persons With Lynch Syndrome.

Am J Epidemiol 2021 02;190(2):230-238

People with Lynch syndrome (LS), who carry a pathogenic mutation in a DNA mismatch repair gene, have increased risks of colorectal cancer (CRC) and endometrial cancer (EC). A high reported variability in cancer risk suggests the existence of factors that modify cancer risk for persons with LS. We aimed to investigate the associations between height and CRC and EC risk for persons with LS using data from 2 large studies. Information on 1,115 men and 1,553 women with LS from the Colon Cancer Family Registry (1998-2007) and the GEOLynch Cohort Study (2006-2017) was harmonized. We used weighted Cox proportional hazards regression models with age on the time axis to estimate adjusted hazard ratios and 95% confidence intervals for each 5-cm increment in self-reported height. CRC was diagnosed in 947 persons during 65,369 person-years of observation, and 171 women were diagnosed with EC during 39,227 person-years. Height was not associated with CRC for either men (per 5-cm increment, hazard ratio (HR) = 1.00, 95% confidence interval (CI): 0.91, 1.11) or women (per 5-cm increment, HR = 1.01, 95% CI: 0.92, 1.11), nor was height associated with EC (per 5-cm increment, HR = 1.08, 95% CI: 0.94, 1.24). Hence, we observed no evidence for an association of height with either CRC or EC among persons with LS.
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http://dx.doi.org/10.1093/aje/kwaa175DOI Listing
February 2021

Breast Cancer Risk Factors and Survival by Tumor Subtype: Pooled Analyses from the Breast Cancer Association Consortium.

Authors:
Anna Morra Audrey Y Jung Sabine Behrens Renske Keeman Thomas U Ahearn Hoda Anton-Culver Volker Arndt Annelie Augustinsson Päivi K Auvinen Laura E Beane Freeman Heiko Becher Matthias W Beckmann Carl Blomqvist Stig E Bojesen Manjeet K Bolla Hermann Brenner Ignacio Briceno Sara Y Brucker Nicola J Camp Daniele Campa Federico Canzian Jose E Castelao Stephen J Chanock Ji-Yeob Choi Christine L Clarke Fergus J Couch Angela Cox Simon S Cross Kamila Czene Thilo Dörk Alison M Dunning Miriam Dwek Douglas F Easton Diana M Eccles Kathleen M Egan D Gareth Evans Peter A Fasching Henrik Flyger Manuela Gago-Dominguez Susan M Gapstur José A García-Sáenz Mia M Gaudet Graham G Giles Mervi Grip Pascal Guénel Christopher A Haiman Niclas Håkansson Per Hall Ute Hamann Sileny N Han Steven N Hart Mikael Hartman Jane S Heyworth Reiner Hoppe John L Hopper David J Hunter Hidemi Ito Agnes Jager Milena Jakimovska Anna Jakubowska Wolfgang Janni Rudolf Kaaks Daehee Kang Pooja Middha Kapoor Cari M Kitahara Stella Koutros Peter Kraft Vessela N Kristensen James V Lacey Diether Lambrechts Loic Le Marchand Jingmei Li Annika Lindblom Jan Lubiński Michael Lush Arto Mannermaa Mehdi Manoochehri Sara Margolin Shivaani Mariapun Keitaro Matsuo Dimitrios Mavroudis Roger L Milne Taru A Muranen William G Newman Dong-Young Noh Børge G Nordestgaard Nadia Obi Andrew F Olshan Håkan Olsson Tjoung-Won Park-Simon Christos Petridis Paul D P Pharoah Dijana Plaseska-Karanfilska Nadege Presneau Muhammad U Rashid Gad Rennert Hedy S Rennert Valerie Rhenius Atocha Romero Emmanouil Saloustros Elinor J Sawyer Andreas Schneeweiss Lukas Schwentner Christopher Scott Mitul Shah Chen-Yang Shen Xiao-Ou Shu Melissa C Southey Daniel O Stram Rulla M Tamimi William Tapper Rob A E M Tollenaar Ian Tomlinson Diana Torres Melissa A Troester Thérèse Truong Celine M Vachon Qin Wang Sophia S Wang Justin A Williams Robert Winqvist Alicja Wolk Anna H Wu Keun-Young Yoo Jyh-Cherng Yu Wei Zheng Argyrios Ziogas Xiaohong R Yang A Heather Eliassen Michelle D Holmes Montserrat García-Closas Soo Hwang Teo Marjanka K Schmidt Jenny Chang-Claude

Cancer Epidemiol Biomarkers Prev 2021 Apr 26;30(4):623-642. Epub 2021 Jan 26.

Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype.

Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer-specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype.

Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype ( > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5-25 kg/m [HR (95% confidence interval (CI), 1.19 (1.06-1.34)]; current versus never smoking [1.37 (1.27-1.47)], high versus low physical activity [0.43 (0.21-0.86)], age ≥30 years versus <20 years at first pregnancy [0.79 (0.72-0.86)]; >0-<5 years versus ≥10 years since last full-term birth [1.31 (1.11-1.55)]; ever versus never use of oral contraceptives [0.91 (0.87-0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen-progestin therapy [0.61 (0.54-0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02-1.21) for current versus never smoking.

Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype.

Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026532PMC
April 2021

CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers.

Authors:
Nichola Johnson Sarah Maguire Anna Morra Pooja Middha Kapoor Katarzyna Tomczyk Michael E Jones Minouk J Schoemaker Clare Gilham Manjeet K Bolla Qin Wang Joe Dennis Thomas U Ahearn Irene L Andrulis Hoda Anton-Culver Natalia N Antonenkova Volker Arndt Kristan J Aronson Annelie Augustinsson Caroline Baynes Laura E Beane Freeman Matthias W Beckmann Javier Benitez Marina Bermisheva Carl Blomqvist Bram Boeckx Natalia V Bogdanova Stig E Bojesen Hiltrud Brauch Hermann Brenner Barbara Burwinkel Daniele Campa Federico Canzian Jose E Castelao Stephen J Chanock Georgia Chenevix-Trench Christine L Clarke Don M Conroy Fergus J Couch Angela Cox Simon S Cross Kamila Czene Thilo Dörk A Heather Eliassen Christoph Engel D Gareth Evans Peter A Fasching Jonine Figueroa Giuseppe Floris Henrik Flyger Manuela Gago-Dominguez Susan M Gapstur Montserrat García-Closas Mia M Gaudet Graham G Giles Mark S Goldberg Anna González-Neira Pascal Guénel Eric Hahnen Christopher A Haiman Niclas Håkansson Per Hall Ute Hamann Patricia A Harrington Steven N Hart Maartje J Hooning John L Hopper Anthony Howell David J Hunter Agnes Jager Anna Jakubowska Esther M John Rudolf Kaaks Renske Keeman Elza Khusnutdinova Cari M Kitahara Veli-Matti Kosma Stella Koutros Peter Kraft Vessela N Kristensen Allison W Kurian Diether Lambrechts Loic Le Marchand Martha Linet Jan Lubiński Arto Mannermaa Siranoush Manoukian Sara Margolin John W M Martens Dimitrios Mavroudis Rebecca Mayes Alfons Meindl Roger L Milne Susan L Neuhausen Heli Nevanlinna William G Newman Sune F Nielsen Børge G Nordestgaard Nadia Obi Andrew F Olshan Janet E Olson Håkan Olsson Ester Orban Tjoung-Won Park-Simon Paolo Peterlongo Dijana Plaseska-Karanfilska Katri Pylkäs Gad Rennert Hedy S Rennert Kathryn J Ruddy Emmanouil Saloustros Dale P Sandler Elinor J Sawyer Rita K Schmutzler Christopher Scott Xiao-Ou Shu Jacques Simard Snezhana Smichkoska Christof Sohn Melissa C Southey John J Spinelli Jennifer Stone Rulla M Tamimi Jack A Taylor Rob A E M Tollenaar Ian Tomlinson Melissa A Troester Thérèse Truong Celine M Vachon Elke M van Veen Sophia S Wang Clarice R Weinberg Camilla Wendt Hans Wildiers Robert Winqvist Alicja Wolk Wei Zheng Argyrios Ziogas Alison M Dunning Paul D P Pharoah Douglas F Easton A Forbes Howie Julian Peto Isabel Dos-Santos-Silva Anthony J Swerdlow Jenny Chang-Claude Marjanka K Schmidt Nick Orr Olivia Fletcher

Br J Cancer 2021 Feb 26;124(4):842-854. Epub 2021 Jan 26.

The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.

Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk.

Methods: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry.

Results: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10).

Conclusions: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.
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http://dx.doi.org/10.1038/s41416-020-01185-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884683PMC
February 2021

Oral contraceptive use and ovarian cancer risk for BRCA1/2 mutation carriers: an international cohort study.

Am J Obstet Gynecol 2021 Jan 22. Epub 2021 Jan 22.

Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands. Electronic address:

Background: Ovarian cancer risk in BRCA1 and BRCA2 mutation carriers has been shown to decrease with longer duration of oral contraceptive use. Although the effects of using oral contraceptives in the general population are well established (approximately 50% risk reduction in ovarian cancer), the estimated risk reduction in mutation carriers is much less precise because of potential bias and small sample sizes. In addition, only a few studies on oral contraceptive use have examined the associations of duration of use, time since last use, starting age, and calendar year of start with risk of ovarian cancer.

Objective: This study aimed to investigate in more detail the associations of various characteristics of oral contraceptive use and risk of ovarian cancer, to provide healthcare providers and carriers with better risk estimates.

Study Design: In this international retrospective study, ovarian cancer risk associations were assessed using oral contraceptives data on 3989 BRCA1 and 2445 BRCA2 mutation carriers. Age-dependent-weighted Cox regression analyses were stratified by study and birth cohort and included breast cancer diagnosis as a covariate. To minimize survival bias, analyses were left truncated at 5 years before baseline questionnaire. Separate analyses were conducted for each aspect of oral contraceptive use and in a multivariate analysis, including all these aspects. In addition, the analysis of duration of oral contraceptive use was stratified by recency of use.

Results: Oral contraceptives were less often used by mutation carriers who were diagnosed with ovarian cancer (ever use: 58.6% for BRCA1 and 53.5% BRCA2) than by unaffected carriers (ever use: 88.9% for BRCA1 and 80.7% for BRCA2). The median duration of use was 7 years for both BRCA1 and BRCA2 carriers who developed ovarian cancer and 9 and 8 years for unaffected BRCA1 and BRCA2 carriers with ovarian cancer, respectively. For BRCA1 mutation carriers, univariate analyses have shown that both a longer duration of oral contraceptive use and more recent oral contraceptive use were associated with a reduction in the risk of ovarian cancer. However, in multivariate analyses, including duration of use, age at first use, and time since last use, duration of oral contraceptive use proved to be the prominent protective factor (compared with <5 years: 5-9 years [hazard ratio, 0.67; 95% confidence interval, 0.40-1.12]; >10 years [hazard ratio, 0.37; 95% confidence interval, 0.19-0.73]; P=.008). The inverse association between duration of use and ovarian cancer risk persisted for more than 15 years (duration of ≥10 years; BRCA1 <15 years since last use [hazard ratio, 0.24; 95% confidence interval, 0.14-0.43]; BRCA1 >15 years since last use [hazard ratio, 0.56; 95% confidence interval, 0.18-0.59]). Univariate results for BRCA2 mutation carriers were similar but were inconclusive because of limited sample size.

Conclusion: For BRCA1 mutation carriers, longer duration of oral contraceptive use is associated with a greater reduction in ovarian cancer risk, and the protection is long term.
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http://dx.doi.org/10.1016/j.ajog.2021.01.014DOI Listing
January 2021

A streamlined model for use in clinical breast cancer risk assessment maintains predictive power and is further improved with inclusion of a polygenic risk score.

PLoS One 2021 22;16(1):e0245375. Epub 2021 Jan 22.

Centre for Epidemiology and Biostatistics, The University of Melbourne, Parkville, VIC, Australia.

Five-year absolute breast cancer risk prediction models are required to comply with national guidelines regarding risk reduction regimens. Models including the Gail model are under-utilized in the general population for various reasons, including difficulty in accurately completing some clinical fields. The purpose of this study was to determine if a streamlined risk model could be designed without substantial loss in performance. Only the clinical risk factors that were easily answered by women will be retained and combined with an objective validated polygenic risk score (PRS) to ultimately improve overall compliance with professional recommendations. We first undertook a review of a series of 2,339 Caucasian, African American and Hispanic women from the USA who underwent clinical testing. We first used deidentified test request forms to identify the clinical risk factors that were best answered by women in a clinical setting and then compared the 5-year risks for the full model and the streamlined model in this clinical series. We used OPERA analysis on previously published case-control data from 11,924 Gail model samples to determine clinical risk factors to include in a streamlined model: first degree family history and age that could then be combined with the PRS. Next, to ensure that the addition of PRS to the streamlined model was indeed beneficial, we compared risk stratification using the Streamlined model with and without PRS for the existing case-control datasets comprising 1,313 cases and 10,611 controls of African-American (n = 7421), Caucasian (n = 1155) and Hispanic (n = 3348) women, using the area under the curve to determine model performance. The improvement in risk discrimination from adding the PRS risk score to the Streamlined model was 52%, 46% and 62% for African-American, Caucasian and Hispanic women, respectively, based on changes in log OPERA. There was no statistically significant difference in mean risk scores between the Gail model plus risk PRS compared to the Streamlined model plus PRS. This study demonstrates that validated PRS can be used to streamline a clinical test for primary care practice without diminishing test performance. Importantly, by eliminating risk factors that women find hard to recall or that require obtaining medical records, this model may facilitate increased clinical adoption of 5-year risk breast cancer risk prediction test in keeping with national standards and guidelines for breast cancer risk reduction.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245375PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822550PMC
January 2021

Association of variably methylated tumour DNA regions with overall survival for invasive lobular breast cancer.

Clin Epigenetics 2021 Jan 18;13(1):11. Epub 2021 Jan 18.

Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Melbourne, VIC, 3010, Australia.

Background: Tumour DNA methylation profiling has shown potential to refine disease subtyping and improve the diagnosis and prognosis prediction of breast cancer. However, limited data exist regarding invasive lobular breast cancer (ILBC). Here, we investigated the genome-wide variability of DNA methylation levels across ILBC tumours and assessed the association between methylation levels at the variably methylated regions and overall survival in women with ILBC.

Methods: Tumour-enriched DNA was prepared by macrodissecting formalin-fixed paraffin embedded (FFPE) tumour tissue from 130 ILBCs diagnosed in the participants of the Melbourne Collaborative Cohort Study (MCCS). Genome-wide tumour DNA methylation was measured using the HumanMethylation 450K (HM450K) BeadChip array. Variably methylated regions (VMRs) were identified using the DMRcate package in R. Cox proportional hazards regression models were used to assess the association between methylation levels at the ten most significant VMRs and overall survival. Gene set enrichment analyses were undertaken using the web-based tool Metaspace. Replication of the VMR and survival analysis findings was examined using data retrieved from The Cancer Genome Atlas (TCGA) for 168 ILBC cases. We also examined the correlation between methylation and gene expression for the ten VMRs of interest using TCGA data.

Results: We identified 2771 VMRs (P < 10) in ILBC tumours. The ten most variably methylated clusters were predominantly located in the promoter region of the genes: ISM1, APC, TMEM101, ASCL2, NKX6, HIST3H2A/HIST3H2BB, HCG4P3, HES5, CELF2 and EFCAB4B. Higher methylation level at several of these VMRs showed an association with reduced overall survival in the MCCS. In TCGA, all associations were in the same direction, however stronger than in the MCCS. The pooled analysis of the MCCS and TCGA data showed that methylation at four of the ten genes was associated with reduced overall survival, independently of age and tumour stage; APC: Hazard Ratio (95% Confidence interval) per one-unit M-value increase: 1.18 (1.02-1.36), TMEM101: 1.23 (1.02-1.48), HCG4P3: 1.37 (1.05-1.79) and CELF2: 1.21 (1.02-1.43). A negative correlation was observed between methylation and gene expression for CELF2 (R = - 0.25, P = 0.001), but not for TMEM101 and APC.

Conclusions: Our study identified regions showing greatest variability across the ILBC tumour genome and found methylation at several genes to potentially serve as a biomarker of survival for women with ILBC.
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http://dx.doi.org/10.1186/s13148-020-00975-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814464PMC
January 2021

Biological Aging Measures Based on Blood DNA Methylation and Risk of Cancer: A Prospective Study.

JNCI Cancer Spectr 2021 Feb 16;5(1):pkaa109. Epub 2020 Nov 16.

Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.

Background: We previously investigated the association between 5 "first-generation" measures of epigenetic aging and cancer risk in the Melbourne Collaborative Cohort Study. This study assessed cancer risk associations for 3 recently developed methylation-based biomarkers of aging: , , and predicted telomere length.

Methods: We estimated rate ratios (RRs) for the association between these 3 age-adjusted measures and risk of colorectal (N = 813), gastric (N = 165), kidney (N = 139), lung (N = 327), mature B-cell (N = 423), prostate (N = 846), and urothelial (N = 404) cancer using conditional logistic regression models. We also assessed associations by time since blood draw and by cancer subtype, and we investigated potential nonlinearity.

Results: We observed relatively strong associations of age-adjusted with risk of colorectal, kidney, lung, mature B-cell, and urothelial cancers (RR per SD was approximately 1.2-1.3). Similar findings were obtained for age-adjusted , but the association with lung cancer risk was much larger (RR per SD = 1.82, 95% confidence interval [CI] = 1.44 to 2.30), after adjustment for smoking status, pack-years, starting age, time since quitting, and other cancer risk factors. Most associations appeared linear, larger than for the first-generation measures, and were virtually unchanged after adjustment for a large set of sociodemographic, lifestyle, and anthropometric variables. For cancer overall, the comprehensively adjusted rate ratio per SD was 1.13 (95% CI = 1.07 to 1.19) for and 1.12 (95% CI = 1.05 to 1.20) for and appeared larger within 5 years of blood draw (RR = 1.29, 95% CI = 1.15 to 1.44 and 1.19, 95% CI = 1.06 to 1.33, respectively).

Conclusions: The methylation-based measures and may provide insights into the relationship between biological aging and cancer and be useful to predict cancer risk, particularly for lung cancer.
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http://dx.doi.org/10.1093/jncics/pkaa109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791618PMC
February 2021

Evaluating the utility of tumour mutational signatures for identifying hereditary colorectal cancer and polyposis syndrome carriers.

Gut 2021 Jan 7. Epub 2021 Jan 7.

Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia

Objective: Germline pathogenic variants (PVs) in the DNA mismatch repair (MMR) genes and in the base excision repair gene underlie hereditary colorectal cancer (CRC) and polyposis syndromes. We evaluated the robustness and discriminatory potential of tumour mutational signatures in CRCs for identifying germline PV carriers.

Design: Whole-exome sequencing of formalin-fixed paraffin-embedded (FFPE) CRC tissue was performed on 33 MMR germline PV carriers, 12 biallelic germline PV carriers, 25 sporadic methylated MMR-deficient CRCs (MMRd controls) and 160 sporadic MMR-proficient CRCs (MMRp controls) and included 498 TCGA CRC tumours. COSMIC V3 single base substitution (SBS) and indel (ID) mutational signatures were assessed for their ability to differentiate CRCs that developed in carriers from non-carriers.

Results: The combination of mutational signatures SBS18 and SBS36 contributing >30% of a CRC's signature profile was able to discriminate biallelic carriers from all other non-carrier control CRCs with 100% accuracy (area under the curve (AUC) 1.0). SBS18 and SBS36 were associated with specific variants p.Gly396Asp (p=0.025) and p.Tyr179Cys (p=5×10), respectively. The combination of ID2 and ID7 could discriminate the 33 MMR PV carrier CRCs from the MMRp control CRCs (AUC 0.99); however, SBS and ID signatures, alone or in combination, could not provide complete discrimination (AUC 0.79) between CRCs from MMR PV carriers and sporadic MMRd controls.

Conclusion: Assessment of SBS and ID signatures can discriminate CRCs from biallelic carriers and MMR PV carriers from non-carriers with high accuracy, demonstrating utility as a potential diagnostic and variant classification tool.
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http://dx.doi.org/10.1136/gutjnl-2019-320462DOI Listing
January 2021

Germline and Tumor Sequencing as a Diagnostic Tool To Resolve Suspected Lynch Syndrome.

J Mol Diagn 2021 Mar 29;23(3):358-371. Epub 2020 Dec 29.

Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia; Centre for Cancer Research, Victorian Comprehensive Cancer Centre, The University of Melbourne, Parkville, Victoria, Australia; Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia. Electronic address:

Patients in whom mismatch repair (MMR)-deficient cancer develops in the absence of pathogenic variants of germline MMR genes or somatic hypermethylation of the MLH1 gene promoter are classified as having suspected Lynch syndrome (SLS). Germline whole-genome sequencing (WGS) and targeted and genome-wide tumor sequencing were applied to identify the underlying cause of tumor MMR deficiency in SLS. Germline WGS was performed on samples from 14 cancer-affected patients with SLS, including two sets of first-degree relatives. MMR genes were assessed for germline pathogenic variants, including complex structural rearrangements and noncoding variants. Tumor tissue was assessed for somatic MMR gene mutations using targeted, whole-exome sequencing or WGS. Germline WGS identified pathogenic MMR variants in 3 of the 14 cases (21.4%), including a 9.5-megabase inversion disrupting MSH2 in a mother and daughter. Excluding these 3 MMR carriers, tumor sequencing identified at least two somatic MMR gene mutations in 8 of 11 tumors tested (72.7%). In a second mother-daughter pair, a somatic cause of tumor MMR deficiency was supported by the presence of double somatic MSH2 mutations in their respective tumors. More than 70% of SLS cases had double somatic MMR mutations in the absence of germline pathogenic variants in the MMR or other DNA repair-related genes on WGS, and, therefore, were confidently assigned a noninherited cause of tumor MMR deficiency.
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http://dx.doi.org/10.1016/j.jmoldx.2020.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927277PMC
March 2021

A Combined Proteomics and Mendelian Randomization Approach to Investigate the Effects of Aspirin-Targeted Proteins on Colorectal Cancer.

Cancer Epidemiol Biomarkers Prev 2020 Dec 14. Epub 2020 Dec 14.

Medical Research Council (MRC) Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, United Kingdom.

Background: Evidence for aspirin's chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk.

Methods: Human colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labeling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL ( = 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium ( = 31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls).

Results: Altered expression was detected for 125/5886 proteins. Of these, aspirin decreased MCM6, RRM2, and ARFIP2 expression, and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR: 1.08, 95% CI, 1.03-1.13; OR: 3.33, 95% CI, 2.46-4.50; and OR: 1.15, 95% CI, 1.02-1.29, respectively).

Conclusions: MCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation, indicating a possible role in aspirin's reduction of metastasis.

Impact: Our approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1176DOI Listing
December 2020

Comparing Five-Year and Lifetime Risks of Breast Cancer in the Prospective Family Study Cohort.

J Natl Cancer Inst 2020 Dec 10. Epub 2020 Dec 10.

Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY.

Background: Clinical guidelines often use predicted lifetime risk from birth to define criteria for making decisions regarding breast cancer screening rather than thresholds based on absolute 5-year risk from current age.

Methods: We used the Prospective Family Cohort Study of 14,657 women without breast cancer at baseline in which, during a median follow-up of 10 years, 482 women were diagnosed with invasive breast cancer. We examined the performances of the IBIS and BOADICEA risk models when using alternative thresholds by comparing predictions based on 5-year risk with those based on lifetime risk from birth and remaining lifetime risk. All statistical tests were two-sided.

Results: Using IBIS, the areas under the receiver-operating characteristic curves were 0.66 (95% confidence interval = 0.63 to 0.68) and 0.56 (95% confidence interval = 0.54 to 0.59) for 5-year and lifetime risks, respectively (Pdiff<0.001). For equivalent sensitivities, the 5-year incidence almost always had higher specificities than lifetime risk from birth. For women aged 20-39 years, 5-year risk performed better than lifetime risk from birth. For women aged 40 years or more, receiver-operating characteristic curves were similar for 5-year and lifetime IBIS risk from birth. Classifications based on remaining lifetime risk were inferior to 5-year risk estimates. Results were similar using BOADICEA.

Conclusions: Our analysis shows that risk stratification using clinical models will likely be more accurate when based on predicted 5-year risk compared with risks based on predicted lifetime and remaining lifetime, particularly for women aged 20-39 years.
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http://dx.doi.org/10.1093/jnci/djaa178DOI Listing
December 2020

Risk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report.

Genet Med 2021 Apr 1;23(4):705-712. Epub 2020 Dec 1.

Department of Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo, Norway.

Purpose: To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR (path_MMR) variants.

Methods: The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages.

Results: Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively.

Conclusion: Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS.
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http://dx.doi.org/10.1038/s41436-020-01029-1DOI Listing
April 2021

Trajectories of asthma and allergies from 7 years to 53 years and associations with lung function and extrapulmonary comorbidity profiles: a prospective cohort study.

Lancet Respir Med 2021 04 17;9(4):387-396. Epub 2020 Nov 17.

Allergy and Lung Health Unit, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia. Electronic address:

Background: Longitudinal trajectories of asthma and allergies from childhood to adulthood might be differentially associated with lung function and chronic obstructive pulmonary disease (COPD), but associations with extrapulmonary comorbidities have not been well investigated. We aimed to assess these trajectories and examine their associations with lung function outcomes and profiles of comorbidities.

Methods: In this prospective cohort study, data for asthma and related allergic conditions (ie, eczema, hay fever, and food allergy) were prospectively collected from the Tasmanian Longitudinal Health Study for participants aged 7-53 years originally recruited in Tasmania, Australia. All surviving individuals in the database with contact details were invited in the most recent follow-up (mean age 53 years). There were no exclusion criteria. With use of latent class analysis, we identified longitudinal trajectories of asthma and allergic conditions from 7-53 years, and profiles of self-reported extrapulmonary conditions recorded at 53 years. The associations between asthma and allergy trajectories and morbidity profiles and lung function at 53 years were investigated with regression models.

Findings: Between Sept 3, 2012, and Nov 8, 2016, of 6128 individuals invited, 3609 (58·9%) individuals were enrolled. We identified five asthma and allergy trajectories: minimal and least asthma and allergies (n= 1767 [49·0%]); late-onset hay fever, no asthma (n=1065 [29·5%]); early-onset remitted asthma and allergies (n=236 [6·5%]); late-onset asthma and allergies (n=317 [8·8%]); and early-onset persistent asthma and allergies (n=224 [6·2%]); and four profiles of extrapulmonary morbidities: minimal or least disease (n=2206 [61·1%]); dominant mental health disorders (n=861 [23·9%]); dominant cardiovascular diseases or risks (n=424 [11·7%]); and multiple disorders (n=117 [3·2%]). The late-onset asthma and allergies trajectory was predominantly associated with the multiple disorders profile (relative risk ratio 3·3 [95% CI 1·9-5·9]), whereas the other asthma and allergy trajectories were associated only with the dominant mental health disorders profile. Both spirometrically defined and clinical COPD were most strongly associated with the early-onset persistent asthma and allergies trajectory (odds ratio [OR] 5·3 [95% CI 3·2-8·6]) and also with the late-onset asthma and allergies trajectory (OR 3·8 [2·4-6·1]).

Interpretation: Distinct longitudinal trajectories of asthma and allergic disease from childhood to 53 years are associated with different profiles of extrapulmonary comorbidities and varying risk of COPD. These findings can inform a personalised approach in clinical guidelines and management focusing on treatable traits. Comorbidity profiles are a new target for early identification and intervention.

Funding: National Health and Medical Research Council of Australia, EU's Horizon 2020, The University of Melbourne, Clifford Craig Medical Research Trust of Tasmania, The Victorian, Queensland & Tasmanian Asthma Foundations, The Royal Hobart Hospital, Helen MacPherson Smith Trust, and GlaxoSmithKline.
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http://dx.doi.org/10.1016/S2213-2600(20)30413-6DOI Listing
April 2021

Novel mammogram-based measures improve breast cancer risk prediction beyond an established mammographic density measure.

Int J Cancer 2021 May 4;148(9):2193-2202. Epub 2020 Dec 4.

Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Parkville, Victoria, Australia.

Mammograms contain information that predicts breast cancer risk. We developed two novel mammogram-based breast cancer risk measures based on image brightness (Cirrocumulus) and texture (Cirrus). Their risk prediction when fitted together, and with an established measure of conventional mammographic density (Cumulus), is not known. We used three studies consisting of: 168 interval cases and 498 matched controls; 422 screen-detected cases and 1197 matched controls; and 354 younger-diagnosis cases and 944 controls frequency-matched for age at mammogram. We conducted conditional and unconditional logistic regression analyses of individually- and frequency-matched studies, respectively. We estimated measure-specific risk gradients as the change in odds per standard deviation of controls after adjusting for age and body mass index (OPERA) and calculated the area under the receiver operating characteristic curve (AUC). For interval, screen-detected and younger-diagnosis cancer risks, the best fitting models (OPERAs [95% confidence intervals]) involved: Cumulus (1.81 [1.41-2.31]) and Cirrus (1.72 [1.38-2.14]); Cirrus (1.49 [1.32-1.67]) and Cirrocumulus (1.16 [1.03 to 1.31]); and Cirrus (1.70 [1.48 to 1.94]) and Cirrocumulus (1.46 [1.27-1.68]), respectively. The AUCs were: 0.73 [0.68-0.77], 0.63 [0.60-0.66], and 0.72 [0.69-0.75], respectively. Combined, our new mammogram-based measures have twice the risk gradient for screen-detected and younger-diagnosis breast cancer (P ≤ 10 ), have at least the same discriminatory power as the current polygenic risk score, and are more correlated with causal factors than conventional mammographic density. Discovering more information about breast cancer risk from mammograms could help enable risk-based personalised breast screening.
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http://dx.doi.org/10.1002/ijc.33396DOI Listing
May 2021

Methylation marks of prenatal exposure to maternal smoking and risk of cancer in adulthood.

Int J Epidemiol 2021 Mar;50(1):105-115

Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.

Background: Prenatal exposure to maternal smoking is detrimental to child health but its association with risk of cancer has seldom been investigated. Maternal smoking induces widespread and long-lasting DNA methylation changes, which we study here for association with risk of cancer in adulthood.

Methods: Eight prospective case-control studies nested within the Melbourne Collaborative Cohort Study were used to assess associations between maternal-smoking-associated methylation marks in blood and risk of several cancers: breast (n = 406 cases), colorectal (n = 814), gastric (n = 166), kidney (n = 139), lung (n = 327), prostate (n = 847) and urothelial (n = 404) cancer and B-cell lymphoma (n = 426). We used conditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between cancer and five methylation scores calculated as weighted averages for 568, 19, 15, 28 and 17 CpG sites. Models were adjusted for confounders, including personal smoking history (smoking status, pack-years, age at starting and quitting) and methylation scores for personal smoking.

Results: All methylation scores for maternal smoking were strongly positively associated with risk of urothelial cancer. Risk estimates were only slightly attenuated after adjustment for smoking history, other potential confounders and methylation scores for personal smoking. Potential negative associations were observed with risk of lung cancer and B-cell lymphoma. No associations were observed for other cancers.

Conclusions: We found that methylation marks of prenatal exposure to maternal smoking are associated with increased risk of urothelial cancer. Our study demonstrates the potential for using DNA methylation to investigate the impact of early-life, unmeasured exposures on later-life cancer risk.
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http://dx.doi.org/10.1093/ije/dyaa210DOI Listing
March 2021

Breast Cancer Chemoprevention: Use and Views of Australian Women and Their Clinicians.

Cancer Prev Res (Phila) 2020 Oct 28. Epub 2020 Oct 28.

Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia.

Guidelines endorse the use of chemoprevention for breast cancer risk reduction. This study examined the barriers and facilitators to chemoprevention use for Australian women at increased risk of breast cancer, and their clinicians. Surveys, based on the Theoretical Domains Framework, were mailed to 1,113 women at ≥16% lifetime risk of breast cancer who were enrolled in the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer cohort study (kConFab), and their 524 treating clinicians. Seven hundred twenty-five women (65%) and 221 (42%) clinicians responded. Only 10 (1.4%) kConFab women had ever taken chemoprevention. Three hundred seventy-eight (52%) kConFab women, two (3%) breast surgeons, and 51 (35%) family physicians were not aware of chemoprevention. For women, the strongest barriers to chemoprevention were side effects (31%) and inadequate information (23%), which operate in the Theoretical Domains Framework domains of "beliefs about consequences" and "knowledge," respectively. Strongest facilitators related to tamoxifen's long-term efficacy (35%, "knowledge," "beliefs about consequences," and "goals" domains), staying healthy for family (13%, "social role" and "goals" domains), and abnormal breast biopsy (13%, "environmental context" domain). The strongest barrier for family physicians was insufficient knowledge (45%, "knowledge" domain) and for breast surgeons was medication side effects (40%, "beliefs about consequences" domain). The strongest facilitators for both clinician groups related to clear guidelines, strong family history, and better tools to select patients ("environmental context and resources" domain). Clinician knowledge and resources, and beliefs about the side-effect consequences of chemoprevention, are key domains that could be targeted to potentially enhance uptake. PREVENTION RELEVANCE: Despite its efficacy in reducing breast cancer incidence, chemoprevention is underutilised. This survey study of Australian women and their clinicians used behavioural change theory to identify modifiable barriers to chemoprevention uptake, and to suggest interventions such as policy change, educational resources and public campaigns, that may increase awareness and use.
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0369DOI Listing
October 2020

Genetic and environmental causes of variation in epigenetic aging across the lifespan.

Clin Epigenetics 2020 10 22;12(1):158. Epub 2020 Oct 22.

Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, 3051, Australia.

Background: DNA methylation-based biological age (DNAm age) is an important biomarker for adult health. Studies in specific age ranges have found widely varying results about its genetic and environmental causes of variation. However, these studies are not able to provide a comprehensive view of the causes of variation over the lifespan.

Results: In order to investigate the genetic and environmental causes of DNAm age variation across the lifespan, we pooled genome-wide DNA methylation data for 4217 people aged 0-92 years from 1871 families. DNAm age was calculated using the Horvath epigenetic clock. We estimated familial correlations in DNAm age for monozygotic (MZ) twin, dizygotic (DZ) twin, sibling, parent-offspring, and spouse pairs by cohabitation status. Genetic and environmental variance components models were fitted and compared. We found that twin pair correlations were - 0.12 to 0.18 around birth, not different from zero (all P > 0.29). For all pairs of relatives, their correlations increased with time spent living together (all P < 0.02) at different rates (MZ > DZ and siblings > parent-offspring; P < 0.001) and decreased with time spent living apart (P = 0.02) at similar rates. These correlation patterns were best explained by cohabitation-dependent shared environmental factors, the effects of which were 1.41 (95% confidence interval [CI] 1.16 to 1.66) times greater for MZ pairs than for DZ and sibling pairs, and the latter were 2.03 (95% CI 1.13 to 9.47) times greater than for parent-offspring pairs. Genetic factors explained 13% (95% CI - 10 to 35%) of variation (P = 0.27). Similar results were found for another two epigenetic clocks, suggesting that our observations are robust to how DNAm age is measured. In addition, results for the other clocks were consistent with there also being a role for prenatal environmental factors in determining their variation.

Conclusions: Variation in DNAm age is mostly caused by environmental factors, including those shared to different extents by relatives while living together and whose effects persist into old age. The equal environment assumption of the classic twin study might not hold for epigenetic aging.
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http://dx.doi.org/10.1186/s13148-020-00950-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583207PMC
October 2020

Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk.

Authors:
Iris Kramer Maartje J Hooning Nasim Mavaddat Michael Hauptmann Renske Keeman Ewout W Steyerberg Daniele Giardiello Antonis C Antoniou Paul D P Pharoah Sander Canisius Zumuruda Abu-Ful Irene L Andrulis Hoda Anton-Culver Kristan J Aronson Annelie Augustinsson Heiko Becher Matthias W Beckmann Sabine Behrens Javier Benitez Marina Bermisheva Natalia V Bogdanova Stig E Bojesen Manjeet K Bolla Bernardo Bonanni Hiltrud Brauch Michael Bremer Sara Y Brucker Barbara Burwinkel Jose E Castelao Tsun L Chan Jenny Chang-Claude Stephen J Chanock Georgia Chenevix-Trench Ji-Yeob Choi Christine L Clarke J Margriet Collée Fergus J Couch Angela Cox Simon S Cross Kamila Czene Mary B Daly Peter Devilee Thilo Dörk Isabel Dos-Santos-Silva Alison M Dunning Miriam Dwek Diana M Eccles D Gareth Evans Peter A Fasching Henrik Flyger Manuela Gago-Dominguez Montserrat García-Closas José A García-Sáenz Graham G Giles David E Goldgar Anna González-Neira Christopher A Haiman Niclas Håkansson Ute Hamann Mikael Hartman Bernadette A M Heemskerk-Gerritsen Antoinette Hollestelle John L Hopper Ming-Feng Hou Anthony Howell Hidemi Ito Milena Jakimovska Anna Jakubowska Wolfgang Janni Esther M John Audrey Jung Daehee Kang C Marleen Kets Elza Khusnutdinova Yon-Dschun Ko Vessela N Kristensen Allison W Kurian Ava Kwong Diether Lambrechts Loic Le Marchand Jingmei Li Annika Lindblom Jan Lubiński Arto Mannermaa Mehdi Manoochehri Sara Margolin Keitaro Matsuo Dimitrios Mavroudis Alfons Meindl Roger L Milne Anna Marie Mulligan Taru A Muranen Susan L Neuhausen Heli Nevanlinna William G Newman Andrew F Olshan Janet E Olson Håkan Olsson Tjoung-Won Park-Simon Julian Peto Christos Petridis Dijana Plaseska-Karanfilska Nadege Presneau Katri Pylkäs Paolo Radice Gad Rennert Atocha Romero Rebecca Roylance Emmanouil Saloustros Elinor J Sawyer Rita K Schmutzler Lukas Schwentner Christopher Scott Mee-Hoong See Mitul Shah Chen-Yang Shen Xiao-Ou Shu Sabine Siesling Susan Slager Christof Sohn Melissa C Southey John J Spinelli Jennifer Stone William J Tapper Maria Tengström Soo Hwang Teo Mary Beth Terry Rob A E M Tollenaar Ian Tomlinson Melissa A Troester Celine M Vachon Chantal van Ongeval Elke M van Veen Robert Winqvist Alicja Wolk Wei Zheng Argyrios Ziogas Douglas F Easton Per Hall Marjanka K Schmidt

Am J Hum Genet 2020 11 5;107(5):837-848. Epub 2020 Oct 5.

The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Division of Molecular Pathology, Amsterdam 1066 CX, the Netherlands; The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Division of Psychosocial Research and Epidemiology, Amsterdam 1066 CX, the Netherlands. Electronic address:

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS was quantified using Cox regression analyses. We assessed PRS interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10 percentile and 20.5% at the 90 percentile of PRS. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.
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http://dx.doi.org/10.1016/j.ajhg.2020.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675034PMC
November 2020

Genetic Variants in the Regulatory T cell-Related Pathway and Colorectal Cancer Prognosis.

Cancer Epidemiol Biomarkers Prev 2020 Dec 2;29(12):2719-2728. Epub 2020 Oct 2.

Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: High numbers of lymphocytes in tumor tissue, including T regulatory cells (Treg), have been associated with better colorectal cancer survival. Tregs, a subset of CD4 T lymphocytes, are mediators of immunosuppression in cancer, and therefore variants in genes related to Treg differentiation and function could be associated with colorectal cancer prognosis.

Methods: In a prospective German cohort of 3,593 colorectal cancer patients, we assessed the association of 771 single-nucleotide polymorphisms (SNP) in 58 Treg-related genes with overall and colorectal cancer-specific survival using Cox regression models. Effect modification by microsatellite instability (MSI) status was also investigated because tumors with MSI show greater lymphocytic infiltration and have been associated with better prognosis. Replication of significant results was attempted in 2,047 colorectal cancer patients of the International Survival Analysis in Colorectal Cancer Consortium (ISACC).

Results: A significant association of the SNP rs7524066 with more favorable colorectal cancer-specific survival [hazard ratio (HR) per minor allele: 0.83; 95% confidence interval (CI), 0.74-0.94; value: 0.0033] was replicated in ISACC (HR: 0.82; 95% CI, 0.68-0.98; value: 0.03). Suggestive evidence for association was found with two SNPs, rs16906568 and rs7845577. Thirteen SNPs with differential associations with overall survival according to MSI in the discovery analysis were not confirmed.

Conclusions: Common genetic variation in the Treg pathway implicating genes such as and was shown to be associated with prognosis of colorectal cancer patients.

Impact: The implicated genes warrant further investigation.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976673PMC
December 2020