Publications by authors named "Katharina Bischof"

8 Publications

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Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers.

Authors:
Dylan M Glubb Deborah J Thompson Katja K H Aben Ahmad Alsulimani Frederic Amant Daniela Annibali John Attia Aurelio Barricarte Matthias W Beckmann Andrew Berchuck Marina Bermisheva Marcus Q Bernardini Katharina Bischof Line Bjorge Clara Bodelon Alison H Brand James D Brenton Louise A Brinton Fiona Bruinsma Daniel D Buchanan Stefanie Burghaus Ralf Butzow Hui Cai Michael E Carney Stephen J Chanock Chu Chen Xiao Qing Chen Zhihua Chen Linda S Cook Julie M Cunningham Immaculata De Vivo Anna deFazio Jennifer A Doherty Thilo Dörk Andreas du Bois Alison M Dunning Matthias Dürst Todd Edwards Robert P Edwards Arif B Ekici Ailith Ewing Peter A Fasching Sarah Ferguson James M Flanagan Florentia Fostira George Fountzilas Christine M Friedenreich Bo Gao Mia M Gaudet Jan Gawełko Aleksandra Gentry-Maharaj Graham G Giles Rosalind Glasspool Marc T Goodman Jacek Gronwald Holly R Harris Philipp Harter Alexander Hein Florian Heitz Michelle A T Hildebrandt Peter Hillemanns Estrid Høgdall Claus K Høgdall Elizabeth G Holliday David G Huntsman Tomasz Huzarski Anna Jakubowska Allan Jensen Michael E Jones Beth Y Karlan Anthony Karnezis Joseph L Kelley Elza Khusnutdinova Jeffrey L Killeen Susanne K Kjaer Rüdiger Klapdor Martin Köbel Bozena Konopka Irene Konstantopoulou Reidun K Kopperud Madhuri Koti Peter Kraft Jolanta Kupryjanczyk Diether Lambrechts Melissa C Larson Loic Le Marchand Shashikant Lele Jenny Lester Andrew J Li Dong Liang Clemens Liebrich Loren Lipworth Jolanta Lissowska Lingeng Lu Karen H Lu Alessandra Macciotta Amalia Mattiello Taymaa May Jessica N McAlpine Valerie McGuire Iain A McNeish Usha Menon Francesmary Modugno Kirsten B Moysich Heli Nevanlinna Kunle Odunsi Håkan Olsson Sandra Orsulic Ana Osorio Domenico Palli Tjoung-Won Park-Simon Celeste L Pearce Tanja Pejovic Jennifer B Permuth Agnieszka Podgorska Susan J Ramus Timothy R Rebbeck Marjorie J Riggan Harvey A Risch Joseph H Rothstein Ingo B Runnebaum Rodney J Scott Thomas A Sellers Janine Senz Veronica Wendy Setiawan Nadeem Siddiqui Weiva Sieh Beata Spiewankiewicz Rebecca Sutphen Anthony J Swerdlow Lukasz Michael Szafron Soo Hwang Teo Pamela J Thompson Liv Cecilie Vestrheim Thomsen Linda Titus Alicia Tone Rosario Tumino Constance Turman Adriaan Vanderstichele Digna Velez Edwards Ignace Vergote Robert A Vierkant Zhaoming Wang Shan Wang-Gohrke Penelope M Webb Emily White Alice S Whittemore Stacey J Winham Xifeng Wu Anna H Wu Drakoulis Yannoukakos Amanda B Spurdle Tracy A O'Mara

Cancer Epidemiol Biomarkers Prev 2021 Jan 3;30(1):217-228. Epub 2020 Nov 3.

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

Background: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers.

Methods: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data.

Results: Genetic correlation analysis revealed significant genetic correlation between the two cancers ( = 0.43, = 2.66 × 10). We found seven loci associated with risk for both cancers ( < 2.4 × 10). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified ( < 5 × 10). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation.

Conclusions: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis.

Impact: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0739DOI Listing
January 2021

CD24-targeted fluorescence imaging in patient-derived xenograft models of high-grade serous ovarian carcinoma.

EBioMedicine 2020 Jun 23;56:102782. Epub 2020 May 23.

Centre for Cancer Biomarkers, CCBIO, Department of Clinical Science, University of Bergen, Jonas Lies vei 91B, 5021 Bergen, Norway. Electronic address:

Background: The survival rate of patients with advanced high-grade serous ovarian carcinoma (HGSOC) remains disappointing. Clinically translatable orthotopic cell line xenograft models and patient-derived xenografts (PDXs) may aid the implementation of more personalised treatment approaches. Although orthotopic PDX reflecting heterogeneous molecular subtypes are considered the most relevant preclinical models, their use in therapeutic development is limited by lack of appropriate imaging modalities.

Methods: We developed novel orthotopic xenograft and PDX models for HGSOC, and applied a near-infrared fluorescently labelled monoclonal antibody targeting the cell surface antigen CD24 for non-invasive molecular imaging of epithelial ovarian cancer. CD24-Alexa Fluor 680 fluorescence imaging was compared to bioluminescence imaging in three orthotopic cell line xenograft models of ovarian cancer (OV-90, Skov-3 and Caov-3, n = 3 per model). The application of fluorescence imaging to assess treatment efficacy was performed in carboplatin-paclitaxel treated orthotopic OV-90 xenografts (n = 10), before the probe was evaluated to detect disease progression in heterogenous PDX models (n = 7).

Findings: Application of the near-infrared probe, CD24-AF680, enabled both spatio-temporal visualisation of tumour development, and longitudinal therapy monitoring of orthotopic xenografts. Notably, CD24-AF680 facilitated imaging of multiple PDX models representing different histological subtypes of the disease.

Interpretation: The combined implementation of CD24-AF680 and orthotopic PDX models creates a state-of-the-art preclinical platform which will impact the identification and validation of new targeted therapies, fluorescence image-guided surgery, and ultimately the outcome for HGSOC patients.

Funding: This study was supported by the H2020 program MSCA-ITN [675743], Helse Vest RHF, and Helse Bergen HF [911809, 911852, 912171, 240222, HV1269], as well as by The Norwegian Cancer Society [182735], and The Research Council of Norway through its Centers of excellence funding scheme [223250, 262652].
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http://dx.doi.org/10.1016/j.ebiom.2020.102782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248428PMC
June 2020

Influence of p53 Isoform Expression on Survival in High-Grade Serous Ovarian Cancers.

Sci Rep 2019 03 27;9(1):5244. Epub 2019 Mar 27.

Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, 5020, Bergen, Norway.

High-grade serous ovarian carcinoma (HGSOC) is characterised by alterations in the p53 pathway. The expression levels of p53 isoforms have been shown to be associated with patient survival in several cancers. This study examined the predictive and prognostic effects of the expression levels of TP53 pre-mRNA splicing isoforms and TP53 mutations in tumour tissues in 40 chemotherapy responders and 29 non-responders with HGSOC. The mRNA expression levels from total p53, and total Δ133p53, p53β, p53γ isoforms were determined by RT-qPCR, and TP53 mutation status by targeted massive parallel sequencing. The results from these analyses were correlated with the clinical outcome parameters. No differential expression of p53 isoforms could be detected between the chemosensitive and chemoresistant subgroups. In a multivariate Cox regression model, high levels of total Δ133p53 were found to be an independent prognosticator for improved overall survival (HR = 0.422, p = 0.018, 95% CI: 0.207-0.861) and reached borderline significance for progression-free survival (HR = 0.569, p = 0.061, 95% CI: 0.315-1.027). TP53 mutations resulting in loss of function or located at known hotspots were predictive of tumour characteristics and disease progression. These findings suggest that total Δ133p53 mRNA can be a biomarker for survival in HGSOC.
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http://dx.doi.org/10.1038/s41598-019-41706-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437169PMC
March 2019

High expression of the p53 isoform γ is associated with reduced progression-free survival in uterine serous carcinoma.

BMC Cancer 2018 Jun 25;18(1):684. Epub 2018 Jun 25.

Centre for Cancer Biomarkers (CCBIO), Department of Clinical Science, Precision Oncology Research Group, University of Bergen, Bergen, Norway.

Background: Uterine serous carcinoma (USC) is a rare but aggressive subtype of endometrial carcinoma. Large-scale comprehensive efforts have resulted in an improved molecular understanding of its pathogenesis, and the p53 pathway has been proposed as a key player and is potentially targetable. Here we attempt to further portray the p53 pathway in USC by assessing p53 isoform expression.

Methods: We applied quantitative Real-Time PCRs (RT-qPCR) for expression analyses of total p53 mRNA as well as quantitative distinction of p53β, p53γ, and the total mRNA of amino-terminal truncated Δ40p53 and Δ133p53 in a retrospective cohort of 37 patients with USC. TP53 mutation status was assessed by targeted massive parallel sequencing. Findings were correlated with clinical data.

Results: The p53 isoform expression landscape in USCs was heterogeneous and dominated by total Δ133p53, while the distinct p53β and p53γ variants were found at much lower levels. The isoform expression profiles varied between samples, while their expression was independent of TP53 mutation status. We found high relative p53γ expression to be associated with reduced progression-free survival (PFS).

Conclusions: This is the first indication that elevated p53γ expression is associated with reduced PFS in USC. This single-center study may offer some insight in the landscape of p53 isoform expression in USC, but further validation studies are crucial to understand the context-dependent and tissue-specific role of the p53 isoform network in gynecological cancer.
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http://dx.doi.org/10.1186/s12885-018-4591-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019524PMC
June 2018

Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study.

Authors:
Jue-Sheng Ong Gabriel Cuellar-Partida Yi Lu Peter A Fasching Alexander Hein Stefanie Burghaus Matthias W Beckmann Diether Lambrechts Els Van Nieuwenhuysen Ignace Vergote Adriaan Vanderstichele Jennifer Anne Doherty Mary Anne Rossing Jenny Chang-Claude Ursula Eilber Anja Rudolph Shan Wang-Gohrke Marc T Goodman Natalia Bogdanova Thilo Dörk Matthias Dürst Peter Hillemanns Ingo B Runnebaum Natalia Antonenkova Ralf Butzow Arto Leminen Heli Nevanlinna Liisa M Pelttari Robert P Edwards Joseph L Kelley Francesmary Modugno Kirsten B Moysich Roberta B Ness Rikki Cannioto Estrid Høgdall Claus K Høgdall Allan Jensen Graham G Giles Fiona Bruinsma Susanne K Kjaer Michelle At Hildebrandt Dong Liang Karen H Lu Xifeng Wu Maria Bisogna Fanny Dao Douglas A Levine Daniel W Cramer Kathryn L Terry Shelley S Tworoger Meir Stampfer Stacey Missmer Line Bjorge Helga B Salvesen Reidun K Kopperud Katharina Bischof Katja Kh Aben Lambertus A Kiemeney Leon Fag Massuger Angela Brooks-Wilson Sara H Olson Valerie McGuire Joseph H Rothstein Weiva Sieh Alice S Whittemore Linda S Cook Nhu D Le C Blake Gilks Jacek Gronwald Anna Jakubowska Jan Lubiński Tomasz Kluz Honglin Song Jonathan P Tyrer Nicolas Wentzensen Louise Brinton Britton Trabert Jolanta Lissowska John R McLaughlin Steven A Narod Catherine Phelan Hoda Anton-Culver Argyrios Ziogas Diana Eccles Ian Campbell Simon A Gayther Aleksandra Gentry-Maharaj Usha Menon Susan J Ramus Anna H Wu Agnieszka Dansonka-Mieszkowska Jolanta Kupryjanczyk Agnieszka Timorek Lukasz Szafron Julie M Cunningham Brooke L Fridley Stacey J Winham Elisa V Bandera Elizabeth M Poole Terry K Morgan Harvey A Risch Ellen L Goode Joellen M Schildkraut Celeste L Pearce Andrew Berchuck Paul Dp Pharoah Georgia Chenevix-Trench Puya Gharahkhani Rachel E Neale Penelope M Webb Stuart MacGregor

Int J Epidemiol 2016 10 4;45(5):1619-1630. Epub 2016 Sep 4.

Statistical Genetics laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia,

Background: In vitro and observational epidemiological studies suggest that vitamin D may play a role in cancer prevention. However, the relationship between vitamin D and ovarian cancer is uncertain, with observational studies generating conflicting findings. A potential limitation of observational studies is inadequate control of confounding. To overcome this problem, we used Mendelian randomization (MR) to evaluate the association between single nucleotide polymorphisms (SNPs) associated with circulating 25-hydroxyvitamin D [25(OH)D] concentration and risk of ovarian cancer.

Methods: We employed SNPs with well-established associations with 25(OH)D concentration as instrumental variables for MR: rs7944926 (DHCR7), rs12794714 (CYP2R1) and rs2282679 (GC). We included 31 719 women of European ancestry (10 065 cases, 21 654 controls) from the Ovarian Cancer Association Consortium, who were genotyped using customized Illumina Infinium iSelect (iCOGS) arrays. A two-sample (summary data) MR approach was used and analyses were performed separately for all ovarian cancer (10 065 cases) and for high-grade serous ovarian cancer (4121 cases).

Results: The odds ratio for epithelial ovarian cancer risk (10 065 cases) estimated by combining the individual SNP associations using inverse variance weighting was 1.27 (95% confidence interval: 1.06 to 1.51) per 20 nmol/L decrease in 25(OH)D concentration. The estimated odds ratio for high-grade serous epithelial ovarian cancer (4121 cases) was 1.54 (1.19, 2.01).

Conclusions: Genetically lowered 25-hydroxyvitamin D concentrations were associated with higher ovarian cancer susceptibility in Europeans. These findings suggest that increasing plasma vitamin D levels may reduce risk of ovarian cancer.
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http://dx.doi.org/10.1093/ije/dyw207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100621PMC
October 2016

The HDACi Panobinostat Shows Growth Inhibition Both In Vitro and in a Bioluminescent Orthotopic Surgical Xenograft Model of Ovarian Cancer.

PLoS One 2016 28;11(6):e0158208. Epub 2016 Jun 28.

Department of Obstetrics and Gynecology, Haukeland University Hospital, Jonas Liesvei 72, 5058 Bergen, Norway.

Background: In most epithelial ovarian carcinomas (EOC), epigenetic changes are evident, and overexpression of histone deacetylases (HDACs) represents an important manifestation. In this study, we wanted to evaluate the effects of the novel HDAC inhibitor (HDACi) panobinostat, both alone and in combination with carboplatin, on ovarian cancer cell lines and in a murine bioluminescent orthotopic surgical xenograft model for EOC.

Methods: The effects of panobinostat, both alone and in combination with carboplatin, on proliferation and apoptosis in ovarian cancer cell lines, were evaluated using colony and WST-1 assays, Hoechst staining and flow cytometry analysis. In addition, mechanisms were characterised by western blotting and phosphoflow analysis. Immuno-deficient mice were engrafted orthotopically with SKOV-3luc+ cells and serial bioluminescence imaging monitored the effects of treatment with panobinostat and/or carboplatin and/or surgery. Survival parameters were also measured.

Results: Panobinostat treatment reduced cell growth and diminished cell viability, as shown by the induced cell cycle arrest and apoptosis in vitro. We observed increased levels of cleaved PARP and caspase-3, downregulation of cdc2 protein kinase, acetylation of H2B and higher pH2AX expression. The combined administration of carboplatin and panobinostat synergistically increased the anti-tumour effects compared to panobinostat or carboplatin treatment alone. In our novel ovarian cancer model, the mice showed significantly higher rates of survival when treated with panobinostat, carboplatin or a combination of both, compared to the controls. Panobinostat was as efficient as carboplatin regarding prolongation of survival. No significant additional effect on survival was observed when surgery was combined with carboplatin/panobinostat treatment.

Conclusions: Panobinostat demonstrates effective in vitro growth inhibition in ovarian cancer cells. The efficacy of panobinostat and carboplatin was equal in the orthotopic EOC model used. We conclude that panobinostat is a promising therapeutic alternative that needs to be further assessed for the treatment of EOC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158208PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4924861PMC
July 2017

Assessing the genetic architecture of epithelial ovarian cancer histological subtypes.

Authors:
Gabriel Cuellar-Partida Yi Lu Suzanne C Dixon Peter A Fasching Alexander Hein Stefanie Burghaus Matthias W Beckmann Diether Lambrechts Els Van Nieuwenhuysen Ignace Vergote Adriaan Vanderstichele Jennifer Anne Doherty Mary Anne Rossing Jenny Chang-Claude Anja Rudolph Shan Wang-Gohrke Marc T Goodman Natalia Bogdanova Thilo Dörk Matthias Dürst Peter Hillemanns Ingo B Runnebaum Natalia Antonenkova Ralf Butzow Arto Leminen Heli Nevanlinna Liisa M Pelttari Robert P Edwards Joseph L Kelley Francesmary Modugno Kirsten B Moysich Roberta B Ness Rikki Cannioto Estrid Høgdall Claus Høgdall Allan Jensen Graham G Giles Fiona Bruinsma Susanne K Kjaer Michelle A T Hildebrandt Dong Liang Karen H Lu Xifeng Wu Maria Bisogna Fanny Dao Douglas A Levine Daniel W Cramer Kathryn L Terry Shelley S Tworoger Meir Stampfer Stacey Missmer Line Bjorge Helga B Salvesen Reidun K Kopperud Katharina Bischof Katja K H Aben Lambertus A Kiemeney Leon F A G Massuger Angela Brooks-Wilson Sara H Olson Valerie McGuire Joseph H Rothstein Weiva Sieh Alice S Whittemore Linda S Cook Nhu D Le C Blake Gilks Jacek Gronwald Anna Jakubowska Jan Lubiński Tomasz Kluz Honglin Song Jonathan P Tyrer Nicolas Wentzensen Louise Brinton Britton Trabert Jolanta Lissowska John R McLaughlin Steven A Narod Catherine Phelan Hoda Anton-Culver Argyrios Ziogas Diana Eccles Ian Campbell Simon A Gayther Aleksandra Gentry-Maharaj Usha Menon Susan J Ramus Anna H Wu Agnieszka Dansonka-Mieszkowska Jolanta Kupryjanczyk Agnieszka Timorek Lukasz Szafron Julie M Cunningham Brooke L Fridley Stacey J Winham Elisa V Bandera Elizabeth M Poole Terry K Morgan Ellen L Goode Joellen M Schildkraut Celeste L Pearce Andrew Berchuck Paul D P Pharoah Penelope M Webb Georgia Chenevix-Trench Harvey A Risch Stuart MacGregor

Hum Genet 2016 07 13;135(7):741-56. Epub 2016 Apr 13.

Statistical Genetics, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD, 4006, Australia.

Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease ([Formula: see text] = 8.8 ± 1.1 %), endometrioid ([Formula: see text] = 3.2 ± 1.6 %), clear cell ([Formula: see text] = 6.7 ± 3.3 %) and all EOC ([Formula: see text] = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.
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http://dx.doi.org/10.1007/s00439-016-1663-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976079PMC
July 2016

Shared genetics underlying epidemiological association between endometriosis and ovarian cancer.

Authors:
Yi Lu Gabriel Cuellar-Partida Jodie N Painter Dale R Nyholt Andrew P Morris Peter A Fasching Alexander Hein Stefanie Burghaus Matthias W Beckmann Diether Lambrechts Els Van Nieuwenhuysen Ignace Vergote Adriaan Vanderstichele Jennifer Anne Doherty Mary Anne Rossing Kristine G Wicklund Jenny Chang-Claude Ursula Eilber Anja Rudolph Shan Wang-Gohrke Marc T Goodman Natalia Bogdanova Thilo Dörk Matthias Dürst Peter Hillemanns Ingo B Runnebaum Natalia Antonenkova Ralf Butzow Arto Leminen Heli Nevanlinna Liisa M Pelttari Robert P Edwards Joseph L Kelley Francesmary Modugno Kirsten B Moysich Roberta B Ness Rikki Cannioto Estrid Høgdall Allan Jensen Graham G Giles Fiona Bruinsma Susanne K Kjaer Michelle A T Hildebrandt Dong Liang Karen H Lu Xifeng Wu Maria Bisogna Fanny Dao Douglas A Levine Daniel W Cramer Kathryn L Terry Shelley S Tworoger Stacey Missmer Line Bjorge Helga B Salvesen Reidun K Kopperud Katharina Bischof Katja K H Aben Lambertus A Kiemeney Leon F A G Massuger Angela Brooks-Wilson Sara H Olson Valerie McGuire Joseph H Rothstein Weiva Sieh Alice S Whittemore Linda S Cook Nhu D Le C Blake Gilks Jacek Gronwald Anna Jakubowska Jan Lubiński Jan Gawełko Honglin Song Jonathan P Tyrer Nicolas Wentzensen Louise Brinton Britton Trabert Jolanta Lissowska John R Mclaughlin Steven A Narod Catherine Phelan Hoda Anton-Culver Argyrios Ziogas Diana Eccles Simon A Gayther Aleksandra Gentry-Maharaj Usha Menon Susan J Ramus Anna H Wu Agnieszka Dansonka-Mieszkowska Jolanta Kupryjanczyk Agnieszka Timorek Lukasz Szafron Julie M Cunningham Brooke L Fridley Stacey J Winham Elisa V Bandera Elizabeth M Poole Terry K Morgan Harvey A Risch Ellen L Goode Joellen M Schildkraut Penelope M Webb Celeste L Pearce Andrew Berchuck Paul D P Pharoah Grant W Montgomery Krina T Zondervan Georgia Chenevix-Trench Stuart MacGregor

Hum Mol Genet 2015 Oct 30;24(20):5955-64. Epub 2015 Jul 30.

Statistical Genetics,

Epidemiological studies have demonstrated associations between endometriosis and certain histotypes of ovarian cancer, including clear cell, low-grade serous and endometrioid carcinomas. We aimed to determine whether the observed associations might be due to shared genetic aetiology. To address this, we used two endometriosis datasets genotyped on common arrays with full-genome coverage (3194 cases and 7060 controls) and a large ovarian cancer dataset genotyped on the customized Illumina Infinium iSelect (iCOGS) arrays (10 065 cases and 21 663 controls). Previous work has suggested that a large number of genetic variants contribute to endometriosis and ovarian cancer (all histotypes combined) susceptibility. Here, using the iCOGS data, we confirmed polygenic architecture for most histotypes of ovarian cancer. This led us to evaluate if the polygenic effects are shared across diseases. We found evidence for shared genetic risks between endometriosis and all histotypes of ovarian cancer, except for the intestinal mucinous type. Clear cell carcinoma showed the strongest genetic correlation with endometriosis (0.51, 95% CI = 0.18-0.84). Endometrioid and low-grade serous carcinomas had similar correlation coefficients (0.48, 95% CI = 0.07-0.89 and 0.40, 95% CI = 0.05-0.75, respectively). High-grade serous carcinoma, which often arises from the fallopian tubes, showed a weaker genetic correlation with endometriosis (0.25, 95% CI = 0.11-0.39), despite the absence of a known epidemiological association. These results suggest that the epidemiological association between endometriosis and ovarian adenocarcinoma may be attributable to shared genetic susceptibility loci.
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http://dx.doi.org/10.1093/hmg/ddv306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4581608PMC
October 2015