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Shared genetics underlying epidemiological association between endometriosis and ovarian cancer.

ABSTRACT: 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.

SUBMITTER: Lu Y

PROVIDER: S-EPMC4581608 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Shared genetics underlying epidemiological association between endometriosis and ovarian cancer.

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

Human molecular genetics 20150730 20

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 Infiniu ...[more]

PMID: 26231222

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Project description:AimEndometriosis is one of the most common reproductive system diseases, but the mechanisms of disease progression are still unclear. Due to its high recurrence rate, searching for potential therapeutic biomarkers involved in the pathogenesis of endometriosis is an urgent issue.MethodsDue to the similarities between endometriosis and ovarian cancer, four endometriosis datasets and one ovarian cancer dataset were downloaded from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified, followed by gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and protein-protein interaction (PPI) analyses. Then, we validated gene expression and performed survival analysis with ovarian serous cystadenocarcinoma (OV) datasets in TCGA/GTEx database, and searched for potential drugs in the Drug-Gene Interaction Database. Finally, we explored the miRNAs of key genes to find biomarkers associated with the recurrence of endometriosis.ResultsIn total, 104 DEGs were identified in the endometriosis datasets, and the main enriched GO functions included cell adhesion, extracellular exosome and actin binding. Fifty DEGs were identified between endometriosis and ovarian cancer datasets including 11 consistently regulated genes, and nine DEGs with significant expression in TCGA/GTEx. Only IGHM had both significant expression and an association with survival, three module DEGs and two significantly expressed DEGs had drug associations, and 10 DEGs had druggability.ConclusionsITGA7, ITGBL1 and SORBS1 may help us understand the invasive nature of endometriosis, and IGHM might be related to recurrence; moreover, these genes all may be potential therapeutic targets.KEY MESSAGEThis manuscript used a bioinformatics approach to find target genes for the treatment of endometriosis.This manuscript used a new approach to find target genes by drawing on common characteristics between ovarian cancer and endometriosis.We screened relevant therapeutic agents for target genes in the drug database, and performed histological validation of target genes with both expression and survival analysis difference in cancer databases.

Project description:BackgroundEndometriosis is a risk factor for epithelial ovarian cancer; however, whether this risk extends to all invasive histological subtypes or borderline tumours is not clear. We undertook an international collaborative study to assess the association between endometriosis and histological subtypes of ovarian cancer.MethodsData from 13 ovarian cancer case-control studies, which were part of the Ovarian Cancer Association Consortium, were pooled and logistic regression analyses were undertaken to assess the association between self-reported endometriosis and risk of ovarian cancer. Analyses of invasive cases were done with respect to histological subtypes, grade, and stage, and analyses of borderline tumours by histological subtype. Age, ethnic origin, study site, parity, and duration of oral contraceptive use were included in all analytical models.Findings13 226 controls and 7911 women with invasive ovarian cancer were included in this analysis. 818 and 738, respectively, reported a history of endometriosis. 1907 women with borderline ovarian cancer were also included in the analysis, and 168 of these reported a history of endometriosis. Self-reported endometriosis was associated with a significantly increased risk of clear-cell (136 [20·2%] of 674 cases vs 818 [6·2%] of 13 226 controls, odds ratio 3·05, 95% CI 2·43-3·84, p<0·0001), low-grade serous (31 [9·2%] of 336 cases, 2·11, 1·39-3·20, p<0·0001), and endometrioid invasive ovarian cancers (169 [13·9%] of 1220 cases, 2·04, 1·67-2·48, p<0·0001). No association was noted between endometriosis and risk of mucinous (31 [6·0%] of 516 cases, 1·02, 0·69-1·50, p=0·93) or high-grade serous invasive ovarian cancer (261 [7·1%] of 3659 cases, 1·13, 0·97-1·32, p=0·13), or borderline tumours of either subtype (serous 103 [9·0%] of 1140 cases, 1·20, 0·95-1·52, p=0·12, and mucinous 65 [8·5%] of 767 cases, 1·12, 0·84-1·48, p=0·45).InterpretationClinicians should be aware of the increased risk of specific subtypes of ovarian cancer in women with endometriosis. Future efforts should focus on understanding the mechanisms that might lead to malignant transformation of endometriosis so as to help identify subsets of women at increased risk of ovarian cancer.FundingOvarian Cancer Research Fund, National Institutes of Health, California Cancer Research Program, California Department of Health Services, Lon V Smith Foundation, European Community's Seventh Framework Programme, German Federal Ministry of Education and Research of Germany, Programme of Clinical Biomedical Research, German Cancer Research Centre, Eve Appeal, Oak Foundation, UK National Institute of Health Research, National Health and Medical Research Council of Australia, US Army Medical Research and Materiel Command, Cancer Council Tasmania, Cancer Foundation of Western Australia, Mermaid 1, Danish Cancer Society, and Roswell Park Alliance Foundation.

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Shared genetics underlying epidemiological association between endometriosis and ovarian cancer.

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Shared genetics underlying epidemiological association between endometriosis and ovarian cancer.

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