GWAS meta-analysis of 16 852 women identifies new susceptibility locus for endometrial cancer

Chen, Maxine M.; O’Mara, Tracy A.; Thompson, Deborah J.; Painter, Jodie N.; Attia, John; Brinton, Louise A.; Chanock, Stephen J.; Chen, Chu; Cheng, Timothy; Cook, Linda S.; Crous‐Bou, Marta; Doherty, Jennifer A.; Friedenreich, Christine M.; Gaudet, Mia M.; Gorman, Maggie; Haiman, Christopher A.; Hankinson, Susan E.; Hartge, Patricia; Henderson, Brian E.; Hodgson, Shirley; Holliday, Elizabeth G.; Horn‐Ross, Pamela L.; Hunter, David J.; Marchand, Loı̈c Le; Liang, Xiaolin; Lissowska, Jolanta; Long, Jirong; Lu, Lingeng; Magliocco, Anthony M.; Martin, Lynn; McEvoy, Mark; Orlow, Irene; Pooler, Loreall; Prescott, Jennifer; Rastogi, Radhai; Rebbeck, Timothy R.; Risch, Harvey A.; Sacerdote, Carlotta; Schumacher, Fredrick; Setiawan, Veronica Wendy; Scott, Rodney J.; Sheng, Xin; Shu, Xiao‐Ou; Turman, Constance; Berg, David Van Den; Wang, Zhaoming; Weiss, Noel S.; Wentzensen, N.; Xia, Lucy; Xiang, Yong‐Bing; Yang, Hannah; Yu, Herbert; Zhang, Wei; Pharoah, Paul D.P.; Dunning, Alison M.; Tomlinson, Ian; Easton, Douglas F.; Kraft, Peter; Spurdle, Amanda B.; Vivo, Immaculata De

doi:10.1093/hmg/ddw092

Cited by 14 publications

(20 citation statements)

References 60 publications

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“…In the largest GWAS meta-analysis assessing endometrial cancer risk, we discovered nine new genetic risk regions. We also confirmed the association of genetic variants with endometrial cancer risk at seven of the eight previously published genetic risk regions for this disease 5 – 8 . Using this larger GWAS-meta dataset, we were also able to confirm the previously published Mendelian randomization studies finding that higher BMI is causal for endometrial cancer risk 20 , and the protective effect of later age of menarche on endometrial cancer risk 19 .…”

Section: Discussionsupporting

confidence: 85%

“…Risk of endometrial cancer is approximately double for women who have a first degree relative with endometrial cancer 2 , 3 . Rare high-risk pathogenic variants in mismatch-repair genes, PTEN , and DNA polymerase genes 4 explain a small proportion of endometrial cancers, and the eight previously published common endometrial cancer-associated single-nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWAS) studies 5 – 8 together explain <5% of the familial relative risk (FRR).…”

Section: Introductionmentioning

confidence: 99%

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Identification of nine new susceptibility loci for endometrial cancer

et al. 2018

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Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Identification of nine new susceptibility loci for endometrial cancer

et al. 2018

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“…Taken together, these reports support the hypothesis that pathogenic germline variants in the exonuclease proofreading domains of POLE (exons [9][10][11][12][13][14] and POLD1 (exons 8-13) that are deleterious to polymerase proofreading function predispose to endometrial cancer. To date, three likely pathogenic POLD1 variants (c.947A4G (p.Asp316Gly); c.1433G4A (p.Ser478Asn); c.1421 T4C (p.Leu474-Pro)) have been identified in nine women with endometrial cancer (proven or obligate carriers) from four families, and two likely pathogenic POLE variants (c.1421 T4C (p.Leu424Val); c.1089C4A (p.Asn363Lys)) in three endometrial cancer patients from two families.…”

Section: Pold1 (And Pole)supporting

confidence: 72%

“…To date, several common single-nucleotide polymorphisms (SNPs) have been shown to be convincingly associated with endometrial cancer risk from largescale candidate locus analysis and genome-wide association analyses. These include 'low-risk' SNPs at/near HNF1B, 8,9 the TERT-CLPTM1L cancer risk region, 10 the CYP19A1 locus encoding the aromatase enzyme pivotal to estrogen biosynthesis, 11 ESR1 encoding the estrogen receptor, 12 SH2B3, 13 SOX4, 14 and also KLF5, AKT1, EIF2AK4, HEY2/NCOA7, and at the MYC multicancer locus. 15 Consistent with findings for most other cancers, the endometrial cancer risks associated with these common variants are considered modest (odds ratios ranging from 0.84 to 1.27).…”

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confidence: 99%

Endometrial cancer gene panels: clinical diagnostic vs research germline DNA testing

et al. 2017

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Endometrial cancer is the most common gynecological cancer, but is nevertheless uncommon enough to have value as a signature cancer for some hereditary cancer syndromes. Commercial multigene testing panels include up to 13 different genes annotated for germline DNA testing of patients with endometrial cancer. Many other genes have been reported as relevant to familial endometrial cancer from directed genome-wide sequencing studies or multigene panel testing, or research. This review assesses the evidence supporting association with endometrial cancer risk for 32 genes implicated in hereditary endometrial cancer, and presents a summary of rare germline variants in these 32 genes detected by analysis of quasi-population-based endometrial cancer patients from The Cancer Genome Atlas project. This comprehensive investigation has led to the conclusion that convincing evidence currently exists to support clinical testing of only six of these genes for diagnosis of hereditary endometrial cancer. Testing of endometrial cancer patients for the remaining genes should be considered in the context of research studies, as a means to better establish the level of endometrial cancer risk, if any, associated with genetic variants that are deleterious to gene or protein function. It is acknowledged that clinical testing of endometrial cancer patients for several genes included on commercial panels may provide actionable findings in relation to risk of other cancers, but these should be considered secondary or incidental findings and not conclusive evidence for diagnosis of inherited endometrial cancer. In summary, this review and analysis provides a comprehensive report of current evidence to guide the selection of genes for clinical and research gene testing of germline DNA from endometrial cancer patients.

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“…Three SNPs have been identified in or around KLF5 that are associated with endometrial cancer. The G allele of rs11841589 (OR 1.15, 95% CI 1.11 to 1.21; p=4.83×10 -11 ), the A allele of rs9600103 (OR 1.23, 95% CI 1.16 to 1.30; p=3.76×10 -12 ) and C allele of rs7981863 (OR 1.16, 95% CI 1.12 to 1.20; p=2.70×10 -17 ) have all been found to be associated with an increased likelihood of endometrial cancer in large European cohorts 21 30 34. It is worth noting that these SNPs are not independent, and hence they quite possibly tag the same causal variant.…”

Section: Resultsmentioning

confidence: 99%

Association between genetic polymorphisms and endometrial cancer risk: a systematic review

et al. 2020

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IntroductionEndometrial cancer is one of the most commonly diagnosed cancers in women. Although there is a hereditary component to endometrial cancer, most cases are thought to be sporadic and lifestyle related. The aim of this study was to systematically review prospective and retrospective case–control studies, meta-analyses and genome-wide association studies to identify genomic variants that may be associated with endometrial cancer risk.MethodsWe searched MEDLINE, Embase and CINAHL from 2007 to 2019 without restrictions. We followed PRISMA 2009 guidelines. The search yielded 3015 hits in total. Following duplicate exclusion, 2674 abstracts were screened and 453 full-texts evaluated based on our pre-defined screening criteria. 149 articles were eligible for inclusion.ResultsWe found that single nucleotide polymorphisms (SNPs) in HNF1B, KLF, EIF2AK, CYP19A1, SOX4 and MYC were strongly associated with incident endometrial cancer. Nineteen variants were reported with genome-wide significance and a further five with suggestive significance. No convincing evidence was found for the widely studied MDM2 variant rs2279744. Publication bias and false discovery rates were noted throughout the literature.ConclusionEndometrial cancer risk may be influenced by SNPs in genes involved in cell survival, oestrogen metabolism and transcriptional control. Larger cohorts are needed to identify more variants with genome-wide significance.

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GWAS meta-analysis of 16 852 women identifies new susceptibility locus for endometrial cancer

Cited by 14 publications

References 60 publications

Identification of nine new susceptibility loci for endometrial cancer

Identification of nine new susceptibility loci for endometrial cancer

Endometrial cancer gene panels: clinical diagnostic vs research germline DNA testing

Association between genetic polymorphisms and endometrial cancer risk: a systematic review

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