Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer

O’Mara, Tracy A.; Glubb, Dylan M.; Painter, Jodie N.; Cheng, Timothy; Dennis, Joe; Attia, John; Holliday, Elizabeth G.; McEvoy, Mark; Scott, Rodney J.; Ashton, Katie A.; Proietto, Tony; Otton, Geoffrey; Shah, Mitul; Ahmed, Shahana; Healey, Catherine S.; Gorman, Maggie; Martin, Lynn; Hodgson, Shirley; Fasching, Peter A.; Hein, Alexander; Beckmann, Matthias W.; Ekici, Arif B.; Hall, Per; Czene, Kamila; Darabi, Hatef; Li, Jingmei; Dürst, Matthias; Runnebaum, Ingo B.; Hillemanns, Peter; Dörk, Thilo; Lambrechts, Diether; Depreeuw, Jeroen; Annibali, Daniela; Amant, Frédéric; Zhao, Hui; Goode, Ellen L.; Dowdy, Sean C.; Fridley, Brooke L.; Winham, Stacey J.; Salvesen, Helga B.; Njølstad, Tormund S.; Trovik, Jone; Werner, Henrica M.J.; Tham, Emma; Liu, Tao; Mints, Miriam; Rendocas,; Bolla, Manjeet K.; Michailidou, Kyriaki; Tyrer, Jonathan P.; Wang, Qin; Hopper, John L.; Peto, Julian; Swerdlow, Anthony; Burwinkel, Barbara; Brenner, Hermann; Meindl, Alfons; Brauch, Hiltrud; Lindblom, Annika; Chang‐Claude, Jenny; Couch, Fergus J.; Giles, Graham G.; Kristensen, Vessela N.; Cox, Angela; Pharoah, Paul D.P.; Dunning, Alison M.; Tomlinson, Ian; Easton, Douglas F.; Thompson, Deborah J.; Spurdle, Amanda B.

doi:10.1530/erc-15-0319

Cited by 24 publications

(17 citation statements)

References 54 publications

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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%

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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Section: Pold1 (And Pole)supporting

confidence: 72%

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

et al. 2017

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“…Finally, there are similarities in tumor phenotype and/or shared tissue of origin between endometrial cancer, the benign gynaecological condition endometriosis, the endometrioid and clear cell histologies of ovarian cancer, and basal-like breast cancer(25–27). Thus, pooling ovarian and endometrial(23, 28, 29) cases could uncover novel loci.…”

Section: Methodsmentioning

confidence: 99%

The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers

Amos

Dennis

Wang

et al. 2017

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background Common cancers develop through a multistep process often including inherited susceptibility. Collaboration among multiple institutions, and funding from multiple sources, has allowed the development of an inexpensive genotyping microarray, the OncoArray. The array includes a genome-wide backbone, comprising 230,000 SNPs tagging most common genetic variants, together with dense mapping of known susceptibility regions, rare variants from sequencing experiments, pharmacogenetic markers and cancer related traits. Methods The OncoArray can be genotyped using a novel technology developed by Illumina to facilitate efficient genotyping. The consortium developed standard approaches for selecting SNPs for study, for quality control of markers and for ancestry analysis. The array was genotyped at selected sites and with prespecified replicate samples to permit evaluation of genotyping accuracy among centers and by ethnic background. Results The OncoArray consortium genotyped 447,705 samples. A total of 494,763 SNPs passed quality control steps with a sample success rate of 97% of the samples. Participating sites performed ancestry analysis using a common set of markers and a scoring algorithm based on principal components analysis. Conclusions Results from these analyses will enable researchers to identify new susceptibility loci, perform fine mapping of new or known loci associated with either single or multiple cancers, assess the degree of overlap in cancer causation and pleiotropic effects of loci that have been identified for disease-specific risk, and jointly model genetic, environmental and lifestyle related exposures. Impact Ongoing analyses will shed light on etiology and risk assessment for many types of cancer.

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“…[4][5][6] Exposure to endogenous estrogens (associated with obesity) is an important contributing factor. 7,8 The role that estrogens play in the development of EC is further highlighted by the fact that germline variants in the estrogen receptor (ESR1) are associated with risk for EC (most strongly with the endometrioid subtype) 9 and that somatic ESR1 mutations are seen in primary EC. 10,11 FOXA2 is a member of the FOXA subfamily of forkhead box proteins that includes FOXA1, FOXA2 and FOXA3.…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of recurrent FOXA2 mutations seen in endometrial cancers

Neff

Rush

Smith

et al. 2018

Intl Journal of Cancer

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FOXA2, a member of the forkhead family of DNA-binding proteins, is frequently mutated in uterine cancers. Most of the mutations observed in uterine cancers are frameshifts and stops. FOXA2 is considered to be a driver gene in uterine cancers, functioning as a haploinsufficient tumor suppressor. The functional consequences of FOXA2 mutations, however, have not yet been determined. We evaluated the effects that frameshift mutations and a recurrent missense mutation have on FOXA2 transcriptional activity. Recurrent N-terminal frameshifts resulted in truncated proteins that failed to translocate to the nucleus and have no transcriptional activity using an E-cadherin/luciferase reporter assay. Protein abundance was reduced for the recurrent p.S169 W mutation, as was transcriptional activity. A C-terminal frameshift mutation had increased FOXA2 levels evidenced by both Western blot and immunofluorescence. Given that FOXA2 is a recognized activator of E-cadherin (CDH1) expression and E-cadherin's potential role in epithelial-to-mesenchymal transition in a wide range of cancer types, we tested the hypothesis that FOXA2 mutations in primary uterine cancer specimens would be associated with reduced CDH1 transcript levels. qRT-PCR revealed significantly lower levels of CDH1 expression in primary tumors with FOXA2 mutations. Our findings in vitro and in vivo suggest that reduced transcriptional activity associated with FOXA2 mutations in uterine cancers is likely to contribute to protumorigenic changes in gene expression.

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Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer

Cited by 24 publications

References 54 publications

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

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

The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers

Functional characterization of recurrent FOXA2 mutations seen in endometrial cancers

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