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

ABSTRACT: Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded by ESR1. Consequently, several studies have investigated whether variation at the ESR1 locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3633 genotyped and imputed single nucleotide polymorphisms (SNPs) in 6607 EC cases and 37 925 controls. There was evidence of an EC risk signal located at a potential alternative promoter of the ESR1 gene (lead SNP rs79575945, P=1.86×10(-5)), which was stronger for cancers of endometrioid subtype (P=3.76×10(-6)). Bioinformatic analysis suggests that this risk signal is in a functionally important region targeting ESR1, and eQTL analysis found that rs79575945 was associated with expression of SYNE1, a neighbouring gene. In summary, we have identified a single EC risk signal located at ESR1, at study-wide significance. Given SNPs located at this locus have been associated with risk for breast cancer, also a hormonally driven cancer, this study adds weight to the rationale for performing informed candidate fine-scale genetic studies across cancer types.

SUBMITTER: O'Mara TA

PROVIDER: S-EPMC4559752 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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

O'Mara Tracy A TA Glubb Dylan M DM Painter Jodie N JN Cheng Timothy T Dennis Joe J Attia John J Holliday Elizabeth G EG McEvoy Mark M Scott Rodney J RJ Ashton Katie K Proietto Tony T Otton Geoffrey G Shah Mitul M Ahmed Shahana S Healey Catherine S CS Gorman Maggie M Martin Lynn L Hodgson Shirley S Fasching Peter A PA Hein Alexander A Beckmann Matthias W MW Ekici Arif B AB Hall Per P Czene Kamila K Darabi Hatef H Li Jingmei J Dürst Matthias M Runnebaum Ingo I Hillemanns Peter P Dörk Thilo T Lambrechts Diether D Depreeuw Jeroen J Annibali Daniela D Amant Frederic F Zhao Hui H Goode Ellen L EL Dowdy Sean C SC Fridley Brooke L BL Winham Stacey J SJ Salvesen Helga B HB Njølstad Tormund S TS Trovik Jone J Werner Henrica M J HM Tham Emma E Liu Tao T Mints Miriam M Bolla Manjeet K MK Michailidou Kyriaki K Tyrer Jonathan P JP Wang Qin Q Hopper John L JL Peto Julian J Swerdlow Anthony J AJ Burwinkel Barbara B Brenner Hermann H Meindl Alfons A Brauch Hiltrud H Lindblom Annika A Chang-Claude Jenny J Couch Fergus J FJ Giles Graham G GG Kristensen Vessela N VN Cox Angela A Pharoah Paul D P PD Dunning Alison M AM Tomlinson Ian I Easton Douglas F DF Thompson Deborah J DJ Spurdle Amanda B AB

Endocrine-related cancer 20151001 5

Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded by ESR1. Consequently, several studies have investigated whether variation at the ESR1 locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3633 genotyped and imputed single nucleotide polymorphi ...[more]

PMID: 26330482

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Project description:Abnormal uterine bleeding (AUB) represents a common diagnostic challenge, as it might be related to both benign and malignant conditions. Endometrial cancer may not be detected with blind uterine cavity sampling by dilatation and curettage or suction devices. Several scoring systems using different ultrasound image characteristics were recently proposed to estimate the risk of endometrial cancer (EC) in women with AUB. The aim of the present study was to externally validate the predictive value of the recently proposed scoring systems including the Risk of Endometrial Cancer scoring model (REC) for EC risk stratification. It was a retrospective cohort study of women with postmenopausal bleeding. From June 2012 to June 2020 we studied a group of 394 women who underwent standard transvaginal ultrasound examination followed by power Doppler intrauterine vascularity assessment. Selected ultrasound features of endometrial lesions were assessed in each patient. The median age was 60.3 years (range ± 10.7). The median body mass index (BMI) was 30.4 (range ± 6.0). Histological examination revealed 158 cases of endometrial hyperplasia (EH) and 236 cases of EC. Of the studied ultrasound endometrial features, the highest areas under the curve (AUCs) were found for endometrial thickness (ET) (AUC = 0.76; 95% CI: 0.71-0.81) and for interrupted endomyometrial junction (AUC = 0.70, 95% CI: 0.65-0.75). Selected scoring systems presented moderate to good predictive performance in differentiating EC and EH. The highest AUC was found for REC model (AUC = 0.75, 95% CI: 0.70-0.79) and for the basic model that included ET, Doppler score and interrupted endometrial junction (AUC = 0.77, 95% CI: 0.73-0.82). REC model was more accurate than other scoring systems and selected single features for differentiating benign hyperplasia from EC at early stages, regardless of menopausal status. New scoring systems, including the REC model may be used in women with AUB for more efficient differentiation between benign and malignant conditions.

Dataset Information

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

Publications

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

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