Risk Stratification for Endometrial Cancer Reveals Independent Contributions of Polygenic Risk and Body Mass Index

Abstract

Background Obesity is a major risk factor for endometrial cancer, but it is unknown whether it impacts the association between genetic risk and endometrial cancer. We incorporated polygenic risk score and epidemiological risk factors in the prediction of and investigated associations of BMI and polygenic risk score with endometrial cancer risk Methods We generated polygenic risk score for endometrial cancer in 129,829 unrelated female participants of European ancestry (including 956 incident cases with endometrial cancer) in the UK Biobank and predicted endometrial cancer using endometrial cancer polygenic risk score and established epidemiological risk factors, including BMI. We evaluated the performance of endometrial cancer prediction models by odds ratios and area under the receiver operating characteristic curves (AUCs) to using logistic regression. Individual and joint associations of BMI and polygenic risk score with endometrial cancer were assessed using Cox proportional hazards models. Results An integrated model incorporating both polygenic risk score and epidemiological risk factors achieved a modest, but statistically significant, improvement in predicting endometrial cancer status compared with the model that included epidemiologic risk factors alone (AUC = 0.74 versus 0.73; P = 3.98 × 10-5). Obese participants (BMI ≥ 30 kg/m2) in the top polygenic risk tertile had the highest endometrial cancer risk. We observed independent effects of genetic risk and BMI on endometrial cancer risk. Conclusion Integrating polygenic risk score with epidemiological risk factors may offer insights into population stratification for endometrial cancer susceptibility. Higher endometrial cancer polygenic risk is associated with endometrial cancer, irrespective of BMI.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This work was supported by a co-funded Worldwide Cancer Research and Cancer Australia project grant awarded to T.A.O′M, E.J.C. and M.J.G (grant number 22-0253). T.A.O′M. is supported by a National Health and Medical Research Council (NHMRC) of Australia Investigator Fellowship (APP1173170). E.J.C is supported by a National Institute for Health and Care Research (NIHR) Advanced Fellowship (NIHR300650) and the NIHR Manchester Biomedical Research Centre (NIHR203308).The endometrial cancer genome-wide association analyses were supported by the NHMRC (APP552402, APP1031333, APP1109286, APP1111246 and APP1061779), the U.S. National Institutes of Health (R01-CA134958), European Research Council (EU FP7 Grant), Wellcome Trust Centre for Human Genetics (090532/Z/09Z) and Cancer Research UK. OncoArray genotyping of ECAC cases was performed with the generous assistance of the Ovarian Cancer Association Consortium (OCAC), which was funded through grants from the U.S. National Institutes of Health (CA1X01HG007491-01 (C.I. Amos), U19-CA148112 (T.A. Sellers), R01-CA149429 (C.M. Phelan) and R01-CA058598 (M.T. Goodman); Canadian Institutes of Health Research (MOP-86727 (L.E. Kelemen)) and the Ovarian Cancer Research Fund (A. Berchuck). OncoArray genotyping of the BCAC controls was funded by Genome Canada Grant GPH-129344, NIH Grant U19 CA148065, and Cancer UK Grant C1287/A16563. All studies and funders are listed in O′Mara et al (2018).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Human Ethics Committee of QIMR Berghofer Medical Research Institute gave ethical approval for this work. This research project (Project Application Number 25331) was approved by the UK Biobank in accordance with their established access procedure.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

This research project (Project Application Number 25331) was approved by the UK Biobank in accordance with their established access procedure. UK Biobank data is available to bona fide researchers for health-related research in the public interest. Endometrial cancer GWAS summary statistics used to generate endometrial cancer polygenic risk scores can be downloaded from the GWAS Catalog (Study accession: GCST006464). GWAS summary statistics used to generate polygenic scores for age at natural menopause can be downloaded from the GWAS Catalog (Study accession: GCST90320256). Female-stratified GWAS summary statistics used to generate polygenic scores for SHBG and testosterone can be downloaded from the GWAS Catalog (Study accession: GCST90012107 for SHBG and GCST90012112 for testosterone). Polygenic scores generate in this study will be available at the PGS Catalog upon publication.

https://www.ebi.ac.uk/gwas/studies/GCST006464

https://www.ebi.ac.uk/gwas/studies/GCST90320256

https://www.ebi.ac.uk/gwas/studies/GCST90012107

https://www.ebi.ac.uk/gwas/studies/GCST90012112

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