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Genetic epidemiology of ovarian cancer and prospects for polygenic risk prediction.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Jones, Michelle R 
Kamara, Daniella 
Karlan, Beth Y 
Pharoah, Paul DP 
Gayther, Simon A 

Abstract

Epithelial ovarian cancer (EOC) is a heterogeneous disease with a major heritable component. The different histotypes of invasive disease - high grade serous, clear cell, endometrioid and mucinous - are associated with different underlying genetic susceptibility and epidemiological and lifestyle risk factors, all of which contribute to the different biology and clinical characteristics of each histotype. A combination of familial and population based sequencing studies, and genome wide association studies (GWAS) have identified a range of genetic susceptibility alleles for EOC comprising rare but highly penetrant genes (e.g. BRCA1, BRCA2) that are responsible for familial clustering of ovarian cancer cases; more moderate penetrance susceptibility genes (e.g. BRIP1, RAD51C/D, MSH6); and multiple common but low penetrance susceptibility alleles identified by GWAS. Identifying genetic risk alleles for ovarian cancer has had a significant impact on disease prevention strategies; for example it is now routine clinical practice for individuals with germline BRCA1 and BRCA2 mutations to undergo risk reducing salpingo-oophorectomy. Because ovarian cancers are commonly diagnosed at a late clinical stage when the prognosis is poor, the continued development of genetic risk prediction and prevention strategies will represent an important approach to reduce mortality due to ovarian cancer. Advances in genomics technologies that enable more high-throughput genetic testing, combined with research studies that identify additional EOC risk alleles will likely provide further opportunities to establish polygenic risk prediction approaches, based on combinations of rare high/moderate penetrance susceptibility genes and common, low penetrance susceptibility alleles. This article reviews the current literature describing the genetic and epidemiological components of ovarian cancer risk, and discusses both the opportunities and challenges in using this information for clinical risk prediction and prevention.

Description

Keywords

Clinical genetic testing, GWAS, Next generation sequencing, Ovarian Cancer, Susceptibility, Carcinoma, Ovarian Epithelial, Female, Genetic Predisposition to Disease, Humans, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms

Journal Title

Gynecol Oncol

Conference Name

Journal ISSN

0090-8258
1095-6859

Volume Title

147

Publisher

Elsevier BV
Sponsorship
Cancer Research Uk (None)
National Cancer Institute (R01CA178535)
National Institutes of Health (NIH) (via Cedars-Sinai Medical Center) (1278196)
Cancer Research Uk (None)
Cancer Research Uk (None)
Cancer Research Uk (None)