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Open AccessReview

Rare Germline Genetic Variants and the Risks of Epithelial Ovarian Cancer

1
School of Women’s and Children’s Health, Faculty of Medicine, University of New South Wales, Sydney 2052, Australia
2
Adult Cancer Program, Lowy Cancer Research Centre, University of New South Wales, Sydney 2052, Australia
3
Strangeways Research Laboratory, University of Cambridge, Cambridge CB1 8RN, UK
4
Center for Cancer Prevention and Translational Genomics, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
5
Applied Genomics, Computation and Translational Core, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
*
Author to whom correspondence should be addressed.
These authors have contributed equally to this work.
Cancers 2020, 12(10), 3046; https://doi.org/10.3390/cancers12103046
Received: 16 September 2020 / Revised: 12 October 2020 / Accepted: 14 October 2020 / Published: 19 October 2020
Several genes have been confirmed as risk genes for epithelial ovarian cancer (EOC). There are five main types of EOC, with different molecular changes and clinical characteristics, suggesting they should be considered different diseases. This review summarises the contribution of rare inherited mutations to EOC susceptibility, focussing on the frequency in each EOC type. Susceptibility genes can have a major clinical impact, reducing ovarian cancer incidence by screening of family members to detect women at higher risk than the general population. They can also lead to the development of new targeted treatments.
A family history of ovarian or breast cancer is the strongest risk factor for epithelial ovarian cancer (EOC). Germline deleterious variants in the BRCA1 and BRCA2 genes confer EOC risks by age 80, of 44% and 17% respectively. The mismatch repair genes, particularly MSH2 and MSH6, are also EOC susceptibility genes. Several other DNA repair genes, BRIP1, RAD51C, RAD51D, and PALB2, have been identified as moderate risk EOC genes. EOC has five main histotypes; high-grade serous (HGS), low-grade serous (LGS), clear cell (CCC), endometrioid (END), and mucinous (MUC). This review examines the current understanding of the contribution of rare genetic variants to EOC, focussing on providing frequency data for each histotype. We provide an overview of frequency and risk for pathogenic variants in the known susceptibility genes as well as other proposed genes. We also describe the progress to-date to understand the role of missense variants and the different breast and ovarian cancer risks for each gene. Identification of susceptibility genes have clinical impact by reducing disease-associated mortality through improving risk prediction, with the possibility of prevention strategies, and developing new targeted treatments and these clinical implications are also discussed. View Full-Text
Keywords: ovarian cancer risk; rare germline variants; susceptibility genes ovarian cancer risk; rare germline variants; susceptibility genes
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MDPI and ACS Style

Pavanello, M.; Chan, I.H.; Ariff, A.; Pharoah, P.D.; Gayther, S.A.; Ramus, S.J. Rare Germline Genetic Variants and the Risks of Epithelial Ovarian Cancer. Cancers 2020, 12, 3046.

AMA Style

Pavanello M, Chan IH, Ariff A, Pharoah PD, Gayther SA, Ramus SJ. Rare Germline Genetic Variants and the Risks of Epithelial Ovarian Cancer. Cancers. 2020; 12(10):3046.

Chicago/Turabian Style

Pavanello, Marina; Chan, Isaac H.; Ariff, Amir; Pharoah, Paul D.; Gayther, Simon A.; Ramus, Susan J. 2020. "Rare Germline Genetic Variants and the Risks of Epithelial Ovarian Cancer" Cancers 12, no. 10: 3046.

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