Abstract
Simple SummarySeveral 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.
Highlights
Epithelial ovarian cancer (EOC) is the seventh most common cancer in women worldwide, with over 295,000 incident cases each year, and is the leading cause of mortality relating to gynaecological malignancies, with 184,000 deaths each year [1]
This review aims to summarise the progress to date in efforts to understand the contribution of rare genetic variants to ovarian cancer and histotype specific differences, as well as the clinical implications of these discoveries
We have presented a comprehensive review of the contribution of rare genetic variants to ovarian cancer, with a focus on the relationship between genetic variation and ovarian cancer histotypes, using data mostly only presented as supplementary in the original papers
Summary
Epithelial ovarian cancer (EOC) is the seventh most common cancer in women worldwide, with over 295,000 incident cases each year, and is the leading cause of mortality relating to gynaecological malignancies, with 184,000 deaths each year [1]. The five different histotypes have different risk factors and molecular characteristics. The inherited genetics of each histotype is likely to be different. The prognosis of ovarian cancer is poor, with a five-year survival rate of just 47% [3]. Ovarian cancer is difficult to diagnose early in its disease course, and 80% of cases are diagnosed after extensive metastasis at stage III or IV, which carry a five-year survival rate of 41% and 20% respectively [3]
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