Perspectives in pathologyHereditary ovarian cancer☆
Introduction
In the Western world, ovarian cancer is the most lethal gynecologic malignancy. Most cases are diagnosed at advanced stage, and current screening methods are not totally reliable. Family history is the strongest risk factor. Although the lifetime risk for developing ovarian cancer in the general population is 1.6%, women with one first-degree relative with ovarian cancer have an approximately 5% risk, and women with two first-degree relatives with ovarian cancer have a 7% risk [1], [2]. In the United States, 10% to 20% of patients with breast cancer and patients with ovarian cancer have a first- or second-degree relative with one of these diseases [3].
In this overview, the term “hereditary” will refer to those cancers associated with highly penetrant, autosomal, dominant genetic predisposition. Over the last decade, the molecular genetic basis of hereditary predisposition to ovarian cancer has been extensively documented. Patients with a family history of ovarian cancer are classified into 3 main groups: (1) “site-specific” ovarian cancer, (2) breast and ovarian cancer syndrome, and (3) hereditary nonpolyposis colorectal cancer (HNPCC; Lynch II) syndrome (Table 1) [4], [5]. The first 2 groups are associated with germ line mutations in the BRCA1 and BRCA2 tumor suppressor genes, whereas the HNPCC syndrome is associated with germ line mutations in the DNA mismatch repair (MMR) genes, primarily hMLH1 and hMSH2. It is currently accepted that at least 10% of all epithelial ovarian cancers are hereditary, with mutations in the BRCA genes accounting for approximately 90% of the cases and most of the remaining 10% attributable to HNPCC [6], [7]. Unlike familial breast cancer patients, in whom germ line mutations in BRCA1 and BRCA2 are found with equal frequency, women with hereditary ovarian cancer have BRCA1 germ line mutation more often than BRCA2 mutations [8]. However, recent studies suggest that the contribution of BRCA2 mutations to ovarian cancer is greater than first thought [7], [9], [10], [11], [12], [13]. BRCA2 germ line mutations may be found in patients with late-onset disease without known family history of breast and ovarian carcinomas. Familial risk not explained by the known susceptibility BRCA genes suggests that other genes or environmental factors may play a role in ovarian carcinogenesis. Combination of chance clustering of sporadic cases and insensitivity of detection methods has also been considered [14].
Section snippets
“Site-specific” ovarian cancer and hereditary breast and ovarian cancer syndrome
No gene that confers increased susceptibility to ovarian cancer alone has yet been found. Thus, site-specific ovarian cancer and hereditary breast/ovarian cancer syndrome are considered part of the same spectrum of disease [2].
Ovarian cancer in patients with HNPCC syndrome
HNPCC, or Lynch II syndrome, was first described in 1966 [93]. It is characterized by autosomal dominant inheritance of predominantly right-sided colonic cancer in the absence of colonic polyposis. HNPCC family members also have a greatly elevated risk of endometrial cancer and a moderately increased risk of other cancers such as ovarian, gastric, biliary tract, urothelial, and central nervous system cancers [94]. The cumulative risk of colorectal cancer in HNPCC families is more than 80% and
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2018, Gynecologic OncologyCitation Excerpt :Many tumors previously classified as high grade endometrioid carcinomas, transitional carcinomas or poorly differentiated carcinomas (not otherwise specified) fall into this category and virtually all contain a mutation in the tumor suppressor TP53 [1]. Most ovarian carcinomas are sporadic, but a hereditary component has been suggested in around 20% of cases [2]. The more common hereditary breast and ovarian cancer syndrome (HBOC, linked to BRCA mutations), and less common Lynch syndrome (i.e., heritable non-polyposis colorectal cancer syndrome (HNPCC) linked to DNA mismatch repair mutations) are the two main syndromes accounting for most familial ovarian cancers [2].
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This study was supported in part by grants FIS PI02-0371 and Tumor Bank RTICCC FIS (C03/010), Department of Health, Madrid, Spain.