Elsevier

Human Pathology

Volume 36, Issue 8, August 2005, Pages 861-870
Human Pathology

Perspectives in pathology
Hereditary ovarian cancer

https://doi.org/10.1016/j.humpath.2005.06.006Get rights and content

Summary

Family history is the strongest risk factor for ovarian cancer. Three clinical manifestations of hereditary ovarian cancer have been recognized: (1) “site-specific” ovarian cancer, (2) the breast and ovarian cancer syndrome, and (3) the hereditary nonpolyposis colorectal cancer (HNPCC; Lynch II) syndrome. The first 2 groups are associated with germ line mutations in the BRCA1 and BRCA2 tumor suppressor genes, whereas HNPCC is associated with germ line mutations in the DNA mismatch repair (MMR) genes, primarily hMLH1 and hMSH2. At least 10% of all epithelial ovarian cancers are hereditary, with mutations in the BRCA genes accounting for approximately 90% of cases and most of the remaining 10% attributable to HNPCC. Hereditary ovarian cancers exhibit distinct clinicopathologic features compared with sporadic cancers. The cumulative lifetime risk of ovarian cancer is 40% to 50% for BRCA1 mutation carriers and 20% to 30% for BRCA2 mutation carriers. Both BRCA proteins participate in transcriptional regulation of gene expression as well as the recognition or repair of certain forms of DNA damage, particularly double-strand breaks. Mutations of BRCA1 and BRCA2 are mainly of the frameshift or nonsense variety. Most ovarian cancers associated with germ line BRCA mutations are diagnosed at a younger age and are high-grade and advanced-stage serous carcinomas. BRCA mutations do not seem to play a significant role in the development of mucinous or borderline ovarian tumors. Hereditary ovarian cancers have a distinctly better clinical outcome with longer overall survival and recurrence-free interval after chemotherapy than sporadic cancers. Women with a family history including 2 or more first- or second-degree relatives with either ovarian cancer alone or both breast and ovarian cancers should undertake prophylactic oophorectomy immediately after childbearing has been completed to reduce the risk of ovarian cancer. The cumulative risk of ovarian cancer in HNPCC families is more than 12%. Ovarian cancer in HNPCC syndrome is diagnosed at younger age than in the general population. Most tumors are low-stage well-differentiated or moderately differentiated carcinomas. Annual follow-up is recommended for these patients.

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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    This study was supported in part by grants FIS PI02-0371 and Tumor Bank RTICCC FIS (C03/010), Department of Health, Madrid, Spain.

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