Hereditary Cancer Syndromes

The Challenge

• Description: Genetic mutations, especially those that impair the cell’s DNA repair functions, can result in errors of cell growth and differentiation going unchecked. This propensity to malignant transformation may result in an increased risk of developing frank cancer. Not all mutations in these genes are associated with an increased cancer risk, but a number have been firmly connected with syndromes of malignancy that are clinically significant.

• Scope of the Problem: Although the majority of breast, ovarian, and other gynecologic cancers are sporadic, about 5%–10% of breast and 10%–15% of ovarian cancers are hereditary. About 1/500 women in the United States has a cancer-related mutation in either the BRCA1 or BRCA2 gene. (If either parent has a BRCA1 or BRCA2 gene mutation, their children have a 50% chance of inheriting the same gene mutation.) Women with BRCA1 mutations have a 60% lifetime risk for breast cancer, and BRCA2 mutations carry an 85% risk for breast cancer and up to 30% risk for ovarian cancer. This has been termed hereditary breast-ovarian cancer (HBOC) syndrome. In a similar way, MSH2, MLH1, PMS2, MSH3, and MSH6 germline mutations have been associated with hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome (the most common cause of hereditary colorectal cancer). Lynch syndrome has an autosomal dominant inheritance and conveys a susceptibility to predominantly right-sided colon cancer, endometrial cancer, ovarian cancer, and other extracolonic cancers. The lifetime risk of ovarian carcinoma in females with Lynch syndrome is estimated to be as high as 17%, and the reported relative risk of ovarian cancer has ranged from 3.6 to 13, depending on the specific gene affected. Other syndromes (Cowden, DICER1, and Peutz–Jeghers syndromes, Li-Fraumeni syndrome, Bannayan–Riley–Ruvalcaba syndrome, rhabdoid tumor predisposition syndrome 2, and others) are less common but also convey their own increased cancer risks.

• Objectives of Management: To realistically appraise the future risks of hereditary cancer and implement appropriate screening and prophylaxis strategies tailored to the needs of the patient and her family.