Screening for familial cancer is an important part of the initial evaluation of a patient, and should be a regular part of each subsequent visit to assess any changes in the family history. Obstetricians and gynecologists have an important role in identifying those women with a potentially hereditary cancer syndrome. Although it is not expected that the practicing OB/GYN would be familiar with all the hereditary cancer syndromes, they should be able to recognize the key features in a family history that suggest the patient may be at risk, and make an appropriate referral for evaluation and counseling. This chapter will outline some common hereditary cancer syndromes likely to be seen by the OB/GYN, and provide a list of key features present in families with hereditary forms of cancer.

Hereditary Breast and Ovarian Cancer

This is a dominantly inherited syndrome most commonly caused by germline mutations in the genes BRCA1 and 2. In the general population the mutated gene is found in approximately 1 in every 500 persons, but in those of Ashkenazi Jewish ancestry the cancer frequency is 1 in every 40 individuals.¹ However, the majority of breast and ovarian cancers are sporadic, with only 5% to 10% of them being caused by a BRCA1 or 2 mutation.

Key features strongly suggestive of a BRCA1 or 2 mutation would be early onset of breast or ovarian cancer in a patient (prior to age 50), a family history with multiple affected members, or the presence in the family history of both breast and ovarian cancer. It is important to recognize that males who carry one of these mutations may be asymptomatic, but also are at risk for breast, prostate, and pancreatic cancer. Even in women with the mutation, the gene is not completely penetrant. For a female with the mutation there is 40% to 66% lifetime risk of breast cancer, and up to a 46% risk of ovarian cancer. These risks are significantly higher than the US general population risk of 12% for breast cancer and 1.5% for ovarian cancer. In addition, many of these cancers will occur before the age of 50.² Equally of concern is the risk of breast cancer in the contralateral breast which is between 40% and 65% over a lifetime, and up to 30% 10 years postdiagnosis.³

Patients with early onset breast or ovarian cancer, or those with family histories similar to that seen in the case study, should be referred to individuals trained in cancer genetic counseling for evaluation and genetic testing. If the patient is found to carry a pathogenic mutation, an appropriate management plan needs to be developed to include both screening options and prophylactic surgical options (mastectomy and oophorectomy).

The absence of a known pathogenic mutation does not exclude the possibility that the family has a hereditary form of breast and/or ovarian cancer. In addition to the other known syndromes outlined below, there are likely many other cancer causing gene mutations that have yet to be discovered. In the presence of a strong family history, but negative gene testing, it is essential that a comprehensive screening plan be developed for the potentially at-risk patient.

Hereditary Nonpolyposis Colon Cancer (Lynch Syndrome)

Although colon cancer is the third leading cause of cancer death in women, the great majority will be late-onset cancers. A family history of early onset colon cancer, and other cancers, such as ovarian or endometrial, should raise suspicion of Lynch syndrome, and prompt a referral for genetic counseling and gene testing for the DNA mismatch genes that are commonly mutated in this disorder. In addition to the associated gynecologic cancers, a wide variety of other cancers may be found in these families, including gastric, small intestine, biliary, brain, skin, and pancreas. In the patient identified with the Lynch syndrome a comprehensive screening plan including both a gastroenterologist and a gynecologist is essential, as the risk for ovarian cancer and endometrial cancer may be up to 12% and 60%, respectively.⁴

Li-Fraumeni Syndrome

This condition is highly penetrant with a 90% risk of cancer by age 60. Most cases are due to germline mutations in the tumor suppression genes, p53 and CHEK2. Soft tissue sarcomas, often expressed in children or young adults, are the most common cancers. However, breast cancer is a commonly associated cancer, as are bone, brain, and adrenal cancers. Unlike most of the other cancer-predisposition genes the frequency of de novo mutations is quite high (7%-20%). In certain circumstances, gene testing may be offered in the absence of a positive family history.⁵