Genetic Factors
Hereditary Cancer Predisposition Syndromes
Summary of Key Points
• The discovery of inherited mutations of genes associated with increased risk for cancer provides important clinical opportunities for early detection and prevention of common and rare forms of human malignancies.
• Syndromes of cancer predisposition often involve multiple organ systems, affect paired organs with bilateral or multifocal tumors, and have onset at an earlier age compared with nonfamilial tumors. The diagnosis of particular cancer predisposition syndromes can usually be confirmed with molecular genetic testing of patients who have hereditary malignancies. Genetic testing can then be extended to relatives as a predictive test to guide their preventive management.
• Medical, surgical, and radiation oncologists, genetic counselors, and allied professionals are playing a leading role in the integration of genetic testing into the practice of preventive oncology. Recently, genomic analysis has been applied to tumors to discover targets for therapy. Because tumor genomic analysis will also include a comparison with the germline, the need for genetic counseling for both cancer and noncancer disease risks will be increased. This chapter reviews both common and more recently described familial cancer syndromes, with an emphasis on the clinical application of cancer genetic and genomic analysis in the management of patients who have or are at risk for cancer.
1. A 51-year-old woman presents with abdominal bloating, pelvic discomfort, and lower limb edema. Physical examination reveals a right-sided pelvic fullness. Ultrasound examination reveals a complex cystic lesion associated with the right ovary. Three years earlier the woman was treated for breast cancer, which was triple-negative (HER2/ER/PR negative), invasive ductal carcinoma. Her family history is significant for high-grade serous ovarian carcinoma diagnosed in a maternal aunt. In which of these genes does this women most likely carry a germline mutation?
2. Routine screening colonoscopy in a 50-year-old otherwise healthy man identifies 19 polyps. Histologic examination reveals multiple pathologies including tubular adenomas, villous adenomas, and hyperplastic polyps. The family history is negative for colorectal polyposis. What autosomal-recessive condition could this presentation potentially represent?
3. A 56-year-old woman diagnosed with follicular thyroid cancer has a history significant for invasive ductal breast carcinoma at age 42 years and endometrial cancer at age 45 years. What feature(s) on examination might you expect to see that can be associated with a potential cause of her multiple primary tumors?
1. Answer: B. In view of the personal history of breast cancer and family history of high-grade serous ovarian cancer, the mass in the patient’s pelvis is highly suspicious for ovarian cancer. Germline mutations in BRCA1 and BRCA2 remain the major high-penetrant hereditary breast and ovarian cancer susceptibility genes. In this case, a germline mutation in BRCA1 is more likely, because triple-negative breast cancer is associated with germline mutations in BRCA1, distinct from breast tumors associated with BRCA2.
2. Answer: D. MUTYH-associated polyposis is the only autosomal-recessive condition listed. However, if an autosomal-recessive inheritance pattern had not been specified, this case could also represent attenuated familial adenomatous polyposis. Alternatively, the case could represent hereditary mixed polyposis syndrome, especially if juvenile and Peutz-Jeghers polyps had also been identified.
3. Answer: B. The patient’s constellation of tumors is consistent with Cowden syndrome. Major criteria include breast cancer, thyroid cancer (especially follicular histology), macrocephaly, and endometrial carcinoma. Cumulative lifetime risks for female breast cancer are 81% to 85.2%; for thyroid cancer, 21% to 35.2%; and for endometrial cancer, 19% to 28.2%. Ash leaf spots are associated with tuberous sclerosis. Polydactyly is associated with Gorlin syndrome. Sebaceous neoplasms are associated with Muir-Torre syndrome, caused by germline mutations in the mismatch repair genes. Axillary freckling is associated with neurofibromatosis type 1.
