Hereditary predisposition to some cancers has been linked to genetic events and is manifested by a family history of a common cancer or cancers occurring frequently in a younger than expected age group or any history of a relatively rare cancer. Examples

include familial retinoblastoma, familial adenomatous polyposis (FAP), multiple endocrine neoplasia (MEN) syndromes, and the hereditary breast and ovarian cancer syndromes. Although FAP is a rare syndrome, somatic mutations in the affected gene (adenomatous polyposis coli; APC) occur in more than 60% of patients with colonic carcinomas and in an equal proportion of patients with adenomas. Genetic mutations associated with an increased risk of developing breast and ovarian cancers appear to be much more common than previously thought and are strongly related to age at diagnosis of cancer. It is estimated that 5–10% of all breast cancers and more than 40% of breast cancers occurring in women under 30 years of age are due to inheritance of an abnormal gene. The risk of ovarian and other cancers is also significantly increased in carriers of these susceptibility genes. A tumor suppressor gene termed BRCA1 on chromosome 17 has been shown to be abnormal in some families with early onset and high frequencies of breast cancer and ovarian cancer. More than 100 mutations have been identified in the BRCA1 gene, making identification of high-risk individuals difficult. Two population-based studies found that up to 20% of Jewish women with breast cancer diagnosed at or before the age of 40 years and approximately 10% of all women with breast cancer diagnosed before the age of 35 years harbor mutations in the BRCA1 gene. Inheritance of a mutated BRCA1 gene confers a lifelong risk of approximately 85% for breast cancer and 50% for ovarian cancer. Inheritance of the BRCA1 gene also appears to increase the risk of developing both colon and prostate cancers. Another susceptibility gene, BRCA2, has been associated with an increased risk for male breast cancer as well as malignant melanoma and other cancers. There is clearly an association of phenotype and inheritance of susceptibility genes. Breast cancers in BRCA1 carriers tend to be hormone receptor negative, whereas cancers in BRCA2 carriers are generally hormone receptor positive. For a woman diagnosed with breast cancer between the ages of 30 and 34 years, the likelihood of a BRCA1 mutation is as high as 27% if her tumor is both hormone receptor negative and of high grade.