Familial Cancer Syndromes A small fraction of cancers occur in patients with a genetic predisposition. In these families, the affected individuals have a predisposing loss-of-function mutation in one allele of a tumor-suppressor gene or caretaker gene. The tumors in these patients show a loss of the remaining normal allele as a result of somatic events (point mutations or deletions), in agreement with the Knudson hypothesis (Fig. 79-3). Thus, most cells of an individual with an inherited loss-of-function mutation in a tumor-suppressor gene are functionally normal, and only the rare cells that develop a mutation in the remaining normal allele. | Chapter 079. Cancer Genetics Part 3 Familial Cancer Syndromes A small fraction of cancers occur in patients with a genetic predisposition. In these families the affected individuals have a predisposing loss-of-function mutation in one allele of a tumor-suppressor gene or caretaker gene. The tumors in these patients show a loss of the remaining normal allele as a result of somatic events point mutations or deletions in agreement with the Knudson hypothesis Fig. 79-3 . Thus most cells of an individual with an inherited loss-of-function mutation in a tumor-suppressor gene are functionally normal and only the rare cells that develop a mutation in the remaining normal allele will exhibit uncontrolled growth. The normal function of tumor suppressors is to restrain growth to promote differentiation gatekeeper genes or to preserve genome integrity caretaker genes . Roughly 100 syndromes of familial cancer have been reported although many are rare. The majority are inherited as autosomal dominant traits although some of those associated with DNA repair abnormalities xeroderma pigmentosum Fanconi s anemia ataxia telangiectasia are autosomal recessive. Table 79-1 shows a number of cancer predisposition syndromes and the responsible genes. The current paradigm states that the genes mutated in familial syndromes can also be targets for somatic mutations in sporadic noninherited tumors. The study of cancer syndromes has thus provided invaluable insights into the mechanisms of progression for many tumor types. This section examines the case of inherited colon cancer in detail but the same general lessons can be applied to all the cancer syndromes listed in Table 79-1. Table 79-1 Cancer Predisposition Syndromes and Associated Genes Syndrome Gene Chromo some Inherit ance Tumors Ataxia telangiectasia ATM 11q22- q23 AR Breast cancer Autoimmun FAS 10q24 AD Lymphom e lymphoproliferativ e syndrome FASL 1q23 as Bloom syndrome BLM AR Cancer of all types Cowden syndrome PTE N 10q23
