Defective DNA Repair Syndromes.

Besides the dominantly inherited precancerous conditions, a group of cancerpredisposing conditions is collectively characterized by defects in DNA repair and resultant DNA instability.

These conditions generally have an autosomal recessive pattern of inheritance. Included in this group are xeroderma pigmentosum, ataxiatelangectasia, and Bloom syndrome, all rare diseases characterized by genetic instability resulting from defects in DNA repair genes. Also included here is hereditary nonpolypoid colon cancer (HNPCC), an autosomal dominant condition caused by inactivation of a DNA mismatch repair gene.[24] HNPCC is the most common cancer predisposition syndrome, increasing the susceptibility to cancer in the colon and also in some other organs such as the small intestine, endometrium, and ovary ( Chapter 17 ).

TABLE 7-4-- Reported Deaths for the Five Leading Cancer Types for Males by Age, US, 2000

Source: US Mortality Public Use Data Tape, 2000, National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, MD 2002.

*ONS = other nervous system.

Familial Cancers.

Besides the inherited syndromes of cancer susceptibility, cancer may occur at higher frequency in certain families without a clearly defined pattern of transmission. Virtually all the common types of cancers that occur sporadically have also been reported to occur in familial forms. Examples include carcinomas of colon, breast, ovary, and brain, as well as melanomas. Features that characterize familial cancers include early age at onset, tumors arising in two or more close relatives of the index case, and sometimes, multiple or bilateral tumors. Familial cancers are not associated with specific marker phenotypes. For example, in contrast to the familial adenomatous polyp syndrome, familial colonic cancers do not arise in pre-existing benign polyps. The transmission pattern of familial cancers is not clear. In general, siblings have a relative risk between two and three (two to three times greater than unrelated individuals). Segregation analyses of large families usually show that predisposition to the tumors is dominant, but multifactorial inheritance cannot be easily ruled out. It is likely that familial susceptibility to cancer may depend on multiple low-penetrance alleles, each contributing to only a small increase in the risk of tumor development. It has been estimated that 10% to 20% of patients with breast or ovarian cancer have a first- or second-degree relative with one of these tumors. Although two breast cancer susceptibility genes, named BRCA1 and BRCA2, have been identified, mutation of these genes occurs in no more than 3% of breast cancers. Thus, mutations in BRCA1 and BRCA2 cannot account for the large proportion of familial breast cancers.[25] Changes in other genes, probably in low-penetrance susceptibility alleles, appear to be necessary for the development of these tumors. A similar situation occurs in familial melanomas, in which a mutation of the p16INK4a tumor suppressor gene has been identified. However, mutation in this gene accounts for only about 20% of familial melanoma kindreds, suggesting that other factors are involved in the familial predisposition.[26]

Date: 2016-04-22; view: 690