Genetic Predisposition and Genetic Susceptibility

In middle to late adult life, cancer occurs as a result of multiple, serially accumulated, genetic changes following decades of exposure to carcinogens like, for example, tobacco smoke. The occurrence of cancer at young ages, when the opportunity for such chronic environmental exposures has not had sufficient time to exist, suggests strongly that individuals are genetically predisposed to develop certain cancers or are genetically susceptible to the carcinogenic effects of environmental agents. In such individuals, the number of genetic changes required to achieve malignant transformation at the cellular level may be reduced and/or metabolic processes modified. In many instances, gene-environment interactions in this age range are more likely to be operative.

Skin cancer, lymphoma, sarcoma, and hepatic cancers also occur at higher frequency in persons with inherited conditions such as neurofibromatosis, ataxia telangiectasia, Li-Fraumeni syndrome, xeroderma pigmentosa, Fanconi pancytopenia, hereditary dys-plastic nevus syndrome, nevoid basal cell carcinoma syndrome, multiple endocrine neoplasia syndromes, and Turner syndrome. In the aggregate, however, the cancers that are known to be due to these conditions account thus far for only a small proportion of the can cers that occur during adolescence and early adulthood.

Genetic factors appear to be of etiological importance in CNS tumors in young people. Brain tumors occur in association with several cancer predisposition syndromes that are characterized by germ-line mutations in cancer-associated genes [68]. Of particular relevance to adolescent and young adult cases of highgrade astrocytoma is the possibility that these may arise in patients with germ-line TP53 mutations [69, 70]. Anaplastic astrocytoma shows a peak incidence in the fourth decade of life, and glioblastoma is rare before the age of 30 years [71]. However, in individuals with germ-line TP53 mutations, these tumors tend to arise at much earlier ages [70, 72]. Medulloblastoma, which overall has an incidence peak before 10 years of age, is diagnosed more commonly in older children, adolescents, and young adults with germ-line mutations to the APC (adenomatous polyposis coli) gene [73]. The unusually early age of onset of brain tumors in familial cancer syndromes may represent a combination of genetic susceptibility and environmental exposure. The detection of SV40 viral sequences in tumors from patients with germ-line TP53 mutations is of interest in this context [74]. It appears that genetic factors may be important in the etiology of both osteo-sarcoma and Ewing tumor. Osteosarcoma is frequently seen in families with germ-line TP53 mutations and cases are usually diagnosed during the teens and twenties [72, 75]. Evidence for genetic susceptibility to Ewing tumor comes from the striking variation in incidence with ethnic origin. Ewing tumor is extremely rare among black Africans and among African Americans [76]. In common with osteosarcoma, STS are a principal component of the cancer predisposition syndrome associated with germ-line TP53 mutations, and in such patients STS are frequently diagnosed at young ages.

Carcinoma of the breast is extremely rare in the adolescent and young adult age range, but is of particular interest since a recent study detected pathogenic alterations in breast cancer susceptibility genes (including BRCA1, BRCA2 and TP53) in 20% of a large series of women with breast cancer diagnosed under the age of 30 years [77]. It is possible that a similarly high rate of mutations in susceptibility genes associated with colorectal carcinoma might also be found among very young patients. Genes of interest in these patients include APC and the mismatch repair genes [78]. The frequency of mutations to relevant genes among these very early onset cases of common carcinomas should be determined.

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