Defects In Dna Repair And Cancer Susceptibility

It is clear from the previous sections that inherited defects in DNA repair are an important source of susceptibility to cancer. A number of syndromes related to DNA repair carry an increased risk of cancers (Table 3.2). Homozygous mutations in the ATM, NBS1, WRN, FANC, and XP/ERCC genes underlie recessively inherited diseases, which confer an increased risk for cancers in the context of syndrome with a wider range of afflictions. Heterozygous mutations in MMR genes and in the BRCAs and perhaps certain ATM mutations lead to cancer predisposition in a dominantly inherited fashion. As a rule, no other consistent symptoms are associated with these mutations. With either type of predisposition, cancers develop at an increased rate as a consequence of an enhanced rate of mutations, either point mutations in MMR deficiency and XP, or chromosomal aberrations in the others. Also typically, in these diseases, cancers appear at an unusually early age.

Obviously, the question arises to what extent defects in DNA repair are involved in sporadic cancers (the great majority) which arise in people not carrying mutations in any of the above genes. In other words, since defective DNA repair is sufficient for cancer development, is it also necessary? Or can cancers arise in the course of the relatively long human lifetime just by accumulation of rare alterations that have occurred in spite of functional DNA repair? The answers to these questions are open.

One also has to consider in this regard that many genes involved in DNA repair are polymorphic. Several of these polymorphisms have been linked to an increased risk for one of the major cancers. Typically, the increases in cancer risk conferred by these polymorphisms to each individual are small compared to those resulting from

Table 3.2. Inherited defects in DNA repair and predisposition to cancer

Syndrome

Mode of

Repair system

Gene(s)

Tissue with

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