Fragile Sites as a Mechanism in Carcinogeneisis

Jorge J. Yunis, MD PhD; William R. Hoffman, MA

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Since the first cancer chromosome defect was discovered nearly 30 years ago, more than 80 different types of human malignancy have been found to have recurrent structural chromosomal rearrangements. How they develop may be generally related to the recent finding of a large number of genetic weak points or chromosomal fragile sites that are highly sensitive to low folic acid and to diverse mutagens and carcinogens. Exposure of cultured blood cells to these agents can yield chromosomal rearrangements that are microscopically indistinguishable from those found in cancer cells. The breakpoints of these defects produced in vitro occur at the same place where fragile sites have been mapped, suggesting that fragile sites may facilitate such rearrangements. Molecular investigation of chromosomal fragile sites may help establish their role in carcinogenesis and whether they are involved in individual predisposition to malignancy.

Concluding Remarks

Chromosomal fragile sites are highly sensitive to mutagens and carcinogens and are presumptively involved in carcinogenesis, although molecular evidence is needed before such an association can be firmly established. Finally, because a large number of fragile sites can be induced by low folic acid or antifolate drugs, it is reasonable to speculate that certain nutritional deficiencies may play a role in DNA instability in vivo. This may be especially true of older people who have a relatively higher expression of fragile sites. We have observed in the bone-marrow cells of three older alcoholic patients, with low serum folate levels, a markedly elevated expression of fragile sites (unpublished observations). Alcohol consumption has been found to be risk factor for esophageal, rectal, lung, and breast cancer in several recent studies. The prospect that fragile site-DNA sequences may hold critical information about individual predisposition to cancer should give added incentive to investigate the molecular basis of these chromosomal landmarks.

4 figures, 1 table, 62 references