Cancer-Prone Human Disorders with Defects in DNA Repair

Abstract

Previous chapters have provided ample evidence that the initiation step of the carcinogenic process involves the interaction of an activated carcinogen with cellular DNA. Whether the alteration in the DNA produced by this interaction will eventually result in neoplastic transformation of the damaged cell is dependent on a variety of factors. If the DNA damage is rapidly, efficiently and accurately repaired or processed, the normal status of the cell will be regained. If not, the cell may die or may be mutated, and, in rare instances, it may progress further along the carcinogenic pathway. The crucial role of DNA repair in the avoidance of carcinogenesis is demonstrated by the identification of several autosomal recessive human genetic disorders (DNA-repair syndromes) in which a deficiency in the repair or processing of DNA damage is associated with an enhanced frequency of cancer, as well as with a variety of other clinical abnormalities. The prototype disease in this category is xeroderma pigmentosum (XP) in which a clearly identifiable defect in the repair of UV damage in DNA is associated with a high frequency of UV-induced mutations in cultured cells and with a greatly increased incidence of skin cancer in affected patients. A variety of other disorders have subsequently been shown to involve cellular hypersensitivity to the lethal or clastogenic effects of carcinogenic, DNA-damaging agents. This cellular hypersensitivity is thought to result from defects in the ability of the cells to repair or process damage produced by the appropriate agent.