Introduction

Consistent with the somatic mutation theory of cancer, hereditary diseases that interfere with the functional integrity of the nuclear genome can generate an increased mutational burden in cells and hence an increased predisposition to neoplastic transformation. Multiple hereditary diseases associated with genomic instability are associated with cancer predisposition. However, some of these are extremely rare and documentation of such cancer predisposition is tenuous. This review considers some of the diseases listed in Table 36.1, all of which interfere with normal biological responses to DNA damage, or arrested or stalled DNA replication. Mouse models have been rendered for many of these human diseases, but are not discussed here in any detail. A comprehensive listing of mutant mouse strains defective in biological responses to DNA damage has been published (1).

Xeroderma pigmentosum (XP)

The skin cancer-prone hereditary disease xeroderma pigmentosum (XP) is the first human hereditary disease in which a definitive causal relationship was demonstrated between exposure to DNA-damaging agents and cancer predisposition. As recounted in detail elsewhere (2,3), this key observation was first documented by James Cleaver in the late 1960s, who showed that cultured cells from XP individuals are defective in the process of nucleotide excision repair (NER) and are consequently abnormally sensitive to killing following exposure to ultraviolet (UV) radiation (3).