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  • Genome instability characterizes a large group of inherited disorders with prominent cutaneous abnormalities; many have an increased cancer risk.

  • Genome instability is caused by impaired repair and/or maintenance of DNA.

  • Xeroderma pigmentosum is a prototype with impaired repair of environmentally induced DNA damage and a greatly increased frequency of sunlight-induced cancer.

  • Although these disorders are rare, heterozygous carriers of affected genes, which may comprise several percent of the general population, may carry an increased cancer risk as well.

Because the genome exerts control of cellular function, maintaining genome stability is important for the continued function of cells, tissues, and organisms. DNA is the carrier of genetic information. Its structure is regularly threatened by damaging agents that include oxidative stress, ultraviolet (UV) and X radiation, and chemical agents. Although much damage is repaired, failure to maintain genomic integrity may lead to abnormal cell function or cell death. If the cell divides, progeny may accumulate additional damage and this progressive accumulation of damage can lead to malignancy.

This chapter describes the relevant skin disorders with genome instability and the underlying defective mechanisms of DNA repair or DNA maintenance (Tables 130-1 and 130-2). All of these disorders exhibit prominent cutaneous abnormalities that involve dermatologists in their diagnosis and management. Most, but not all, are also characterized by an increased risk of malignancies. This demonstrates that the maintenance of genome integrity is important for the prevention of malignant transformation. Malignant transformation requires the accumulation of several mutations in specific genes of a single cell. Thus a mutator phenotype is often regarded a prerequisite for carcinogenesis, because without genome instability it would be exceedingly unlikely that all of those mutations would occur in a single cell.1-4 The same genes that are affected in the hereditary genome instability disorders can also confer genome instability to individual cells when impaired through acquired mutations, thereby playing an important role early in spontaneous carcinogenesis.

Table 130-1Clinical Features of Hereditary Disorders of Genome Instability and DNA Repair

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