Organ Site Specificity for Cancer in Chromosomal Instability Disorders1

DNA rearrangement rather than point mutation is an emerg ing hypothesis for human carcinogenesis. Although there is no direct evidence for this hypothesis, indirect evidence is pro vided by cancer cytogenetics and genetics. It has been sug gested that patients with Bloom's syndrome, a disorder of spontaneous chromosomal rearrangement, develop the com mon fatal internal cancers and thus that genetic rearrange ments, rather than chemical mutagens, cause most internal human cancers. To test this observation, we have derived ageand sexadjusted cancer incidence rate ratios for specific organ sites in patients with three chromosomal instability disorders (Bloom's syndrome, xeroderma pigmentosum, and dyskeratosis congen ita) and have found that the increased incidence of cancer in all three disorders is limited to specific and often uncommon organ sites. We conclude that chromosomal instability disor ders do not predispose patients to the common fatal internal cancers. Although DNA rearrangement remains a promising concept in human carcinogenesis, the organ site specificity of cancers associated with Bloom's syndrome, xeroderma pig mentosum, and dyskeratosis congenita cannot be used as evidence to implicate this mechanism.