Exploring the genetic and molecular basis of differences in multiple myeloma of individuals of African and European descent

Multiple Myeloma is a typical example of a neoplasm that shows significant differences in incidence, age of onset, type, and frequency of genetic alterations between patients of African and European ancestry. This perspective explores the hypothesis that both genetic polymorphisms and spontaneous somatic mutations in the TP53 tumor suppressor gene are determinants of these differences. In the US, the rates of occurrence of MM are at least twice as high in African Americans (AA) as in Caucasian Americans (CA). Strikingly, somatic TP53 mutations occur in large excess (at least 4-6-fold) in CA versus AA. On the other hand, TP53 contains polymorphisms specifying amino-acid differences that are under natural selection by the latitude of a population and have evolved during the migrations of humans over several hundred thousand years. The p53 protein plays important roles in DNA strand break repair and, therefore, in the surveillance of aberrant DNA recombination, leading to the B-cell translocations that are causal in the pathogenesis of MM. We posit that polymorphisms in one region of the TP53 gene (introns 2 and 3, and the proline-rich domain) specify a concentration of the p53 protein with a higher capacity to repress translocations in CA than AA patients. This, in turn, results in a higher risk of acquiring inactivating, somatic mutations in a different region of the TP53 gene (DNA binding domain) in CA than in AA patients. Such a mechanism, by which the polymorphic status of a gene influencing its own "spontaneous" mutation frequency, may provide a genetic basis to address ethnicity-related differences in the incidence and phenotypes of many different forms of cancer.