Abstract
A number of theories have been proposed to account for the origins of metastasis, although none as yet have adequately explained all of its characteristics. With ∼ 90% of cancer-related deaths due to the effects of disseminated tumors, improved understanding of this process is critical for reducing cancer-associated morbidity and mortality. Extensive research to investigate the molecular basis of this process has been conducted, and our lab has focused on the role of germline polymorphism in this complex process. Simple breeding experiments using a highly metastatic mouse model showed that germline polymorphisms significantly contribute to metastasis susceptibility. Genetic mapping studies revealed that a number of genomic regions are linked to metastasis susceptibility, including a metastasis modifier on mouse chromosome 19. Subsequent analysis identified Sipa1 as the most likely candidate for the observed linkage on Chr 19. Evaluation of SNPs in SIPA1 in a pilot association study in a human breast cancer cohort supported this possibility and demonstrated that SIPA1 polymorphisms are associated with various markers of poor prognosis including differential sentinel lymph node status. Taken together, these data suggest that germline polymorphism is an important modulating component in metastatic progression that needs to be investigated if we are to fully understand the metastatic process.