ANALYSIS OF COLORECTAL-CANCER BY COMPARATIVE GENOMIC HYBRIDIZATION - EVIDENCE FOR INDUCTION OF THE METASTATIC PHENOTYPE BY LOSS OF TUMOR-SUPPRESSOR GENES

Current models suggest that colon cancer initiation and progression ar e secondary to both the activation of oncogenes and the deletion of tu mor suppressor genes. The role of each, however, is still poorly under stood, particularly with regard to the induction of metastasis. We hyp othesized that genetic differences exist between tumors that metastasi ze distantly and those that do not, and that oncogenes and tumor suppr essor genes participate equally in this process. To address this hypot hesis, human tumor specimens from localized [tumor-node-metastasis (TN M) stage I-III] and primary colon cancers (n = 10) were directly compa red with metastatic (TNM stage IV) lesions (ii = 10) using comparative genomic hybridization analysis. Although several alterations were sha red equally between primary tumors and metastases (+7q, +19q, and +20q ), two patterns of distinguishing alterations were observed: (a) alter ations that were more extensive in Liver metastases than in primary tu mors (+8q, +13q, -4p, -8p, -15q, -17p, -18q, -21q, and -22q); and (b) alterations that were unique to metastatic lesions (-9q, -11q, and -17 q). Overall, genetic losses were more common than gains, and, more imp ortantly, the number of losses/tumor was significantly higher for meta stases than for primary tumors (9.3 + 1.3 versus 4.1 + 0.7; P = 0.0006 2, Wilcoxon's rank-sum test). The distinct predominance of genetic los ses in the metastatic lesions when compared with the primary localized tumors provides evidence that the metastatic phenotype is induced by the deletion of tumor suppressor genes and permits the construction of physical maps targeting regions where novel tumor suppressor genes ar e likely to exist.