title: Analysis of colorectal cancer by comparative genomic hybridization: evidence for induction of the metastatic phenotype by loss of tumor suppressor genes.
abstract: Current models suggest that colon cancer initiation and progression are secondary to both the activation of oncogenes and the deletion of tumor suppressor genes. The role of each, however, is still poorly understood, particularly with regard to the induction of metastasis. We hypothesized that genetic differences exist between tumors that metastasize distantly and those that do not, and that oncogenes and tumor suppressor genes participate equally in this process. To address this hypothesis, human tumor specimens from localized [tumor-node-metastasis (TNM) stage I-III] and primary colon cancers (n = 10) were directly compared with metastatic (TNM stage IV) lesions (n = 10) using comparative genomic hybridization analysis. Although several alterations were shared equally between primary tumors and metastases (+7q, +19q, and +20q), two patterns of distinguishing alterations were observed: (a) alterations that were more extensive in liver metastases than in primary tumors (+8q, +13q, -4p, -8p, -15q, -17p, -18q, -21q, and -22q); and (b) alterations that were unique to metastatic lesions (-9q, -11q, and -17q). Overall, genetic losses were more common than gains, and, more importantly, the number of losses/tumor was significantly higher for metastases than for primary tumors (9.3 + 1.3 versus 4.1 + 0.7; P = 0.00062, Wilcoxon's rank-sum test). The distinct predominance of genetic losses 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 are likely to exist.
authors.affiliation: Department of Surgery, H. Lee Moffitt Cancer Center, University of South Florida, Tampa 33612, USA.
authors.forename: A
authors.initials: A
authors.lastname: Paredes-Zaglul
authors.forename: J J
authors.initials: JJ
authors.lastname: Kang
authors.forename: Y P
authors.initials: YP
authors.lastname: Essig
authors.forename: W
authors.initials: W
authors.lastname: Mao
authors.forename: R
authors.initials: R
authors.lastname: Irby
authors.forename: M
authors.initials: M
authors.lastname: Wloch
authors.forename: T J
authors.initials: TJ
authors.lastname: Yeatman
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000556:secondary*; D000328:Adult; D000368:Aged; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor / Q000235:genetics*; D006801:Humans; D017403:In Situ Hybridization; D008113:Liver Neoplasms / Q000235:genetics* / Q000556:secondary*; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010641:Phenotype