Refining molecular analysis in the pathways of colorectal carcinogenesis.

Journal article

BACKGROUND and AIMS: In the stepwise model, specific genetic and epigenetic changes accumulate as colorectal adenomas progress to carcinomas (CRCs). CRCs also acquire global phenotypes, particularly microsatellite instability (MSI) and aneuploidy/polyploidy (chromosomal instability, CIN). Few changes specific to MSI-low or CIN+ cancers have been established. METHODS: We investigated 100 CRCs for: mutations and loss of heterozygosity (LOH) where appropriate, of APC, K-ras, BRAF, SMAD4, and p53; deletion on 5q around APC and 18q around SMAD4; total chromosomal-scale losses and gains; MSI; and CIN. RESULTS: As expected, CIN- cancers had fewer chromosomal changes overall than CIN+ lesions, but after correcting for this, 5q deletions alone predicted CIN+ status. 5q deletions were not, however, significantly associated with APC mutations, which were equally frequent in CIN+ and CIN- tumors. We therefore found no evidence to show that mutant APC promotes CIN. p53 mutations/LOH were more common in CIN+ than CIN- lesions, and all chromosomal amplifications were in CIN+ tumors. CIN- cancers could be subdivided according to the total number of chromosomal-scale changes into CIN-low and CIN-stable groups; 18q deletion was the best predictor, being present in nearly all CIN-low lesions and almost no CIN-stable tumors. MSI-low was not associated with CIN, any specific mutation, a mutational signature, or clinicopathologic characteristic. CONCLUSIONS: Overall, the components of the stepwise model (APC, K-ras, and p53 mutations, plus 18q LOH) tended to co-occur randomly. We propose an updated version of this model comprising 4 pathways of CRC pathogenesis, on the basis of 5q/18q deletions, MSI (high/low), and CIN (high/low/stable).

Authors: Rowan, A; Halford, S; Gaasenbeek, M; Kemp, Z; Sieber, O

• Publication status: Published
• Journal: Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
• Volume: 3
• Issue: 11
• Pages: 1115-1123
• Publication date: 2005-11-01
• DOI: 10.1016/s1542-3565(05)00618-x
• EISSN: 1542-7714
• ISSN: 1542-3565
• Language: English
• Keywords: Genes, ras; Genes, APC; Chromosome Deletion; Disease Progression; Mutation; Genes, p53; Colorectal Neoplasms; Carcinoma; Chromosomal Instability; Loss of Heterozygosity; Microsatellite Repeats