SMAD4 mutations in colorectal cancer probably occur before chromosomal instability, but after divergence of the microsatellite instability pathway
| Autor: | Andrew Rowan, Harpreet Wasan, Kelly Woodford-Richens, Rebecca Roylance, Patricia Gorman, Sarah Halford, I. P. M. Tomlinson, Walter F. Bodmer, David C. Bicknell |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
animal structures
Time Factors Deleted in Colorectal Cancer Blotting Western DNA Mutational Analysis Loss of Heterozygosity Adenocarcinoma Biology medicine.disease_cause Loss of heterozygosity Transforming Growth Factor beta Chromosome instability Tumor Cells Cultured medicine Humans Allele neoplasms Polymorphism Single-Stranded Conformational Smad4 Protein Genetics Mutation Ploidies Multidisciplinary integumentary system Gene Expression Profiling Point mutation Cancer Microsatellite instability DNA Neoplasm Biological Sciences medicine.disease digestive system diseases Neoplasm Proteins DNA-Binding Proteins Cell Transformation Neoplastic Genes DCC embryonic structures Trans-Activators Cancer research Chromosome Deletion Chromosomes Human Pair 18 Colorectal Neoplasms Gene Deletion Microsatellite Repeats Signal Transduction |
| Zdroj: | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 98(17) |
| ISSN: | 0027-8424 |
| Popis: | Loss of chromosome 18q21 is well documented in colorectal cancer, and it has been suggested that this loss targets the DCC , DPC4 / SMAD4 , and SMAD2 genes. Recently, the importance of SMAD4 , a downstream regulator in the TGF-β signaling pathway, in colorectal cancer has been highlighted, although the frequency of SMAD4 mutations appears much lower than that of 18q21 loss. We set out to investigate allele loss, mutations, protein expression, and cytogenetics of chromosome 18 copy number in a collection of 44 colorectal cancer cell lines of known status with respect to microsatellite instability (MSI). Fourteen of thirty-two MSI − lines showed loss of SMAD4 protein expression; usually, one allele was lost and the other was mutated in one of a number of ways, including deletions of various sizes, splice site changes, and missense and nonsense point mutations (although no frameshifts). Of the 18 MSI − cancers with retained SMAD4 expression, four harbored missense mutations in the 3′ part of the gene and showed allele loss. The remaining 14 MSI − lines had no detectable SMAD4 mutation, but all showed allele loss at SMAD4 and/or DCC . SMAD4 mutations can therefore account for about 50–60% of the 18q21 allele loss in colorectal cancer. No MSI + cancer showed loss of SMAD4 protein or SMAD4 mutation, and very few had allelic loss at SMAD4 or DCC , although many of these MSI + lines did carry TGFBIIR changes. Although SMAD4 mutations have been associated with late-stage or metastatic disease, our combined molecular and cytogenetic data best fit a model in which SMAD4 mutations occur before colorectal cancers become aneuploid/polyploid, but after the MSI + and MSI − pathways diverge. Thus, MSI + cancers may diverge first, followed by CIN + (chromosomal instability) cancers, leaving other cancers to follow a CIN − MSI − pathway. |
| Databáze: | OpenAIRE |
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