Document Detail

Colorectal cancers show distinct mutation spectra in members of the canonical WNT signaling pathway according to their anatomical location and type of genetic instability.
MedLine Citation:
PMID:  20544848     Owner:  NLM     Status:  MEDLINE    
It is unclear whether the mutation spectra in WNT genes vary among distinct types of colorectal tumors. We have analyzed mutations in specific WNT genes in a cohort of 52 colorectal tumors and performed a meta-analysis of previous studies. Notably, significant differences were found among the mutation spectra. We have previously shown that in familial adenomatous polyposis, APC somatic mutations are selected to provide the "just-right" level of WNT signaling for tumor formation. Here, we found that APC mutations encompassing at least two beta-catenin down-regulating motifs (20 a.a. repeats) are significantly more frequent in microsatellite unstable (MSI-H) than in microsatellite stable (MSS) tumors where truncations retaining less than two repeats are more frequent (P = 0.0009). Moreover, in cases where both APC hits are detected, selection for mutations retaining a cumulative number of two 20 a.a. repeats became apparent in MSI-H tumors (P = 0.001). This type of mutations were also more frequent in proximal versus distal colonic tumors, regardless of MSI status (P = 0.0008). Among MSI-H tumors, CTNNB1 mutations were significantly more frequent in HNPCC than in sporadic lesions (28% versus 6%, P < 10-6) and were preferentially detected in the proximal colon, independently of MSI status (P = 0.017). In conclusion, the observed spectra of WNT gene mutations in colorectal tumors are likely the result from selection of specific levels of beta-catenin signaling, optimal for tumor formation in the context of specific anatomical locations and forms of genetic instability. We suggest that this may underlie the preferential location of MMR deficient tumors in the proximal colon.
Cristina Albuquerque; Célia Baltazar; Bruno Filipe; Filipa Penha; Teresa Pereira; Ron Smits; Marília Cravo; Pedro Lage; Paulo Fidalgo; Isabel Claro; Paula Rodrigues; Isabel Veiga; José Silva Ramos; Isabel Fonseca; Carlos Nobre Leitão; Riccardo Fodde
Related Documents :
18726168 - Recurring mlh1 deleterious mutations in unrelated chinese lynch syndrome families in si...
16283678 - Neurofibromatosis von recklinghausen type i phenotype and early onset of cancers in sib...
16969708 - Assessing the predictive accuracy of hmlh1 and hmsh2 mutation probability models.
20223028 - Deletion mutations in an australian series of hnpcc patients.
2025008 - Leukaemia mortality among relatives of cystic fibrosis patients.
18424338 - Common variable immunodeficiency: an update on etiology and management.
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Genes, chromosomes & cancer     Volume:  49     ISSN:  1098-2264     ISO Abbreviation:  Genes Chromosomes Cancer     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-06-14     Completed Date:  2010-09-16     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9007329     Medline TA:  Genes Chromosomes Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  746-59     Citation Subset:  IM    
Centro de Investigação de Patobiologia Molecular (CIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, EPE, Lisboa, Portugal.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Adenocarcinoma / genetics,  metabolism,  pathology
Adenoma / genetics,  metabolism,  pathology
Colorectal Neoplasms / genetics*,  metabolism,  pathology
Cytoskeletal Proteins / genetics*
Genes, APC*
Immunoenzyme Techniques
Microsatellite Instability*
Mutation / genetics*
Signal Transduction
Wnt Proteins / genetics*
beta Catenin / genetics*,  metabolism
Reg. No./Substance:
0/AXIN2 protein, human; 0/CTNNB1 protein, human; 0/Cytoskeletal Proteins; 0/Wnt Proteins; 0/beta Catenin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  Somatic alterations in the melanoma genome: A high-resolution array-based comparative genomic hybrid...
Next Document:  Disruption of transient receptor potential canonical channel 1 causes incomplete cytokinesis and slo...