Colorectal cancers show distinct mutation spectra in members of the canonical WNT signaling pathway according to their anatomical location and type of genetic instability.
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.
Albuquerque
Cristina
C
Centro de Investigação de Patobiologia Molecular (CIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, EPE, Lisboa, Portugal. mc.albuquerque@sapo.pt
Baltazar
Célia
C
Filipe
Bruno
B
Penha
Filipa
F
Pereira
Teresa
T
Smits
Ron
R
Cravo
Marília
M
Lage
Pedro
P
Fidalgo
Paulo
P
Claro
Isabel
I
Rodrigues
Paula
P
Veiga
Isabel
I
Ramos
José Silva
JS
Fonseca
Isabel
I
Leitão
Carlos Nobre
CN
Fodde
Riccardo
R
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D060466:Axin Protein; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000235:genetics*; D017491:Genes, APC; D006801:Humans; D007124:Immunoenzyme Techniques; D053842:Microsatellite Instability; D009154:Mutation / Q000235:genetics*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
C491761:AXIN2 protein, human; D060466:Axin Protein; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D051153:Wnt Proteins; D051176:beta Catenin