Genetic progression in microsatellite instability high (MSI-H) colon cancers correlates with clinico-pathological parameters: A study of the TGRbetaRII, BAX, hMSH3, hMSH6, IGFIIR and BLM genes.
Colon carcinomas with microsatellite mutator phenotype exhibit specific genetic and clinico-pathological features. This report describes the analysis of 63 "microsatellite instability-high" (MSI-H) tumors for the presence of mutations in microsatellites located in the coding regions (CDRs) of 6 genes: TGFbetaRII, BAX, hMSH3, hMSH6, IGFIIR, and BLM. The following frequencies of mutations were detected: TGFbetaRII (70%), BAX (54%), hMSH3 (36.5%), IGFIIR (22%), hMSH6 (17.5%), and BLM (16%). The overall picture revealed combinations of mutations suggestive of a progressive order of accumulation, with mutations of TGFbetaRII and BAX first, followed by frameshifts in hMSH3, hMSH6, IGFIIR, and BLM. Correlations with 12 clinico-pathological parameters revealed that tumors with frameshifts in 1 or 2 CDRs were significantly better differentiated than tumors with frameshifts in more than 2 CDRs. We also found that mutations in the hMSH3 gene were significantly associated with decreased wall invasiveness and aneuploidy, and frameshifts in the BLM gene were significantly associated with the mucinous histotype. A trend toward an association between hMSH3 and IGFIIR with the medullary and conventional adenocarcinoma histotypes, respectively, was seen. Our results strengthen the concept that mutations in target genes have a role in the tumorigenic process of MSI-H tumors, and indicate that frameshifts in microsatellites located in CDRs occur in a limited number of combinations that could determine distinct clinico-pathological traits.
Calin
G A
GA
Department of Experimental and Diagnostic Medicine, University of Ferrara, Ferrara, Italy.
Gafà
R
R
Tibiletti
M G
MG
Herlea
V
V
Becheanu
G
G
Cavazzini
L
L
Barbanti-Brodano
G
G
Nenci
I
I
Negrini
M
M
Lanza
G
G
D000251:Adenosine Triphosphatases / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D016368:Frameshift Mutation; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000074081:MutS Homolog 3 Protein; D011003:Ploidies; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2; D053484:RecQ Helicases; D017527:Receptor, IGF Type 2 / Q000235:genetics*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D051028:bcl-2-Associated X Protein
D000251:Adenosine Triphosphatases; D004265:DNA Helicases; D004268:DNA-Binding Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000074081:MutS Homolog 3 Protein; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053484:RecQ Helicases; D017527:Receptor, IGF Type 2; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D051028:bcl-2-Associated X Protein; C494826:BAX protein, human; C094443:G-T mismatch-binding protein; C078444:MSH3 protein, human; C097151:Bloom syndrome protein; C421109:multidrug resistance-associated protein 1