Histologic characteristics of non-microsatellite-instable colon adenomas correlate with distinct molecular patterns.
Colon carcinogenesis encompasses the stepwise accumulation of genomic aberrations correlated with the transition of aberrant crypt-adenoma-carcinoma. Recent data have revealed that, in addition to the microsatellite-instable phenotype, the chromosome instability pathway, representing four fifth of the colon carcinoma, could be involved in heterogeneous molecular alterations. Our project was aimed at determining the existence of distinct molecular subtypes in 159 non-microsatellite-instable colon polyps and their correlation with histology and dysplasia, using allelotyping, MGMT promoter gene methylation status, and K-RAS mutation analyses. Allelic imbalance, MGMT methylation, and K-RAS mutations arise in 62%, 39%, and 32% of polyps, respectively. Only 14% of polyps had no alterations. A 2-way hierarchical clustering analysis of the allelic imbalances identified subgroups of polyps according to their allelic imbalance frequency and distribution. Not only tubulovillous adenoma but also high-grade adenomas were correlated with high global allelic imbalance frequency (P = .005 and P = .003), with allelic imbalance at microsatellites targeting chromosomes 1, 6, and 9. In conclusion, the data presented in this study show that a large heterogeneity exists in the molecular patterns of alterations in precancerous colon lesions, favoring different modes of tumor initiation. Therefore, molecular alterations correlated with tubulovillous-type and high-grade dysplasia could represent targets identifying predictive factors of progression.
EA 4438, Université de Strasbourg, F-67200 Bâtiment Inserm, France. agnes.mechine@chru-strasbourg.fr
Agnès
A
Neuville
Céline
C
Nicolet
Nicolas
N
Meyer
Anne
A
Schneider
Michèle
M
Legrain
Cécile
C
Brigand
Bernard
B
Duclos
Philippe
P
Bachellier
Pierre
P
Oudet
Jean-Pierre
JP
Bellocq
Michèle
M
Kedinger
Marie-Pierre
MP
Gaub
Dominique
D
Guenot
D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000368:Aged; D022981:Allelic Imbalance; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D003111:Colonic Polyps / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D004273:DNA, Neoplasm / Q000032:analysis; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D025521:Tumor Suppressor Proteins / Q000235:genetics
D004273:DNA, Neoplasm; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes