Molecular phenotype of inflammatory bowel disease-associated neoplasms with microsatellite instability.
OBJECTIVE
Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer (CRC). We sought to determine the frequency of high-level microsatellite instability (MSI-H) and the mutational and methylation profile of MSI-H IBD-related neoplasms (IBDNs).


METHODS
A total of 124 IBDNs (81 cancers, 43 dysplasias) from 78 patients were studied for the frequency of MSI-H and hypermethylation of 3 target genes: MLH1 , HPP1 , and RAB-32 . Fifteen MSI-H IBDNs were characterized according to their profile of frameshift mutations in 28 mononucleotide repeats and compared with 46 sporadic MSI-H CRCs.


RESULTS
Nineteen of 124 IBDNs were MSI-H. The frequency of frameshift mutations in coding mononucleotide repeats was significantly lower in MSI-H IBDNs than in sporadic MSI-H CRCs for TGFBR2 (7 of 14 vs 34 of 43 samples; P = .047) and ACVR2 (3 of 14 vs 25 of 43 samples; P = .029). In contrast, ICA1 was mutated in 3 of 9 MSI-H IBDNs vs 2 of 54 sporadic MSI-H CRCs ( P = .028). HPP1 and RAB32 methylation was independent of MSI status and was observed in 4 of 59 and 0 of 64 nondysplastic mucosae, 20 of 38 and 1 of 25 dysplasias, and 28 of 61 and 20 of 60 carcinomas, respectively.


CONCLUSIONS
The profiles of coding microsatellite mutations (instabilotypes) differ significantly between MSI-H IBDNs and MSI-H sporadic CRCs. Specifically, TGFBR2 and ACVR2 mutations are significantly rarer in MSI-H IBDNs than in MSI-H sporadic CRCs. Furthermore, HPP1 methylation occurs early, in 7% of nondysplastic and approximately half of dysplastic mucosae, whereas RAB32 methylation occurs at the transition to invasive growth, being rarer in dysplasias.
Schulmann
Karsten
K
Division of Gastroenterology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Mori
Yuriko
Y
Croog
Victoria
V
Yin
Jing
J
Olaru
Andreea
A
Sterian
Anca
A
Sato
Fumiaki
F
Wang
Suna
S
Xu
Yan
Y
Deacu
Elena
E
Berki
Agnes T
AT
Hamilton
James P
JP
Kan
Takatsugu
T
Abraham
John M
JM
Schmiegel
Wolff
W
Harpaz
Noam
N
Meltzer
Stephen J
SJ
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D019175:DNA Methylation; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D015995:Prevalence; D011401:Promoter Regions, Genetic / Q000502:physiology; D012307:Risk Factors; D020691:rab GTP-Binding Proteins / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C423567:TMEFF2 protein, human; C466094:Rab32 protein, human; D000070957:MutL Protein Homolog 1; D020691:rab GTP-Binding Proteins