Low-level microsatellite instability in most colorectal carcinomas.
Twelve to 16% of colorectal cancers (CRCs) display a high degree of microsatellite instability (MSI-H), whereas most are believed to be microsatellite stable (MSS). The existence of a low degree of instability (MSI-L) group has also been proposed. By using the Bethesda panel of microsatellite markers, the microsatellite instability (MSI) status of CRCs can be determined. This set is recommended to distinguish between MSI-H and MSI-L/MSS. No definition for MSI-L has emerged. Most reports on MSI-L rely on the Bethesda panel, using 5-15markers. Tumors with more than 30% MSI are designated as MSI-H, but the lower limit for MSI-L is ambiguous. We hypothesized that if many markers are studied, almost all CRCs would show some MSI. It would be necessary to establish a cutoff level for MSI-L by showing that, above this cutoff level, tumors display molecular and/or clinical features different from those under the cutoff level. To perform this task, we analyzed 90 BAT26 stable CRC samples with 377 markers. MSI at 1-11 loci was observed in 71 (79%) of the 90 cases. K-RAS mutation, loss of heterozygosity, and MLH1 and MGMT hypermethylation analyses were performed, as well as clinical features being scrutinized, to examine possible differences between MSI-L and MSS tumors using all of the possible cutoff levels for MSI-L. Convincing differences between putative MSI-L and MSS groups were not observed. Our results show that the sensitivity of a typically used marker number to detect MSI-L is very low, and they suggest that MSS and MSI-L tumors have a common molecular background.
Laiho
Päivi
P
Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, FIN-00014 Helsinki, Finland.
Launonen
Virpi
V
Lahermo
Päivi
P
Esteller
Manel
M
Guo
Mingzhou
M
Herman
James G
JG
Mecklin
Jukka-Pekka
JP
Järvinen
Heikki
H
Sistonen
Pertti
P
Kim
Kyoung-Mee
KM
Shibata
Darryl
D
Houlston
Richard S
RS
Aaltonen
Lauri A
LA
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D011905:Genes, ras; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000070957:MutL Protein Homolog 1