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Low-Level Microsatellite Instability in Most Colorectal Carcinomas¹

Department of Medical Genetics, Biomedicum Helsinki [P. Lai., V. L., L. A. A.] and Finnish Genome Center [P. Lah.], University of Helsinki, FIN-00014 Helsinki, Finland; Cancer Epigenetics Laboratory, Molecular Pathology Program, Centro Nacional de Investigaciones Oncologicas, 28029 Madrid, Spain [M. E.]; The Johns Hopkins Oncology Center, Baltimore, Maryland 21231 [M. E., M. G., J. G. H.]; Department of Surgery, Jyväskylä Central Hospital, FIN-40620 Jyväskylä, Finland [J-P. M.]; Second Department of Surgery [H. J.] and Department of Oncology [L. A. A.], Helsinki University Central Hospital, FIN-00029 Helsinki, Finland; Finnish Red Cross Blood Transfusion Service, FIN-00310 Helsinki, Finland [P. S.]; Department of Pathology, Norris Cancer Center, University of Southern California School of Medicine, Los Angeles, California 90033 [K-M. K., D. S.]; and Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom [R. S. H.]

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.

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