Low microsatellite instability is associated with poor prognosis in stage C colon cancer.
OBJECTIVE
The significance of low microsatellite instability (MSI-L) in colorectal cancer is poorly understood. No clear biologic distinction has been found between MSI-L and microsatellite stable (MSS) colorectal cancer, and these two phenotypes are usually combined when analyzed against the well-defined high MSI (MSI-H) phenotype. Evidence is emerging that an O(6)-methylguanine DNA methyltransferase (MGMT) gene defect is associated with MSI-L. Therefore, to further define this phenotype, we undertook a detailed analysis of the prognostic significance of MSI-L and loss of MGMT expression in colon cancer.


METHODS
The study cohort was 183 patients with clinicopathologic stage C colon cancer who had not received adjuvant therapy. We analyzed MSI status, MGMT, and mismatch repair protein expression, as well as MGMT and p16 promoter hypermethylation.


RESULTS
We showed that MSI-L defines a group of patients with poorer survival (P = .026) than MSS patients, and that MSI-L was an independent prognostic indicator (P = .005) in stage C colon cancer. Loss of MGMT protein expression was associated with the MSI-L phenotype but was not a prognostic factor for overall survival in colon cancer. p16 methylation was significantly less frequent in MSI-L than in MSI-H and MSS tumors and was not associated with survival.


CONCLUSIONS
MSI-L characterizes a distinct subgroup of stage C colon cancer patients, including the MSI-L subset of proximal colon cancer, who have a poorer outcome. Neither the MGMT defect nor p16 methylation are likely to contribute to the worse prognosis of the MSI-L phenotype.
Kohonen-Corish
Maija R J
MR
Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney NSW 2010, Australia. m.corish@garvan.org.au
Daniel
Joseph J
JJ
Chan
Charles
C
Lin
Betty P C
BP
Kwun
Sun Young
SY
Dent
Owen F
OF
Dhillon
Varinderpal S
VS
Trent
Ronald J A
RJ
Chapuis
Pierre H
PH
Bokey
E Leslie
EL
D000328:Adult; D000368:Aged; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology*; D019175:DNA Methylation; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D019942:Genes, p16; D042822:Genomic Instability; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000096:biosynthesis* / Q000235:genetics*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016019:Survival Analysis
D019853:O(6)-Methylguanine-DNA Methyltransferase