Defective DNA mismatch repair determines a characteristic transcriptional profile in proximal colon cancers.
OBJECTIVE
Colon cancers with defective DNA mismatch repair (MMR) have peculiar molecular, pathologic, and clinical features, including high-level microsatellite instability, conspicuous lymphocytic infiltration, preferential location in the proximal colon, and better prognosis. Our aim was to characterize the transcriptional profile of this colon cancer subset.


METHODS
An oligonucleotide microarray containing 12,625 probes was used to evaluate gene expression in 25 proximal colon cancers, 10 samples of normal colon mucosa, and 14 colon cancer cell lines. Transcriptional profiles of MMR-deficient cancers and cell lines were compared with those of their MMR-proficient counterparts.


RESULTS
Unsupervised analysis of microarray data showed that MMR status exerts a predominant influence on the gene expression profile of proximal colon cancers. Hierarchical clustering divided the cancers into 2 groups corresponding almost perfectly with their MMR status. Supervised analysis identified numerous gene expression changes that represent a genetic signature of MMR-deficient colon cancers. Changes in genes involved in apoptosis and the immune response were consistent with the better prognosis of MMR-deficient cancers. In MMR-deficient cancers and cell lines, 4-1BBL, a crucial gene in the anti-tumor immune response, was, respectively, 2.4 and 6.0 times more expressed than in their MMR-proficient counterparts. This difference was confirmed by quantitative reverse-transcription polymerase chain reaction and flow cytometric assessment of 4-1BBL protein expression in colon cancer cell lines. Our analysis also showed novel possible gene targets of microsatellite instability.


CONCLUSIONS
MMR inactivation produces distinct changes in the cellular messenger RNA pool, which is consistent with a unique tumorigenesis pathway.
di Pietro
Massimiliano
M
Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.
Sabates Bellver
Jacob
J
Menigatti
Mirco
M
Bannwart
Fridolin
F
Schnider
Annelies
A
Russell
Anna
A
Truninger
Kaspar
K
Jiricny
Josef
J
Marra
Giancarlo
G
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020137:Base Pair Mismatch; D002352:Carrier Proteins; D003106:Colon / Q000473:pathology / Q000502:physiology; D003110:Colonic Neoplasms / Q000235:genetics*; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D007413:Intestinal Mucosa / Q000473:pathology / Q000502:physiology; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D017384:Sequence Deletion; D014158:Transcription, Genetic
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004273:DNA, Neoplasm; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1