DNA repair pathway profiling and microsatellite instability in colorectal cancer.
BACKGROUND
The ability to maintain DNA integrity is a critical cellular function. DNA repair is conducted by distinct pathways of genes, many of which are thought to be altered in colorectal cancer. However, there has been little characterization of these pathways in colorectal cancer.


METHODS
By using the TaqMan real-time quantitative PCR, RNA expression profiling of 20 DNA repair pathway genes was done in matched tumor and normal tissues from 52 patients with Dukes' C colorectal cancer.


RESULTS
The relative mRNA expression level across the 20 DNA repair pathway genes varied considerably, and the individual variability was also quite large, with an 85.4 median fold change in the tumor tissue genes and a 127.2 median fold change in the normal tissue genes. Tumor-normal differential expression was found in 13 of 20 DNA repair pathway genes (only XPA had a lower RNA level in the tumor samples; the other 12 genes had significantly higher tumor levels, all P<0.01). Coordinated expression of ERCC6, HMG1, MSH2, and POLB (RS>or=0.60) was observed in the tumor tissues (all P<0.001). Apoptosis index was not correlated with expression of the 20 DNA repair pathway genes. MLH1 and XRCC1 RNA expression was correlated with microsatellite instability status (P=0.045 and 0.020, respectively). An inverse correlation was found between tumor MLH1 RNA expression and MLH1 DNA methylation (P=0.003).


CONCLUSIONS
Our study provides an initial characterization of the DNA repair pathways for understanding the cellular DNA damage/repair system in human colorectal cancer.
Yu
Jinsheng
J
Department of Medicine, Washington University School of Medicine and Siteman Cancer Center, Saint Louis, Missouri 63110-1093, USA.
Mallon
Mary A
MA
Zhang
Wanghai
W
Freimuth
Robert R
RR
Marsh
Sharon
S
Watson
Mark A
MA
Goodfellow
Paul J
PJ
McLeod
Howard L
HL
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004265:DNA Helicases / Q000235:genetics; D019175:DNA Methylation; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D024243:HMGB1 Protein / Q000235:genetics; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D000075223:Poly-ADP-Ribose Binding Proteins; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D000076105:X-ray Repair Cross Complementing Protein 1; D000099270:Y-Family DNA Polymerases
D048868:Adaptor Proteins, Signal Transducing; D004265:DNA Helicases; D045643:DNA Repair Enzymes; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D004259:DNA-Directed DNA Polymerase; D024243:HMGB1 Protein; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009687:Nuclear Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D012333:RNA, Messenger; D000076105:X-ray Repair Cross Complementing Protein 1; C501486:MLH1 protein, human; C000619371:XRCC1 protein, human; C404302:POLK protein, human; D000099270:Y-Family DNA Polymerases; C497172:MSH2 protein, human; C078673:ERCC6 protein, human