DNA Repair Pathway Profiling and Microsatellite Instability in Colorectal Cancer

Abstract

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. Method: By using theTaqMan 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. Tumornormal 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 (R S z 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). Conclusion: Our study provides an initial characterization of the DNA repair pathways for understanding the cellular DNA damage/repair system in human colorectal cancer.

Functional, Genetic, and Epigenetic Aspects of Base and Nucleotide Excision Repair in Colorectal Carcinomas

“…Aberrant promoter methylation of BER and NER genes have already been reported in other types of cancer, but not studied in CRC (15). An investigation of expression profiles of some BER and NER genes in tumor tissue did provide preliminary characterizations (16). Previous studies carried out on peripheral blood mononuclear cells (PBMC) showed suppressed BER and NER capacities in patients with CRC compared with healthy individuals (17)(18)(19).…”

Genetic Variants of Nucleotide Excision Repair Genes Are Associated with DNA Damage in Coke Oven Workers

“…Investigation on transcription-coupled repair has mainly focused on the mutations in Cockayne syndromes (11). SNPs in the CSB gene have been reported to affect cell survival (11) and to be associated with cancer risk (12,13). For example, the CSB Met1097-Val polymorphism had a significant impact on recurrence of superficial bladder cancer (14).…”

Genetic Polymorphisms of DNA Repair Gene: XRCC1 Pro206Pro and Gln632Gln in a Chinese Han Population

“…Regions conserved between species are likely to contain functionally important domains. Recently, one colorectal cancer study observed that XRCC1 RNA expression was correlated with microsatellite instability status among Caucasian Americans (Yu et al 2006); one study of familial breast cancer showed that XRCC1 IVS10 + 141G?A was associated with increased expression of XRCC1 mRNA and protein among Caucasian Americans (Bu et al 2006); and one bladder cancer study reported that XRCC1 proteins were strongly associated with patient outcome following radiotherapy among Caucasian British (Sak et al 2005). Those results suggested that XRCC1 plays an important functional role in cancer development and prognosis, although the underlying molecular mechanisms of XRCC1 Pro206Pro and Gln632Gln remain to be established.…”