Deficient mismatch repair system in patients with sporadic advanced colorectal cancer

Abstract

A deficient mismatch repair system (dMMR) is present in 10 -20% of patients with sporadic colorectal cancer (CRC) and is associated with a favourable prognosis in early stage disease. Data on patients with advanced disease are scarce. Our aim was to investigate the incidence and outcome of sporadic dMMR in advanced CRC. Data were collected from a phase III study in 820 advanced CRC patients. Expression of mismatch repair proteins was examined by immunohistochemistry. In addition microsatellite instability analysis was performed and the methylation status of the MLH1 promoter was assessed. We then correlated MMR status to clinical outcome. Deficient mismatch repair was found in only 18 (3.5%) out of 515 evaluable patients, of which 13 were caused by hypermethylation of the MLH1 promoter. The median overall survival in proficient MMR (pMMR), dMMR caused by hypermethylation of the MLH1 promoter and total dMMR was 17.9 months (95% confidence interval 16.2 -18.8), 7.4 months (95% CI 3.7 -16.9) and 10.2 months (95% CI 5.9 -19.8), respectively. The disease control rate in pMMR and dMMR patients was 83% (95% CI 79 -86%) and 56% (30 -80%), respectively. We conclude that dMMR is rare in patients with sporadic advanced CRC. This supports the hypothesis that dMMR tumours have a reduced metastatic potential, as is observed in dMMR patients with early stage disease. The low incidence of dMMR does not allow drawing meaningful conclusions about the outcome of treatment in these patients.

Colorectal Carcinoma in Malaysians: DNA Mismatch Repair Pattern in a Multiethnic Population

“…dMMR was noted in 9.9% (14/142) of CRC in this study. This rate is comparable to those generally observed, except for being on the lower end of the range (Koopman et al, 2009;Kanthan et al, 2012;Legolvan et al, 2012). This could be due to inclusion of rectal carcinoma, which have been observed to show lower incidence of MSI (Hoogerbrugge et al, 2003), in this study.…”

“…50-85% of CRC develop through the chromosomal instability pathway while deficient DNA mismatch repair resulting in MSI accounts for about 10-20% of colorectal carcinoma (Koopman et al, 2009;Kanthan et al, 2012 ;Legolvan et al, 2012). Of the latter, germline mutation, followed by subsequent somatic knock-out of one of the mismatch repair genes, most frequently MLH1 or MSH2, resulting in HNPCC makes up less than 5% of all CRCs (Koopman et al, 2009).…”

“…Of the latter, germline mutation, followed by subsequent somatic knock-out of one of the mismatch repair genes, most frequently MLH1 or MSH2, resulting in HNPCC makes up less than 5% of all CRCs (Koopman et al, 2009). More frequently, MSI is due to sporadic hypermethylation silencing of the MLH1 promoter.…”

Optimization of a pentaplex panel for MSI analysis without control DNA in a Brazilian population: correlation with ancestry markers

“…In stage IV or metastatic CRC, the MSI is relatively uncommon (B4%). 13,21,22 It is well accepted that CRC patients with MSI have an overall better survival than MSS patients. [23][24][25] Importantly, MSI is being considered as a predictive biomarker of 5-fluorouracil (5-FU), irinotecan, and other chemotherapeutic agents response.…”

Relationship between telomere shortening, genetic instability, and site of tumour origin in colorectal cancers

“…There are at least two major pathways by which molecular events can lead to CRC: loss of heterozygosity with chromosomal instability, and a deficient DNA mismatch repair pathway with microsatellite instability (MSI) (Grady and Carethers, 2008;Ogino and Goel, 2008;Koopman et al, 2009). Although p53 and K-ras genes are known to be involved in chromosomal instability-associated carcinogenesis, MSI is frequently associated with the CpG island methylator phenotype (Barault et al, 2008).…”