hMLHl and hMSH2 somatic inactivation mechanisms in sporadic colorectal cancer patients

Abstract

Much is known about the role of germline inactivation in mismatch repair (MMR) genes in hereditary non-polyposis colorectal cancer (HNPCC), but the impact of somatic MMR gene changes on sporadic colorectal cancer remains to be elucidated. In hereditary cases the hMLH1 and hMSH2 genes were shown to have a great importance, and in order to examine the somatic inactivation mechanisms of the two MMR genes hMLH1 and hMSH2 we screened 37 Hungarian sporadic colorectal cancer patients for allelic imbalance (AI), microsatellite instability (MSI), hMLH1 promoter hypermethylation and somatic mutations. Thirteen of the examined tumours (35%) were characterized by low-level MSI and none of the cases belonged to the high MSI group. Nine (24%) and seven (19%) cases had AI at the hMLH1 and hMSH2 genes, respectively. Seven tumours (19%) showed dense promoter hypermethylation of hMLH1, but only two patients had somatic mutations, one for each MMR gene. According to our study on this limited set of cases the most prominent mismatch repair inactivation mechanism in sporadic colorectal cancer patients is the hMLH1 promoter hypermethylation which may have a role in the carcinogenesis of sporadic colorectal cancer.

Fruits, Vegetables, and hMLH1 Protein–Deficient and –Proficient Colon Cancer: The Netherlands Cohort Study

“…First, the percentage of hMLH1 protein -deficient colon cancers in our study corresponds with the literature (10,11,16). Second, we found a high agreement with classification based on the MSI marker BAT-26 6 as expected (39)(40)(41).…”

“…1). In sporadic colorectal cancer, hMLH1 gene inactivation by promoter hypermethylation is thought to be the main mechanism behind MMR deficiency (2)(3)(4)(5)(6)(7)(8).…”

Evidence for the role of aberrant DNA methylation in the pathogenesis of Lynch syndrome adenomas

“…[6][7][8][9] The underlying role of the MMR proteins in CRC was demonstrated when many of these genes, including MLH1, MSH2, MSH6 and PMS2, were discovered to be the cause of the Lynch syndrome (also known as HNPCC). The Lynch syndrome is associated with a 60-80% lifetime risk of CRC as well as with an increased risk of endometrial and genitourinary tract cancer.…”

Novel hMSH2, hMSH6 and hMLH1 gene mutations and microsatellite instability in sporadic colorectal cancer

“…The alterations in the hMSH2 and hMLH1 genes are the most common in HNPCC in several countries (Mitchell et al 2002), whereas germline mutations in hMSH6, hPMS1, and hPMS2 seem to be rare (Peltomäki 2001). In contrast, few reports revealed somatic gene mutations in the DNA mismatch repair gene in colorectal cancers (Liu et al 1995;Jeong et al 2003;Kámory et al 2003). In this study, 8 of 31 cases (25.8%) exhibited Wve novel exonic gene mutations in each of hMSH2, hMSH6, hMLH1, and, several intronic polymorphisms.…”