The Frequency of Hereditary Defective Mismatch Repair in a Prospective Series of Unselected Colorectal Carcinomas

Abstract

A comprehensive analysis of somatic and germline mutations related to DNA mismatch-repair (MMR) genes can clarify the prevalence and mechanism of inactivation in colorectal carcinoma (CRC). In the present study, 257 unselected patients referred for CRC resection were examined for evidence of defective DNA MMR. In particular, we sought to determine the frequency of hereditary defects in DNA MMR in this cohort of patients. MMR status was assessed by testing of tumors for the presence or absence of hMLH1, hMSH2, and hMSH6 protein expression and for microsatellite instability (MSI). Of the 257 patients, 51 (20%) had evidence of defective MMR, demonstrating high levels of MSI (MSI-H) and an absence of either hMLH1 (n=48) or hMSH2 (n=3). All three patients lacking hMSH2, as well as one patient lacking hMLH1, also demonstrated an absence of hMSH6. DNA sequence analysis of the 51 patients with defective MMR revealed seven germline mutations-four in hMLH1 (two truncating and two missense) and three in hMSH2 (all truncating). A detailed family history was available for 225 of the 257 patients. Of the seven patients with germline mutations, only three had family histories consistent with hereditary nonpolyposis colorectal cancer. Of the remaining patients who had tumors with defective MMR, eight had somatic mutations in hMLH1. In addition, hypermethylation of the hMLH1 gene promoter was present in 37 (88%) of the 42 hMLH1-negative cases available for study and in all MSI-H tumors that showed loss of hMLH1 expression but no detectable hMLH1 mutations. Our results suggest that, although defective DNA MMR occurs in approximately 20% of unselected patients presenting for CRC resection, hereditary CRC due to mutations in the MMR pathway account for only a small proportion of patients. Of the 257 patients, only 5 (1.9%) appear to have unequivocal evidence of hereditary defects in MMR. The epigenetic (nonhereditary) mechanism of hMLH1 promoter hypermethylation appears to be responsible for the majority of the remaining patients whose tumors are characterized by defective DNA MMR.

Tumor-infiltrating lymphocytes in colorectal cancers with microsatellite instability are correlated with the number and spectrum of frameshift mutations

“…1 In colorectal cancers with microsatellite instability, inactivation of the DNA mismatch repair system results either from a somatic biallelic hypermethylation of the MLH1 gene, 2,3 an epigenetic alteration associated with aging, 4 or from a germline alteration of one gene allele of the DNA mismatch repair system followed by the somatic inactivation of the other. 1,5 Heterozygous germline mutations of genes of the DNA mismatch repair system are the cause of the Lynch syndrome or hereditary nonpolyposis colorectal cancer, the most common form of inherited colorectal cancers.…”

Patients with an unexplained microsatellite instable tumour have a low risk of familial cancer

“…Lynch syndrome (Hereditary NonPolyposis Colorectal Cancer (HNPCC)) accounts for about 5% of colorectal cancers and is caused by a germline mutation in one of the mismatch repair (MMR) genes (Aaltonen et al, 1998;Cunningham et al, 2001;Lynch and de la Chapelle, 2003;Hampel et al, 2005;Barnetson et al, 2006). Known MMR genes causing Lynch syndrome are MLH1, PMS2, MSH2, and MSH6.…”

“…MSI reflects either the presence of a germline mutation in the MMR system or somatic hypermethylation of the promoter region of the MLH1 gene (Cunningham et al, 2001). Patients with a tumour with MSI and somatic hypermethylation of the MLH1 promoter rarely carry a germline mutation in the MMR system, although rare exceptions have been reported.…”

Defective mismatch repair in the pathogenesis of low-grade appendiceal mucinous neoplasms and adenocarcinomas

“…[4][5][6] Conversely, defective hMSH2 or hMSH6 is almost always due to germline mutations. 7 Several investigators have reported that colorectal carcinomas with defective MMR often show distinctive clinicopathologic features including location in the proximal colon, younger patient age, mucinous differentiation, and a host-immune response characterized by a Crohn's-like lymphoid reaction or tumor infiltrating lymphocytes. [8][9][10][11][12][13][14][15][16][17][18][19][20] Serrated colonic polyps (hyperplastic polyps, mixed hyperplastic and adenomatous polyps, and serrated adenomas), particularly right-sided ones, are also associated with defective MMR 2,21 and are regarded as the precursor lesions for colorectal carcinomas with MSI, thus forming the basis of a 'serrated pathway' of colorectal tumorigenesis.…”