Missense mutations in hMLH1 associated with colorectal cancer

Abstract

One of the most prevalent hereditary syndromes associated with colorectal cancer is hereditary nonpolyposis colorectal cancer (HNPCC). The inherited gene defects in HNPCC have been shown to reside in DNA mismatch repair genes, mostly hMSH2 or hMLH1. Most HNPCC patients are heterozygous with regard to the relevant mismatch repair gene; they have one normal and one mutated allele, and mismatch repair in normal somatic cells is functional. Cancer predisposition in HNPCC is believed to be associated with the loss of the wild-type allele in somatic cells, resulting in defective DNA mismatch repair. This gives rise to DNA microsatellite instability (MSI), an increased somatic mutation rate, and eventually, to the accumulation of mutations in genes involved in colorectal carcinogenesis. In support of this theory, colorectal tumors in HNPCC patients and in mice deficient for hMSH2 or hMLH1 show MSI. Here, we describe two missense mutations in hMLH1 exon 16 associated with colorectal cancer. Interestingly, the tumors do not show MSI. This raises some potentially important issues. First, even microsatellite-negative colorectal tumors can be associated with germline mutations and these will be missed if an MSI test is used to select patients for mutation screening. Second, the lack of MSI in these cases suggests that the mechanism involved in carcinogenesis could be different from that generally hypothesized.

Accuracy of Revised Bethesda Guidelines, Microsatellite Instability, and Immunohistochemistry for the Identification of Patients With Hereditary Nonpolyposis Colorectal Cancer

“…These contradictory results bring about the issue of determining the pathogenic significance of missense mismatch repair gene mutations. With respect to the MLH1: Lys618Ala variant, although it has been shown to segregate with the HNPCC phenotype, 23,[42][43][44] it has also been reported in healthy controls. 13 Regarding the MSH2:Ile145Met variant, it has been reported in other HNPCC families (http: //www.insight-group.org), but functional results raised some concerns with respect to its pathogenicity.…”

The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer

“…Perhaps the most notable feature of MLH1 D132H is that it does not cause a strong MSI phenotype like classic MLH1 mutations. Previously, MLH1 K618A and MLH1 E578G were described in probands with HNPCC and CRCs without MSI 11,12 . But these mutations occur in a region of the protein that is not conserved across multiple species, and thus their interpretation has been controversial [13][14][15] .…”

GermlineMLH1andMSH2mutational spectrum including frequent large genomic aberrations in Hungarian hereditary non-polyposis colorectal cancer families: Implications for genetic testing

“…Although K618A is one of the few changes listed as pathogenic and also as non-pathogenic in the InSiGHT database, previously published data indicate that both of these alterations are associated with an increased risk of colorectal cancer [23][24][25] . Furthermore, this C-terminal part of the MLH1 protein was shown to play a crucial role in proteinprotein interactions, and a mutation of the same amino acid, K618T, caused nearly complete disruption of the interaction between MLH1 and MRE11, perhaps highlighting the potential function of this residue [26] .…”