Alterations of the human MSH2 gene, a homologue of the bacterial MutS mismatch repair gene, co-segregate with the majority of hereditary non-polyposis colon cancer (HNPCC) cases.
Protein truncating mutations in the hMLH1 or hMSH2 genes were found in 50% of families with HNPCC (6 of 12) but were not observed in any of the remaining familial aggregations that did not fulfill the standard criteria for HNPCC.
Major advances in the molecular genetics of HNPCC have occurred during the past two years with identification of the hMSH2 gene at chromosome 2p and the hMLH1 gene at chromosome 3p, both of which have been cloned.
By screening members of Finnish families displaying hereditary nonpolyposis colorectal cancer (HNPCC) for predisposing germline mutations in MSH2 and MLH1, we show that two mutations in MLH1 together account for 63% (19/30) of kindreds meeting international diagnostic criteria.
As a correlation between point mutations in MSH2 gene and the presence of genetic instability in hereditary non-polyposis colon cancer (HNPCC) and related tumors has been found, we analyzed the sequence of a conversed region of this gene in the cases showing this phenomenon.
These methods have been used to analyze two large HNPCC kindreds exhibiting features of the Muir-Torre syndrome and demonstrate that cancer susceptibility is due to the inheritance of a frameshift mutation in the MSH2 gene in one family and a nonsense mutation in the MSH2 gene in the other family.
Analysis of all the 16 exons of hMSH2, in 34 unrelated HNPCC kindreds, has revealed seven novel pathogenic germ-line mutations resulting in stop codons either directly or through frameshifts.
A gene on chromosome 2 called hMSH2, which demonstrates homology with the bacterial repair gene MutS, has been shown to be altered in some families with hereditary nonpolyposis colorectal cancer.
We have identified the source of the genetic instability in one ovarian tumor as a point mutation (R524P) in the human mismatch-repair gene MSH2 (Salmonella MutS homologue), which has recently been shown to be involved in hereditary nonpolyposis colorectal cancer.
Two susceptibility loci for hereditary nonpolyposis colorectal cancer (HNPCC) have been identified, and each contains a mismatch repair gene: MSH2 on chromosome 2p and MLH1 on chromosome 3p.
Two (mismatch repair) genes (hMSH2 on chromosome 2p and hMLH1 on chromosome 3p) have recently been identified which appear to be involved in the development of cancer in most of the HNPCC families.
With the development of the International Hereditary Nonpolyposis Colorectal Cancer Collaborative Group, knowledge can be disseminated worldwide about the public health importance of HNPCC and the need to implement highly targeted surveillance and management strategies in all clinical practice settings.
Mutations in genes associated with the DNA mismatch repair system were considered to play important roles in predisposition to cancer, since hMSH2 and hMLH1, human homologues of yeast MSH2 and MLH1 as well as bacterial mutS and mutL genes, were found to be involved in hereditary nonpolyposis colorectal cancer (HNPCC).
The results suggest that at least 40% of classic HNPCC kindreds are associated with germline mutations in hMSH2 and that most of these mutations produce drastic alterations in the predicted protein product.
In particular, hMSH2 and hMLH1 homologues of the bacterial DNA mismatch repair genes mutS and mutL, respectively, were shown to be mutated in a subset of HNPCC cases.
These data suggest the involvement of mismatch repair deficiency in the premalignant stage of tumorigenesis in HNPCC cases, and suggest that mismatch repair genes (MSH2 or others) are defective in the germline of nearly all these patients.
These data and reports indicating that S. cerevisiae msh2 mutations cause an instability of dinucleotide repeats like those associated with HNPCC suggest that hMSH2 is the HNPCC gene.
Hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome) is an autosomal dominant disease characterized by early-onset intestinal neoplasms, localization of tumors in the proximal colon, and frequent association with cancers at other sites, especially the endometrium, skin, and stomach.
Hereditary nonpolyposis colon cancer (HN-PCC) is an autosomally inherited predisposition to cancer that has recently been linked to defects in the human mismatch repair genes hMSH2 and hMLH1.