Hereditary non‐polyposis colorectal cancer and the role of hPMS2 and hEXO1 mutations

Abstract

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant, inherited condition that is characterized primarily by the development of early-onset colorectal cancer and a number of other epithelial malignancies. The underlying genetic basis of the disease is associated with a breakdown of DNA-mismatch repair. There are many genes involved in DNA-mismatch repair, and five of them have been implicated in HNPCC. Two of the genes (hMSH2 and hMLH1) account for the majority of HNPCC families (approximately 60%), and it is not known what the exact contributions of the remaining three genes (hPMS1, hPMS2, and hMSH6) are in relation to this condition. In addition, a sixth gene (hEXO1) has been associated with a disease phenotype that is consistent with HNPCC. Current estimates suggest that all four of these genes, combined, may account for up to 5% of families. In this report, we examine the contribution of hPMS2 and hEXO1 to a well-defined set of families that fulfill the diagnostic criteria for HNPCC. The genes, hPMS2 and hEXO1, were studied by denaturing high performance liquid chromatography (DHPLC) analysis in 21 families that have previously been determined not to have mutations in hMSH2 or hMLH1. hPMS2 accounts for a small proportion of HNPCC families, and none were deemed to be associated with hEXO1. Mutations in hPMS2 appear to account for a small proportion of families adhering to the Amsterdam II criteria, whereas hEXO1 does not appear to be associated with HNPCC.

The role of DNA exonucleases in protecting genome stability and their impact on ageing

“…Eukaryotic EXO1 is a member of the Rad2/FEN1 family of nucleases (Lee and Wilson 1999) (Table 2) and is one of four nucleases that may be involved in MMR, although it is not (as originally reported) an orthologue of the Escherichia coli MMR protein EXO1 (Genschel et al 2002;Tishkoff et al 1997Tishkoff et al , 1998. There are some reports that loss of EXO1 gives rise to one form of the MMR-deficient syndrome human nonpolyposis colon cancer, HNPCC (Wu et al 2001), but a direct association has been questioned (Thompson et al 2004). Eukaryotic EXO1 is involved in various DNA metabolic pathways other than MMR, including meiosis (Fiorentini et al 1997) and recombination (Tsubouchi and Ogawa 2000).…”

The role of MLH1, MSH2 and MSH6 in the development of multiple colorectal cancers

“…In addition, the relatively high incidence of methylation in MLH1-negative cancers (65%) throughout the group suggests that the majority of these patients have a sporadic MSI-H cancer and that an underlying germline mutation is not responsible. Although the majority of the patients in our group do not appear to have classical HNPCC, the role of alternative MMR genes such as MSH6, PMS1, PMS2, MLH3 and EXO1 should be considered (Akiyama et al, 1997;Miyaki et al, 1997;Thompson et al, 2004). Since PMS1, MLH3 and EXO1 have only been implicated in the development of colorectal cancers in case reports (Liu et al, 1996;Hienonen et al, 2003;Thompson et al, 2004), they are unlikely to be implicated in the development of cancer in our group.…”

“…Although the majority of the patients in our group do not appear to have classical HNPCC, the role of alternative MMR genes such as MSH6, PMS1, PMS2, MLH3 and EXO1 should be considered (Akiyama et al, 1997;Miyaki et al, 1997;Thompson et al, 2004). Since PMS1, MLH3 and EXO1 have only been implicated in the development of colorectal cancers in case reports (Liu et al, 1996;Hienonen et al, 2003;Thompson et al, 2004), they are unlikely to be implicated in the development of cancer in our group. However, MSH6 mutations may be involved in 5% of all HNPCC families and give rise to atypical HNPCC with a delayed onset of cancer.…”

“…Mutational analysis in these cases may help clarify the role of MSH6. Mutations of PMS2 have been shown to be important in a small group of HNPCC patients (Thompson et al, 2004). Although primary mutations of PMS2 are uncommon, the inclusion of PMS2 immunohistochemistry may aid the identification of MLH1 germline mutations in MSI-H cancers that continue to express MLH1 (Thompson et al, 2004).…”

Genetic Bases for Predisposition to Common Multifactorial Disease in Man. Part II

“…These genes include MLH1, MSH2, MSH6, PMS2, MLH3, and PMS1, in decreasing frequency of occurrence (52). Two genes that were previously implicated as the cause of HNPCC in some families, EXO1 and TGFBR2, have been shown to be unlikely causes of HNPCC (73). Mutations in MSH2 (chromosome 2p16), MLH1 (chromosome 3p21), and MSH6 (chromosome 2p16) account for >95% of the germline mutations in the families with defi ned genetic aetiology (52,73).…”