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Another form o f inherited predisposition to colorectal cancer which is characterised by dominant transmission and high penetrance is hereditary nonpolyposis colorectal cancer (HNPCC) (Fitzgibbons et aL, 1987; Lynch et aL,

1993). The incidence o f HNPCC is higher than that o f FAP, accounting for 4% to 15% o f all colorectal cancer in industrialised nations (Lynch et aL, 1985). Some authors have even speculated that as many as 1 in 200 individuals may be affected by the disorder (Papadopoulos et aL, 1994). Although colon cancer is the most common form o f malignancy in HNPCC families, approximately two fifths of patients develop neoplasia at other sites (Fitzgibbons et aL, 1987; Mecklin and Jarvinen, 1991). The most common o f these is endometrial cancer, although predisposition to neoplasia extends to a wide range of extracolonic tissues including stomach, small intestine, upper renal tract, and ovary (Cristofaro et aL, 1987; Lynch et aL, 1990; Lynch and Lynch, 1989). Members of HNPCC families are also at increased risk of developing multiple independent primary tumours, and o f developing metachronous colorectal cancer (Lynch et aL, 1977; Fitzgibbons et aL, 1987). The presence of extracolonic cancers in some families but not others is used to divide HNPCC into two syndromes: Lynch I in which cancer is restricted to the colon, and Lynch II where there is a wider cancer susceptibility affecting a number o f organs (Boland and Troncale, 1984; Lynch et aL, 1985). Additionally a rare group o f families that have features similar to Lynch n but also present with sebaceous gland tumours and skin cancers are said to have Muir-Torre syndrome (Cohen et aL, 1991). Although it is possible to make clinical distinctions between these syndromes it has only recently been possible to separate some o f them at a genetic level (Kolodner et aL, 1995). A recent report suggests mutations that result in Lynch II may be caused by the production of mutant proteins that can interact with normal mismatch repair proteins, inactivating them in a dominant negative manner (Jager et aL, 1997). A fi-equent hMLHl founder mutation that is associated with a much reduced firequency of extracolonic tumours and is predicted to silence the mutant allele has now been reported (Jager et aL, 1997).

The underlying genetic cause o f HNPCC is mutation in one of several genes that function in DNA mismatch repair. The use of highly polymorphic microsatellite repeats, to look for loss o f heterozygosity in the cancers o f HNPCC patients, led to the

discovery that such sequences are unstable in a high proportion of tumours (Fischel et aL, 1993; Leach et aL, 1993). The instability was manifest as a high rate of mutation at microsatellite repeat loci, causing increases or decreases in the number of repeat units. This is probably due to slippage and consequent misalignment o f the growing DNA strand during replication (Streisinger and Owen, 1985; Roberts et aL, 1993). The repetitive nature of microsatellite repeat sequences leaves them particularly prone to slippage, however these errors are usually repaired with high efficiency. Tumours displaying allele sizes that are not found in the constitutional DNA o f the patient are termed replication error positive (RER^) (Leach et aL, 1993).

The first gene to be implicated in HNPCC was hMSH2, the human homologue o f the mutS gene of Escherichia coli (Fischel et aL, 1993; Leach et aL, 1993). The MutS protein is an essential component of the bacterial mismatch repair pathway, and facilitates the identification of mismatched nucleotides by binding to them (Su and Modrich, 1986). Other human homologues o f bacterial genes that fimction in the well characterised MutHLS mismatch repair pathway (Modrich, 1989) were soon isolated. Several o f these genes have now been shown to fimction in human mismatch repair and HNPCC including three homologues o f bacterial rnutL: hMLHl (human MutL homologue 1); hPMSl and hPMS2 (post meiotic segregation 1 and 2) (Papadopoulos et aL, 1994; Bronner et aL, 1994; Nicolaides et aL, 1994).

Over 90% of HNPCC mutations can be attributed to mutation in hMSH2 or hM LHl. However, there are cases in which no mutation has been found in any of the known mismatch repair genes, suggesting that there are still more genes to be identified, or that alternative DNA repair pathways exist. In most cases it seems that the RER^ phenotype is recessive at the cellular level, as HNPCC tumours have been detected with mutation in both alleles o f a mismatch repair gene (Leach et aL, 1993; Papadopoulos et aL, 1994; Hemminki et aL, 1994; Lu et aL, 1996). This has been confirmed by cell hybridisation experiments that show that the RER^I phenotype can be corrected by fusion with mismatch repair competent (RER") cells (Lengauer et aL,

1997).

The RER^ phenotype, and mutations o f mismatch repair genes have also been found in a significant proportion of sporadic colorectal cancers (15%), indicating that tumours without an inherited component can arise by the same mechanism (Liu et aL, 1995). Furthermore, microsatellite instability has been detected in the extracolonic

tumours of HNPCC patients, and to a lesser extent in their sporadic equivalents. Such cancers include those of the breast, liver, stomach, pancreas, endometrium, and ovary (Han et a l, 1993; Mironov et a l , 1994).

The phenotype conferred by inactivation o f a mismatch repair gene, not only increases the frequency of small deletions and insertions due to slippage at repetitive sequences, but also affects the frequency o f single base substitutions in coding sequences (Eshleman et a l, 1996; Bhattacharyya et a l, 1995). Ultimately, it is the accumulation of mutations in tumour suppressor genes and oncogenes that causes cancer to develop, an increased mutation rate causes these defects to be acquired more rapidly. The APC gene, inactivation o f which is thought to be essential for colorectal tumour formation, is mutated with equal prevalence in RER^ and RER* colorectal tumours (Huang et a l, 1996). This suggests that both types of tumour undergo a similar combination of genetic alterations during progression to cancer. Furthermore, the APC mutations detected in RER^ tumours were distinguished by an excess of frameshifr mutations, characteristic o f mismatch repair deficiency, suggesting that instability precedes APC mutation in RER^ colorectal tumours (Huang et a l, 1996). That microsatellite instability arises early in colorectal tumourigenesis is supported by evidence that the earliest adenoma precursor lesions, aberrant crypts, can display an RER^ phenotype (Augenlicht et a l, 1996), although some evidence to the contrary has also been presented (Young et a l, 1993).