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In about 15% of all colon tumors another initiating mutation is likely. These tumors
reveal widespread instability of microsatellite sequences, whereas loss of heterozygosity for
chromosomal loci is mostly absent (Thibodeau et aI., 1993). This implicates that we deal
with a different group of colon tumors. Furthermore, these alterations were also found in
tumors from HNPCC patients. Linkage analysis in HNPCC families suggested that at least
three genes are involved: one at chromosome 2p16, another at chromosome 3p21-23, and a
third at an unidentified locus (Aaltonen et aI., 1993; Peltomiiki et aI., 1993; Lindblom et aI.,
1993). Both the candidate gene approach (Fishel et aI., 1993) and the positional cloning
approach (Leach et aI., 1993) have resulted in the identification of the hMSH2 gene at
chromosome 2p16. Mutations in this gene were found in sporadic colon tumors that showed
dinucleotide repeat instability and HNPCC patients. Both splice acceptor site mutations and
mis- and non-sense mutations were observed: The human hMSH2 gene shows high homology
with the prokaryotic MillS gene, which is part of the mismatch repair pathway in E. coli.
MutS mutants exhibit dinucleoide repeat instability like that observed in HNPCC patients
(Levinson and Gutman, 1987; Strand et aI., 1993). In vitro experiments with extracts of
HNPCC tumor cells showed a profound defect in strand-specific mismatch repair (Parsons
et aI., 1993). In addition, very recently a candidate mismatch repair gene on chromosome
3p has been isolated because of its homology with MIIlL, another gene involved in the
mismatch repair pathway in E. coli (Bronner et aI., 1994). This gene was called hMLHI. In
a chromosome 3-linked HNPCC family missense mutations were found in affected
individuals. Mutations in APe, K-ras and p53 are also observed in this group of tumors. It
might be that mutations in mismatch repair genes result in an increase risk of generating
mutations in other oncogenes and tumor suppressor genes. The hMSH2 and hMLHl genes
probably playa role in carcinogenesis by inducing a mutator phenotype. Yet, why would
mutations in these genes only predispose to specific tumors? Future studies should shed light
on this intriguing question.
3.4 The isolation of the WTl and VHL genes
Wilms' tumor is a pediatric kidney cancer which probably arises from blastemal kidney cells
(Beckwith et aI., 1990). Most tumors occur sporadically, however these tumors are also
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