Microsatellite Instability in Colorectal Cancer
Section snippets
Models of CRC Pathogenesis
It was not immediately obvious that CRCs would be so diverse genetically. The initial attempt to characterize multistep carcinogenesis resulted in a novel conceptual model in which specific genetic alterations were associated with the sequential evolution of the neoplastic phenotype in the colon. In the model proposed by Fearon and Vogelstein, inactivation of the adenomatous polyposis coli (APC) gene led to the initial appearance of the adenoma from normal colonic mucosa, mutations in KRAS were
MSI as a Unique Mechanism in Tumor Development
Shortly after publication of the multistep genetic model of colorectal carcinogenesis, many investigators began searching the genome for novel tumor suppressor genes using powerful techniques. In 1992, Manuel Perucho used an arbitrarily primed polymerase chain reaction (PCR), extracting DNA from colonic tissues and amplifying thousands of sequences using a small number of randomly chosen PCR primers. This technique yielded unique but reproducible electrophoretic signatures from each sample.7
DNA MMR System
The “mutator phenotype” was discovered in bacteria in the 1970s and 1980s and was well-characterized by the beginning of the 1990s.13 It is caused by mutational inactivation of genes involved in DNA repair. The first human disease that was clearly associated with defects in DNA repair was xeroderma pigmentosa, a rare autosomal recessive disease caused by biallelic inactivating mutations in genes involved in nucleotide excision repair. Several other DNA repair systems had been characterized that
MSI is Caused by Deficiencies in MMR
By 1993, it was recognized that about 15% of colorectal tumors have a unique mechanism of pathogenesis; they might have been first solid tumors with subclasses that had features so distinct they could be considered as separate diseases. To identify the different pathogenic mechanisms, researchers analyzed the PCR products of colorectal tumors with MSI.
Microsatellite sequences are abundant throughout the genome; they are polymorphic among individuals but are unique and uniform in length in every
MSH2 and HNPCC
Because much of the attention was focused on MSI in hereditary CRC, several groups set out to determine whether germline mutations in MMR genes were responsible for Lynch syndrome. Fishel et al cloned the human MSH2 gene based on its homology to the yeast sequence, mapped it to human chromosome 2p22–21 (close to the locus implicated earlier in the year12), and found a sequence variation in patients with familial CRC23 at the −6 position of intron 13 of MSH2. It was proposed that this variant
MLH1, PMS2, PMS1, and MSH6
Shortly after the 2p locus was linked with familial CRC, CRC in 3 Swedish families was linked to chromosome 3p21–23.27 The association between MSH2 and Lynch syndrome indicated that other genes that encode MMR factors might be located on 3p, which would represent a second familial CRC locus. Two groups found MLH1 on 3p21—Bronner et al identified the human homologue of yeast MLH1 and found germline mutations in multiple members of a CRC family with significant linkage to the 3p locus.28
At
Lynch Syndrome
The focus of MSI in CRC was immediately aimed at Lynch syndrome because of its inherited and unique features.33 These patients develop tumors at early ages, often between 20 and 30 years old. They frequently have multiple tumors, including those of the colon, rectum, endometrium, stomach, ovary, urinary tract, small intestine, and other sites, but no increase in the frequency of cancers of the breast, lung, or prostate.34 Before 1993, there was no agreement on whether this syndrome actually
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Conflicts of interest The authors disclose no conflicts.
Funding Supported by grants from the National Cancer Institute and National Institutes of HealthR01 CA72851 (to Dr Boland) and R01 CA129286 (to Drs Goel and Boland).