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Microsatellite instability as a marker June 2000 One of the most promising molecular markers in colorectal cancer, called microsatellite instability (MSI), was first discovered as the basis of hereditary nonpolyposis colorectal cancer and later found in a sizable minority of sporadic colorectal cancers as well. MSI refers to increases or decreases in the length of repeating mono- or dinucleotides, such as (CACACA)n, located mostly in intronic DNA. MSI is due to mutations in genes that correct DNA mismatches occurring during replication. "This is equivalent to turning off normal DNA repair," says Mark Redston, MD, staff pathologist at Mt. Sinai Hospital, Toronto. In colon cancer, MSI is due predominantly to inactivation of one of two major mismatch repair (MMR) genes, hMSH2 or hMLH1. (The "h" stands for "human"; these genes are homologues of MMR genes originally found in E. coli.) Dr. Redston and his colleagues reported early this year (N Engl J Med. 2000;342:69-77) in a population-based series of colorectal cancer patients 50 years of age or younger at diagnosis that the presence of MSI was associated with a significant survival advantage independent of tumor stage and other standard prognostic factors. Dr. Redston’s group and others have shown that hMSH2 and hMLH1 deficiency can be as reliably identified by immunohistochemistry for the involved proteins in colon cancer cells as by direct analysis of the genes. "The two are almost synonymous," Dr. Redston told CAP TODAY, especially in cases with high-frequency MSI-where two of the five repeat regions of DNA tested show MSI. He notes that the 17 percent incidence of MSI in their cohort might be a bit high, since these patients were younger, but that 15 percent is a truly representative figure. It is not surprising to find a difference in survival between patients whose tumors have the MMR defect and those without it, since the two types of colorectal cancer are biologically distinct in other ways as well. Specific tumor suppressor genes, such as transforming growth factor beta-2 receptor, are mutated only in MMR-deficient colorectal cancers. And, Dr. Redston notes, "Many colon cancers with MSI are T4M0-they are very large and invade locally, but don’t metastasize. That is very unusual. So there is something different about their biology." MSI-positive colorectal cancers show a prominent host immune response and are often surrounded by a band of lymphocytes and tumor infiltrating lymphocytes. "There is something very important to be learned about the immune response to tumors in the setting of microsatellite instability," Dr. Redston says. Because of these biological differences, Dr. Redston and others believe that tumors with MSI and those without it will respond to treatments differently. "It has yet to be shown that microsatellite instability can be used as a predictive marker in planning treatment strategy," Dr. Redston acknowledges. But, he says, most large multicenter oncology trials in North America now are starting to build MSI into the study design as a variable to differentiate treatment responses. And some groups are looking retrospectively at paraffin blocks from studies in the 1980s that showed 5-fluorouracil to be superior to placebo to see if microsatellite instability correlated with response. "It is our hope and belief," Dr. Redston says, "that studies in the next couple of years, given the biological differences between tumors with microsatellite instability and those without, should show this to be one of the most powerful markers for separating two distinct types of tumors." Colorectal cancers with the MMR phenotype have other clinical implications, according to Jurgen Stahl, MD, senior lecturer in anatomic pathology at Flinders University School of Medicine, Adelaide, Australia, who wrote a commentary on this topic. (Advances in Anatomic Pathology. 2000;7:85-93) "Even in populations with sporadic colorectal cancer, these mutations can occur and have very important clinical implications," Dr. Stahl told CAP TODAY. "People who have those genetic abnormalities have a higher chance of developing a second colorectal carcinoma in the near future and can develop other cancers as well. In women we see particularly endometrial and ovarian adenocarcinoma." Detection of the MMR defect in patients with colorectal cancer identifies those who need further screening, whereas individuals with typical colorectal cancer would be able to stop screening a few years after surgery, Dr. Stahl notes. Although some authors have recommended screening for MMR in all persons with colorectal cancer, Dr. Stahl comments, "I’m not really sure how practical that is from a cost and work point of view. I would screen colorectal cancers in people under age 50 and those that had developed on the right side, in the ascending colon." -William Check, PhD |
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