Colorectal cancer. Precision medicine therapy. Microsatellite Instability. 7
What is microsatellite instability in colorectal cancer? What high microsatellite instability means for cancer prognosis? How to select chemotherapy in cancer patients with high microsatellite instability? Leading colorectal cancer genetics expert discusses colon cancer. Dr. C. Richard Boland, MD. Precision medicine in treatment of colorectal cancer means we have to separate the notion of colon cancer as one entity – into many colon cancers that differ by distinct molecular nature of the tumors. About 15% of colorectal cancer tumors have a specific genetic change called microsatellite instability. Microsatellite instability in colon cancer is very important for treatment selection and prognosis. What is microsatellite instability in colon cancer? What is the role of microsatellite instability for personalizing the treatment and assessing prognosis in colorectal cancer? OK, excellent question! Let’s go back and get a little historical perspective. In the old days, before the mid-1990s, the only characteristics that we could use to distinguish one colon cancer from another were: was it “well-differentiated” or was it “poorly differentiated” and making a lot of mucin? None of those things were terribly helpful. And we didn’t use them at all for any therapeutic decisions. Then microsatellite instability was discovered in colorectal cancer tumors. Microsatellite instability is a type of genetic signature. Microsatellite sequences are short repetitive nucleotide sequences in DNA. For example, a whole series of adenines in a row. Or a whole series of “CA” nucleotides that are repeated over and over in DNA. Microsatellite sequences are replicated exactly from parent cell to daughter cell. But they require the DNA mismatch repair system for replication to happen properly. So in cancers with defective DNA mismatch repair activity cells cannot replicate those sequences well. And the tumor gets hundreds of thousands of mutations in these microsatellite sequences. So we selected microsatellite sequences that are very sensitive to the loss of DNA mismatch repair activity. You can then do a simple test. If there are two or more microsatellite sequences that are mutated – that’s microsatellite instability. Dr. C. Richard Boland, MD. So the first thing we found led us to almost all of the Lynch syndrome colon cancers and another 12% of colorectal cancer cases that had gene silencing caused by methylation of MLH1 gene. That told us about inheritance of colorectal cancer in families. We also realized that tumors that had microsatellite instability did not respond in the same way to chemotherapy – they did not get any additional benefit from chemotherapy. There was additional harm from chemotherapy in colon cancer with microsatellite instability. But also colon cancers with microsatellite instability had a better natural history, So there were two competing phenomena. Patients with microsatellite instability in colorectal tumors were more likely to survive cancer. But we also were unlikely to help these patients by treating them with standard chemotherapy. So that was the first step into personalized medicine for colorectal cancer treatment. Dr. Anton Titov, MD.
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