Colorectal cancer prognosis. Epigenetics. DNA methylation importance. 5
Mutations in tumors receive most attention when we talk about precision medicine. But other type of genetic alterations in tumors plays an equally important role in cancer initiation and progression. What is epigenetics? How is DNA methylation in tumor and in patient increase risks for cancer? Leading colorectal cancer genetics expert discusses colon cancer. Dr. C. Richard Boland, MD. Cancer genetics and genomics is the driver in cancer diagnostics and treatment revolution, the Precision Medicine. Most attention is focused on mutations in tumor-causing genes. But you have extensively studied another major form of genetic changes in colorectal cancer called Еpigenetics. Epigenetic mechanisms act as an off-on master switches for cancer-causing or cancer-fighting genes. As such, epigenetic mechanisms are very important for colon cancer initiation and colon cancer progression. What are the main epigenetic factors in colorectal cancer? How does epigenetic information help to prevent, diagnose, and treat colon cancer? Epigenetics is the study of alterations in gene expression that occur without a change in the DNA sequence. The first epigenetic phenomenon that was discovered was DNA methylation. So there are DNA sequences that consist of many “C” and “G”. These are called “CpG” sites. “C” stands for cytosine, “P” stands for phosphodiester bond, “G” stands for guanine. Most CpG sites have been edited out of the genome. Those that remain are located mainly in the promoter regions of cells. [“Promoter” is the part of gene that initiates gene activation.] There is a methylation step of the cytosine that can occur. It is very carefully regulated. If you methylate many of the cytosines in the CpG sites, it changes the configuration of DNA. This turns off the promoter of the gene. So that on-off switch is now locked in an OFF position, and that silences that gene. And certain genes are silenced for normal physiological purposes. You don’t need most genes in most cells. Sometimes excessive inflammation causes excessive DNA methylation. Dr. C. Richard Boland, MD. Largely, we do not know the reasons, But in certain situations DNA methylation becomes excessive and starts to shut down genes the cell really needs to be successful. And when that occurs, you can turn off tumor suppressor genes, and a cancer can occur by silencing some constellation of tumor suppressor genes. When this occurs, we call it the “CpG Island Methylator Phenotype” or “CIMP”. This abnormal DNA methylation probably drives 30 to 40% of all cancers. We became aware of the importance of the “CpG Island Methylator Phenotype” when we studied Lynch syndrome [inherited colorectal cancer]. We found that 15% of all colon cancers had microsatellite instability, in other words, they had characteristics of Lynch syndrome colorectal cancer. But we knew that it was too large proportion – 15% of all colon cancer patients could not be all due to Lynch syndrome. We found that among these 15% of colorectal cancers with microsatellite instability, only about 3% had Lynch syndrome. But another 12% had methylation and silencing of one of the DNA mismatch repair genes. Dr. C. Richard Boland, MD. Specifically, MLH1 gene. So that colon cancer tumor not only has lots of methylation and CIMP colon cancer type. After that gene methylation happens for several years – by random accident, we think – both alleles of the MLH1 gene are methylated and silenced. Now you get microsatellite instability layered on top of gene methylation. So finding the role of MLH1 gene was probably the first big step forward to understand role of methylation in colon cancer. Then we found other tumor suppressor genes. For example, we found P-16 gene and other genes that were frequently methylated in cancer. So that was a big part of epigenetics cancer research. To look at gene methylation. Dr. Anton Titov, MD.
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