Epigenetics in Colorectal Cancer: How DNA Methylation Silences Tumor Suppressor Genes

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• What Is Epigenetics in Cancer?
• DNA Methylation Mechanism Explained
• CpG Island Methylator Phenotype (CIMP) in Colon Cancer
• MLH1 Gene Discovery and Microsatellite Instability
• Other Methylated Tumor Suppressor Genes
• Clinical Implications for Cancer Diagnosis
• Full Transcript

What Is Epigenetics in Cancer?

Epigenetics refers to changes in gene expression that occur without alterations to the DNA sequence itself. Dr. C. Richard Boland, MD emphasizes that while genetic mutations receive more attention in precision medicine, epigenetic modifications serve as master switches that activate or silence cancer-related genes. These mechanisms play a critical role in colorectal cancer initiation and progression.

DNA Methylation Mechanism Explained

The primary epigenetic mechanism involves DNA methylation at CpG sites - sequences where cytosine (C) and guanine (G) nucleotides are connected by a phosphodiester bond (p). Dr. C. Boland, MD, explains that methylation of cytosine in these promoter regions changes DNA configuration, effectively locking genes in an "off" position. While some gene silencing is normal, excessive methylation due to inflammation or other factors can dangerously suppress tumor suppressor genes.

CpG Island Methylator Phenotype (CIMP) in Colon Cancer

When abnormal DNA methylation patterns silence multiple tumor suppressor genes simultaneously, it creates what researchers call the CpG Island Methylator Phenotype (CIMP). Dr. C. Richard Boland, MD notes this phenomenon likely drives 30-40% of all cancers. In colorectal cancer specifically, CIMP represents a distinct molecular pathway separate from traditional mutation-driven carcinogenesis.

MLH1 Gene Discovery and Microsatellite Instability

A breakthrough came when Dr. Boland's team investigated why 15% of colon cancers showed microsatellite instability (MSI) - a hallmark of Lynch syndrome - yet only 3% actually had this inherited condition. They discovered 12% of cases resulted from methylation silencing of the MLH1 mismatch repair gene. This epigenetic alteration creates MSI without underlying genetic mutations, demonstrating how methylation alone can mimic hereditary cancer patterns.

Other Methylated Tumor Suppressor Genes

Beyond MLH1, Dr. C. Richard Boland, MD's research identified additional tumor suppressor genes frequently silenced by methylation in colorectal cancer, including the P16 gene. These findings expanded understanding of how epigenetic changes collaborate with genetic mutations to drive cancer progression through multiple parallel pathways.

Clinical Implications for Cancer Diagnosis

The discovery of CIMP and methylation-related MSI has significant diagnostic implications. Dr. C. Boland, MD, emphasizes that epigenetic testing can now distinguish between hereditary Lynch syndrome and sporadic methylation-induced MSI in colorectal cancer patients. This precision differentiation guides appropriate screening for patients and their families while opening new avenues for targeted epigenetic therapies.

Full Transcript

Dr. Anton Titov, MD: Mutations in tumors receive most attention when we talk about precision medicine. But another type of genetic alteration in tumors plays an equally important role in cancer initiation and progression. What is epigenetics? How does DNA methylation in tumors and patients increase cancer risks?

A leading colorectal cancer genetics expert discusses colon cancer.

Dr. C. Boland, MD: Cancer genetics and genomics are the drivers in the cancer diagnostics and treatment revolution—precision medicine. Most attention is focused on mutations in tumor-causing genes. But I have extensively studied another major form of genetic change in colorectal cancer called epigenetics.

Epigenetic mechanisms act as on-off master switches for cancer-causing or cancer-fighting genes. As such, epigenetic mechanisms are very important for colon cancer initiation and progression.

Dr. Anton Titov, MD: What are the main epigenetic factors in colorectal cancer? How does epigenetic information help prevent, diagnose, and treat colon cancer?

Dr. C. Boland, MD: Epigenetics is the study of alterations in gene expression that occur without a change in the DNA sequence. The first epigenetic phenomenon discovered was DNA methylation.

There are DNA sequences that consist of many "C" and "G" nucleotides. These are called "CpG" sites. "C" stands for cytosine, "P" stands for phosphodiester bond, and "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 genes.

The promoter is the part of a gene that initiates gene activation. A methylation step of the cytosine can occur, and 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.

That on-off switch is now locked in the OFF position, silencing that gene. Certain genes are silenced for normal physiological purposes—you don't need most genes in most cells.

Sometimes excessive inflammation causes excessive DNA methylation. 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 function successfully.

When that occurs, you can turn off tumor suppressor genes, and cancer can develop by silencing some constellation of tumor suppressor genes. We call this 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 CIMP 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 15% of all colon cancer patients could not be due to Lynch syndrome. We found that among these 15% of colorectal cancers with microsatellite instability, only about 3% had Lynch syndrome. Another 12% had methylation and silencing of one of the DNA mismatch repair genes—specifically, the MLH1 gene.

That colon cancer tumor not only has extensive 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.

Discovering the role of the MLH1 gene was probably the first big step forward in understanding methylation's role in colon cancer. Then we found other tumor suppressor genes, like the P-16 gene and others that were frequently methylated in cancer.

That was a big part of epigenetics cancer research—to look at gene methylation.