Rare and missed cause of hereditary cancer

New research from Cedars-Sinai Cancer investigators could warrant reconsideration of current screening guidelines to include a poorly recognized cause of Lynch syndrome, the most common cause of hereditary colorectal and endometrial cancers. Their study concluded that the guidelines leave a significant number of patients undiagnosed.

In most cases of Lynch syndrome, mismatch repair deficiency is caused by an inherited mutation in a DNA mismatch repair gene. But mismatch repair deficiency can also be caused by something called methylation. This is a change to a gene called MLH1.

MLH1 methylation is present in as many as 75% of tumors with mismatch repair deficiency, Hitchins said. It is usually present only in the tumor, meaning the defect is not inherited and the patient does not have Lynch syndrome.

Megan Hitchins said, “However, our study found that in a small fraction of patients, the methylation is present in normal tissues. It isn’t confined to the tumor. This predisposes cells to cancer development. Because methylation is usually only present in the tumor, these patients have been automatically identified as non-Lynch patients, and never given the blood testing that would diagnose them with Lynch syndrome.”

To help determine how often this takes place, investigators reviewed data from two large retrospective population-based studies and tested blood DNA from all mismatch repair deficient colorectal cancer patients who participated. Among patients aged 55 and younger who had methylation in their tumors, 25%-75% also had methylation in their blood, meaning they had Lynch syndrome but had not been diagnosed.

Reference: Constitutional MLH1 Methylation Is a Major Contributor to Mismatch Repair–Deficient, MLH1-Methylated Colorectal Cancer in Patients Aged 55 Years and Younger, Journal of the National Comprehensive Cancer Network, DOI 10.6004/jnccn.2023.7020