MLH1 Methylation Status and Screenings for Colorectal or Endometrial Cancer

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New research could warrant reconsideration of current screening guidelines to include a poorly recognized cause of Lynch syndrome, according to a novel study published by Hitchins et al in JNCCN–Journal of the National Comprehensive Cancer Network. The findings suggest that the guidelines leave a significant number of patients undiagnosed.


Lynch syndrome is regarded as the most common cause of hereditary colorectal and endometrial cancers.

“When patients with Lynch syndrome—whose first cancers generally appear at an early age—aren’t diagnosed promptly, they don’t get appropriate follow-up or surveillance,” stressed lead study author Megan Hitchins, PhD, Research Associate Professor and Director of Translational Genomics in the Department of Biomedical Sciences at Cedars-Sinai. “They can go on to have multiple different cancers before they are finally diagnosed. If we could identify them when they have their first cancer, we could prevent additional cancers—or at least detect them earlier,” she added.

Many colorectal and endometrial cancers have mismatch repair deficiency, where the tumor forms because of mistakes that occurred when DNA was copied during cell division.

In most cases of Lynch syndrome, this mismatch repair deficiency is caused by an inherited mutation in a DNA mismatch repair gene; however, mismatch repair deficiency can also be caused by MLH1 methylation in some cases.

“Methylation isn’t hard-wired into the gene the way a mutation is. It’s added on, like debris clogging an engine. The engine itself is not defective, but it doesn’t work properly because it’s been clogged,” Dr. Hitchins noted.

MLH1 methylation, present in as many as 75% of tumors with mismatch repair deficiency, is usually only present in the tumors—meaning that the defect would not inherited and the patient would not have Lynch syndrome.

“[Nonetheless], 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,” Dr. Hitchins warned. “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,” she suggested.

Study Methods and Results

In the new study, investigators examined the data from two large retrospective population-based studies and tested the blood DNA of patients with mismatch repair deficient colorectal cancer in order to help determine how often normal tissue methylation may take place.

The investigators found that among the patients aged 55 and younger who had methylation in their tumors, 25% to 75% of them also had methylation in their blood, demonstrating that they had Lynch syndrome but had not been diagnosed.

In a previous study—published by Hitchins et al in Gynecologic Oncology—researchers tested the blood of patients with endometrial cancer from the same patient population. They found that approximately 30% of these patients had methylation in their tumors and that among those aged under 50 years, 15% to 20% of them had methylation in their blood.


“Taken together, these studies suggest this population of patients would benefit from a change in screening guidelines,” highlighted Dan Theodorescu, MD, PhD, Professor of Surgery as well as Pathology and Laboratory Medicine, Director of the Samuel Oschin Comprehensive Cancer Institute, and the Distinguished Chair of the PHASE One Foundation at Cedars-Sinai. “Appropriate screenings can provide the opportunity for potentially lifesaving surveillance and early detection and treatment of subsequent cancers,” he underscored.

The investigators urged patients aged under 56 years with colorectal cancer and patients aged under 50 years with endometrial cancer to ask their primary care providers about additional screenings for themselves as well as their parents, siblings, and adult children. They also suggested that primary care providers and oncologists reach out to young patients from the past 5 years whose endometrial or colorectal tumors tested positive for MLH1 methylation.

“We’ve been finding young patients with endometrial or colorectal cancer who are told they don’t have Lynch syndrome, then go on to develop a colon [tumor] or other [type of] cancer that might have been prevented, or at least detected earlier. Those patients are walking around oblivious to their risks, and should be made aware of that fact and given the option of having a test,” Dr. Hitchins concluded.

Disclosure: The research in this study was funded by grants from the National Cancer Institute of the National Institutes of Health; a Cedars-Sinai Medical Center Precision Health Initiative Award; grants from the Spanish Ministry of Science; and travel fellowships from the Spanish Ministry of Economy, Industry, and Competitiveness and the RTICC network. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.