Watch for MLH1 Methylation in Younger Endometrial, Colorectal Cancer Patients

High-risk constitutional MLH1 methylation underlies a significant proportion of early-onset endometrial cancers and colorectal cancers with tumor MLH1 methylation. At the American Society of Clinical Oncology (ASCO) annual meeting, researchers presented a study that aimed to determine the frequency of constitutional MLH1 methylation in patients with early-onset endometrial or colorectal cancers displaying MLH1 methylation.

In this exclusive MedPage Today video, investigator Megan Hitchins, PhD, of Cedars-Sinai Cancer Institute in Los Angeles, detailed the findings and discussed why additional screening may be warranted for younger patients who have a MLH1 methylated tumor.

Following is a transcript of her remarks:

So we’ve known for about 20 years that there are these rare cases of early-onset cancer with a high-risk cause, namely constitutional MLH1 methylation. And these patients look like Lynch syndrome patients, but do not typically have a germline sequence mutation that affects the protein function. What they have instead is methylation of the promoter on one allele throughout their normal tissues, and this switches that allele off. So there’s no transcriptional protein produced at all.

But in the past, the reports have just been case reports of individual families, observational studies in those looking at whether it’s inherited, etc. We’ve never known, up to this point, how rare or in which particular patients we should be focusing our screening on. So the study that we did, we took two populations from Ohio, taken from two different time periods. And a lot of work had already been done on these population-based cohorts. And so we already knew who had a MLH1 methylated tumor.

And so we looked in patients with colorectal cancer and patients with endometrial cancer, which are the major Lynch-associated cancers. And we took all of the patients whose tumors had MLH1 methylation, and these are patients that had been assumed to be non-Lynch precisely because their tumor had MLH1 methylation. So that is a molecular pathology test that is routinely performed to omit patients from having further follow-up for Lynch syndrome — germline follow-up, that is.

And so we looked in all of those patients — regardless of age or BRAF mutation status in their tumors — and we looked for the presence of methylation in their blood DNA. And what we found was that this high-risk cause is rare overall. But what was interesting was that in the patients that were at a young age of onset: so in the colorectal cancer cases, it was primarily 55 years and under; and in the endometrial cancer cases it was age 50 and under, or under 50 actually, that we actually found a high prevalence of this.

So when you look at patients with MLH1 methylation in their tumors, that is usually what we call somatic in origin. The methylation’s present only in the tumor and not in the normal tissues. And those cases are typically of advanced age. So when you have patients that are young with methylation in their tumor, that’s really unusual. And they only made up maybe 4% to 6% of all of the patients that we actually screened. But among those younger cases, we had really high prevalence of constitutional methylation. So in endometrial cancer it was 17%. And in the colorectal cancer group, it was anywhere from 23.5% to 75%. When you’re looking at small numbers, of course you’ve got a wide range, but nevertheless, that is higher prevalence than what you find germline mutations in among cases that are universally tested.

So what we are trying to suggest now is that people who are treating these patients and managing them, consider when they see the presence of MLH1 methylation in the tumor testing report, and the patient is young — so under 60 we’re saying at this point — then they really need to be referred for blood-based testing for constitutional methylation. And that’s important because they’re at high risk of developing other cancers as well.