Dr Hitchins on Investigating Constitutional MLH1 Methylation in CRC and Endometrial Cancers

Megan Hitchins, PhD, director, Translational Genomics, associate professor, Department of Biomedical Sciences, Cedars-Sinai, member, Cedars-Sinai Cancer Institute, discusses the rationale for conducting an analysis on the prevalence of high-risk constitutional MLH1 methylation in patients with early-onset colorectal cancer (CRC) and endometrial cancer.

An increasing amount of literature has identified constitutional MLH1methylation of the mismatch repair gene as an alternative mechanism for the development of Lynch syndrome in patients with early-onset cancers such as CRC, Hitchins begins. However, the accurate diagnosis of this high-risk predisposition has been challenging for several reasons, Hitchins says.

First, constitutional MLH1 methylation is rare, and is therefore both poorly recognized and not commonly assessed through blood-based testing, Hitchins states. Second, many patients with constitutional MLH1 methylation who develop cancer at a young age do not display a family history of the disease, Hitchins adds.

Lastly, patients that have MLH1 methylation in their tumors also have MLH1methylation present in their normal tissue, which predisposes them to tumor development, Hitchins explains. The presence of this tumor feature, however, is often used to rule out Lynch syndrome in typical molecular pathology tests, she notes. Moreover, the majority of tumors with MLH1 methylation are designated as sporadic, which typically have a later onset, Hitchins details. This often leads to a misdiagnosis of patients with high-risk tumors as being sporadic rather than caused by methylation, HItchins says.

Based on these reasons, an analysis of patients whose tumors were positive for MLH1 hypermethylation and were mismatch-repair deficient was conducted to determine the frequency of constitutional MLH1 methylation within that population, Hitchins states. Among those patients, the study further aimed to discern other predictive clinical factors indicating that a patient should undergo an extra blood-based test for constitutional methylation, she concludes.