Dr Hitchins on the Association Between Constitutional MLH1 Methylation and MRD in Select Cancers

Megan Hitchins, PhD, director, Translational Genomics, research associate professor, Department of Biomedical Sciences, Cedars-Sinai, member, Cedars-Sinai Cancer Institute, discusses results from an analysis on the prevalence of high-risk constitutional MLH1 methylation in early-onset colorectal and endometrial cancers displaying mismatch repair deficiency (MRD).

This analysis included patients with colorectal and endometrial cancer who had constitutional MLH1 methylation and MRD, who were identified from cancer clinic- or population-based cases in the Columbus, Ohio, area who were referred by oncologists and genetic counsellors. Patients' blood DNA was screened for constitutional MLH1 methylation using pyrosequencing and methylation-specific qPCR. The aim of this study was to identify the frequency of patients with constitutional MLH1 methylation in this patient population and determine if an age threshold may better inform the use of additional screening measures.

Results showed that constitutional MLH1 methylation was infrequently observed in the overall population but occurred in a larger percentage of patients younger than 60 years of age, Hitchins reports. In clinical cases, 37.5% of patients with CRC (n = 8) and 50% of those with endometrial cancer (n = 7) who were younger than 60 displayed constitutional MLH1 methylation, she continues. In the population-based cohort from the Columbus area, constitutional MLH1 methylation was identified in 4.2% (n = 95) of CRC cases and 0% of endometrial cancer patients (n = 68) across all age groups. In the OCCP1 cohort, these percentages were 1.4% (n =281) across all ages and 17% (n = 24) for patients younger than 60 years of age, respectively.

The optimal screening age threshold in CRC was identified as 55 years of age or younger, as this age was associated with the highest detection rate, fewestmissed cases, and minimal screening. Within these age parameters, the detection rates were 75% in Columbus and 23.5% in OCCPI, Hitchins states.

In endometrial cancer, the detection rate in the combined cohorts (n = 6) was 17% for patients younger than 50 years of age, Hitchins notes. The study concludes that incident cases should be referred for blood-based screening if patients are younger than 50 years of age at first cancer diagnosis, although some older cases may be missed.