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 

 methylation in patients with early-onset colorectal cancer (CRC) and endometrial cancer.

An increasing amount of literature has identified constitutional 

methylation 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.

 methylation is rare, and is therefore both poorly recognized and not commonly assessed through blood-based testing, Hitchins states. Second, many patients with constitutional 

 methylation who develop cancer at a young age do not display a family history of the disease, Hitchins adds. 

methylation 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 

 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 

 hypermethylation and were mismatch-repair deficient was conducted to determine the frequency of constitutional 

 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.

Videos

Megan Hitchins, PhD, discusses the rationale for conducting an analysis on the prevalence of high-risk constitutional MLH1 methylation in patients with early-onset colorectal cancer and endometrial cancer.

Dr Hitchins on Investigating Constitutional MLH1 Methylation in CRC and Endometrial 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 

 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 

 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 

 methylation using pyrosequencing and methylation-specific qPCR. The aim of this study was to identify the frequency of patients with constitutional 

 methylation in this patient population and determine if an age threshold may better inform the use of additional screening measures.

 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 

 methylation, she continues. In the population-based cohort from the Columbus area, constitutional 

 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.

Megan Hitchins, PhD, 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. 

Megan Hitchins, PhD

Articles

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

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