A team of investigators from the US has found that some cases of Lynch syndrome, the most common hereditary cancer condition, are missed in younger patients under current screening guidelines, which leaves a significant number of patients undiagnosed.
Cedars-Sinai Cancer scientists say their research could warrant reconsideration of current screening guidelines to include a poorly recognised cause of Lynch syndrome, the most common cause of hereditary colorectal and endometrial cancers, they wrote in their study, published in the Journal of the National Comprehensive Cancer Network.
“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,” said Megan Hitchins, PhD, director of Translational Genomics in the Department of Biomedical Sciences at Cedars-Sinai and lead author of the study.
“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.”
Many colorectal and endometrial cancers have something called mismatch repair deficiency. This means that the tumour formed 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. But mismatch repair deficiency can also be caused by something called methylation. This is a change to a gene called MLH1.
“Methylation isn’t hard-wired into the gene the way a mutation is,” said Hitchins. “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.”
MLH1 methylation is present in as many as 75% of tumours with mismatch repair deficiency, Hitchins said. It is usually present only in the tumour, meaning the defect is not inherited and the patient does not have Lynch syndrome.
“However, our study found that in a small fraction of patients, the methylation is present in normal tissues. It isn’t confined to the tumour. This predisposes cells to cancer development,” Hitchins said. “Because methylation is usually only present in the tumour, these patients have been automatically identified as non-Lynch patients, and never given the blood testing that would diagnose them with Lynch syndrome.”
To help determine how often this takes place, investigators reviewed data from two large retrospective population-based studies, and tested blood DNA from all mismatch repair deficient colorectal cancer patients who participated. Among patients aged 55 and younger who had methylation in their tumours, 25%-75% also had methylation in their blood, meaning they had Lynch syndrome but had not been diagnosed.
In a previous study published in the journal Gynaecologic Oncology, Hitchins and fellow investigators tested the blood of patients with endometrial cancer from the same patient populations. They found that approximately 30% of endometrial cancer patients had methylation in their tumours. And among those under 50, 15%-20% also had methylation in their blood, indicating Lynch syndrome, Hitchins said.
“Taken together, these studies suggest this population of patients would benefit from a change in screening guidelines,” said Dr Dan Theodorescu, director of Cedars-Sinai Cancer and the PHASE ONE Distinguished Chair. “Appropriate screening can provide the opportunity for potentially lifesaving surveillance and early detection and treatment of subsequent cancers.”
For now, Hitchins recommends that colorectal cancer patients under 56 and endometrial cancer patients under 50 ask their healthcare providers about additional screening for themselves – and their parents, siblings and adult children. She also suggested that primary care providers and oncologists contact young patients from the past five years whose endometrial or colorectal tumours 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 or other cancer that might have been prevented, or at least detected earlier,” she said. “They are walking around oblivious to their risk, and should be made aware of that fact and given the option of having a test.”
Study details
Constitutional MLH1 Methylation Is a Major Contributor to Mismatch Repair–Deficient, MLH1-Methylated Colorectal Cancer in Patients Aged 55 and Younger
Abstract
Background
Most mismatch repair–deficient (MMRd) colorectal cancer (CRC) cases arise sporadically, associated with somatic MLH1 methylation, whereas approximately 20% have germline mismatch repair pathogenic variants causing Lynch syndrome (LS). Universal screening of incident CRC uses presence of MLH1 methylation in MMRd tumours to exclude sporadic cases from germline testing for LS. However, this overlooks rare cases with constitutional MLH1 methylation (epimutation), a poorly recognised mechanism for LS. We aimed to assess the frequency and age distribution of constitutional MLH1 methylation among incident CRC cases with MMRd, MLH1-methylated tumours.
Methods
In retrospective population-based studies, we selected all CRC cases with MMRd, MLH1-methylated tumours, regardless of age, prior cancer, family history, or BRAF V600E status, from the Columbus-area HNPCC study (Columbus) and Ohio Colorectal Cancer Prevention Initiative (OCCPI) cohorts. Blood DNA was tested for constitutional MLH1 methylation by pyrosequencing and real-time methylation-specific PCR, then confirmed with bisulfite-sequencing.
Results
Results were achieved for 95 of 98 Columbus cases and all 281 OCCPI cases. Constitutional MLH1 methylation was identified in 4 of 95 (4%) Columbus cases, ages 34, 38, 52, and 74 years, and 4 of 281 (1.4%) OCCPI cases, ages 20, 34, 50, and 55 years, with 3 showing low-level mosaic methylation. Mosaicism in blood and normal colon, plus tumour loss of heterozygosity of the unmethylated allele, demonstrated causality in 1 case with sample availability. Age stratification showed high rates of constitutional MLH1 methylation among younger patients. In the Columbus and OCCPI cohorts, respectively, these rates were 67% (2 of 3) and 25% (2 of 8) of patients aged <50 years but with half of the cases missed, and 75% (3 of 4) and 23.5% (4 of 17) of patients aged ≤55 years with most cases detected.
Conclusions
Although rare overall, a significant proportion of younger patients with MLH1-methylated CRC had underlying constitutional MLH1 methylation. Routine testing for this high-risk mechanism is warranted in patients aged ≤55 years for a timely and accurate molecular diagnosis that will significantly alter their clinical management while minimising additional testing.
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