Tumor sequencing useful for Lynch-syndrome screening

Last Updated: 2018-04-09

By Will Boggs MD

NEW YORK (Reuters Health) - Tumor sequencing offers advantages over current approaches to Lynch-syndrome screening in patients with colorectal cancer (CRC), researchers report.

"We believe that tumor sequencing will eventually be the first and only molecular test needed for all CRC patients since it can both 1) screen for Lynch syndrome and 2) identify actionable therapeutic targets," said Heather Hampel from Ohio State University Comprehensive Cancer Center in Columbus.

"It has the added benefits of providing pharmacogenetic information (the DPYD mutation status) and potentially identifying germline mutations in other hereditary cancer genes," she told Reuters Health by email.

Lynch syndrome, the most common hereditary syndrome that predisposes individuals to develop CRC, also raises the risk of developing endometrial, ovarian, gastric and other cancers. Guidelines recommend universal tumor screening for Lynch syndrome for all patients with CRC at diagnosis.

Hampel and colleagues in the Ohio CRC Prevention Initiative Study compared the performance of up-front tumor sequencing with the current multistep approach for detecting Lynch syndrome in their study of 465 CRC patients.

Tumor sequencing identified 100% of the 76 tumors found to have high microsatellite instability (MSI) by MSI analysis and agreed with MSI analysis in 340 of 341 tumors classified as microsatellite stable, the team reported in JAMA Oncology, online March 29.

Tumor sequencing identified tumors with MLH1 promoter methylation with 84% sensitivity and 100% specificity.

In a separate analysis, current screening methods would have missed one of 12 patients known to have Lynch syndrome, whereas tumor sequencing correctly identified all 12.

Tumor sequencing also correctly identified 46 of 46 pathogenic germline mismatch repair gene mutations in a validation set of samples.

Overall, tumor sequencing successfully identified all Lynch syndrome cases, whereas MSI followed by BRAF testing missed five cases, and immunohistochemistry followed by BRAF testing missed six cases. Tumor sequencing was, therefore, 100% sensitive and 95.3% specific for detecting Lynch syndrome.

In total, 81.7% (380/465) of CRC tumors had at least one somatic mutation that could have therapeutic implications, including eight patients with pathogenic germline mutations that placed them at risk for severe reactions to fluorouracil chemotherapy.

"As the cost of tumor sequencing begins to decline, it will likely become the test of choice for not only all CRC patients, but probably for all cancer patients, at the time of diagnosis," Hampel said. "Replacing multiple tests with one test will also preserve more tumor tissue for any other testing that may need to be done for treatment purposes in the future."

Dr. Mohammad Ilyas from the University of Nottingham School of Medicine, in the U.K., who recently described a simple and rapid screening test for Lynch syndrome, told Reuters Health by email, "It is expected that next-generation sequencing (NGS) is more sensitive than traditional testing; in this study it is equally specific (i.e., it is not picking up false positives), but I expect that if it were to become a universal test for Lynch syndrome, the specificity will reduce (i.e., it will pick up lots of germline changes which may or may not be disease causing). It will only be possible to confirm pathogenicity by MSI testing."

"For Lynch-syndrome screening, it remains a moot point which is the best strategy," he said. "The U.K.'s National Institute for Health and Care Excellence (NICE) guidance performed economic analysis and found that - in the U.K. at least - it was more cost-effective to follow a traditional strategy than (proceed) straight to NGS."

"NGS-based tumor testing will soon become the norm," said Dr. Ilyas, who was not involved in the new work. "This report indicates all the extra information that comes from such testing. Screening for Lynch syndrome is a different thing - this approach may or may not be the way forward."

SOURCE: https://bit.ly/2IExmzn

JAMA Oncol 2018. (Reporting by Shawana Alleyne-Morris)