NEW YORK (GenomeWeb) – Lynch syndrome diagnoses in individuals with colorectal cancer (CRC) may be simplified by sequencing CRC tumors from the outset, rather than relying on sequential single gene screening tests, according to a study published online today in JAMA Oncology.
"While this new test is more expensive, it will eliminate many other tests for a subset of patients so that it may be more cost-effective overall," first author Heather Hampel, a human genetics researcher and licensed genetic counselor with Ohio State University's Comprehensive Cancer Center, said in a statement. "If it is not now, it will certainly be in the future as the costs of tumor sequencing continue to decline."
Hampel and colleagues from the Ohio Colorectal Cancer Prevention Initiative Study Group initially used panel sequencing to assess tumor and/or germline samples from 419 individuals with CRC who were enrolled consecutively from fall 2015 to early 2016 for a multi-center population study. They also did blinded validation testing on samples from 46 individuals with CRC and Lynch syndrome mutations.
The team found that the tumor sequencing strategy uncovered a dozen Lynch syndrome cases in the prospectively collected CRC cohort, including several cases that were missed using more traditional microsatellite instability (MSI) or immunohistochemical (IHC) testing for Lynch syndrome culprits. Likewise, the panel sequencing approach picked up all of the documented Lynch cases in the validation group and led to potentially targetable mutations in genes such as KRAS or BRAF across the broader CRC tumor set.
"This new approach points to the exact mutation patients were born with and does so through a single test," Hampel said. "The previous method could sometimes require patients to get up to five individual tests before knowing if they had Lynch syndrome."
Based on their findings, the researchers estimated that the sensitivity of tumor sequencing exceeded both MSI testing for Lynch syndrome (done in combination with a test for the BRAF pV600E mutations), and IHC and BRAF testing for Lynch syndrome. The specificity of sequencing was similar to both of those established screening approaches.
In the 419 CRC patients considered in the prospective cohort, for example, MSI-BRAF testing missed five of the Lynch syndrome cases. The IHC-BRAF test failed to find six of the 12 cases.
The team also touted the next-generation approach as a means for finding targetable tumor mutations and germline alterations that are informative beyond the Lynch syndrome screening application. Nearly 300 of the sequenced CRC cases involved potentially informative mutations in KRAS, BRAF, or NRAS, for example, while germline mutations implicated in enhanced chemotherapy toxicity turned up in eight of the individuals tested.
"Up-front [tumor sequencing] in CRC is simpler and has superior sensitivity to current multitest approaches to [Lynch syndrome] screening," the authors wrote, "while simultaneously providing critical information for treatment selection."
Last year, Hampel and colleagues from the Ohio Colorectal Cancer Prevention Initiative Study Group published a study in JAMA Oncology highlighting the potential for panel sequencing to find hereditary cancer-related mutations in individuals with early-onset CRC.