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Could Upfront Tumor Sequencing Replace Current Screening Approaches to Lynch Syndrome?

By: Sarah Campen, PharmD
Posted: Thursday, August 2, 2018

Utilizing upfront tumor sequencing to identify Lynch syndrome in patients with colorectal cancer seems to be simpler and more sensitive than the current approach, which involves up to six sequential tests, revealed researchers with the Ohio Colorectal Cancer Prevention Initiative. Colin C. Pritchard, MD, PhD, of the University of Washington, Seattle, and colleagues, found that the single test may simplify the diagnostic workup for patients with colorectal cancer while simultaneously providing critical information for treatment selection. The results were published in JAMA Oncology.

Tumor DNA from 419 colorectal cancer cases undergoing standard universal tumor screening and germline genetic testing was also screened using tumor sequencing. Additionally, researchers performed blinded tumor sequencing on DNA samples from 46 patients known to have Lynch syndrome.

Upfront tumor sequencing identified all 46 known Lynch syndrome cases in the validation cohort and an additional 12 cases from the 419-member prospective cohort, whereas standard testing missed 5 and 6 cases of Lynch syndrome in each cohort, respectively. Tumor sequencing demonstrated superior sensitivity and similar specificity compared with standard testing, which includes both microsatellite instability analysis and immunohistochemical staining followed by BRAF p.V600E testing.

Tumor sequencing was successful in identifying 284 cases with KRAS, NRAS, or BRAF mutations, which could affect therapy for stage IV colorectal cancer. It thereby eliminated the need for an additional test. In addition, in eight patients, it also detected germline mutations that confer toxicity to fluorouracil chemotherapy, which could be valuable information for treatment selection.

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