Tumor Sequencing Superior to Current Approaches for Lynch Syndrome Screening in Colorectal Cancer

A simpler approach to current multi-test approaches to Lynch syndrome (LS) screening in patients with colorectal cancer (CRC) has superior sensitivity and provides critical information for treatment selection, according to a study published in JAMA Oncology (online: March 29, 2018; doi:10.1001/jamaoncol.2018.0104).

Universal tumor screening for LS in CRC is currently recommended and involves up to six sequential tests. The diagnostic workup for patient with CRC may be simplified and improved using a single up-front tumor next-generation sequencing test, but further research to validate this method is needed.

Heather Hampel, MS, CGC, Ohio State University, and colleagues examined whether up-front tumor sequencing could replace the current multiple sequential test approach for universal tumor screening for LS.

The study included tumor DNA from 419 consecutive CRC cases undergoing standard universal tumor screening and germline genetic testing when indicated as part of the multicenter, population-based Ohio Colorectal Cancer Prevention Initiative from October 2015 through February 2016. An additional 46 patients with CRC known to have LS due to a germline mutation in a mismatch repair gene from January 2013 through September 2015 underwent blinded tumor sequencing.

Researchers reported the mean age at diagnosis was 59.9 years and 241 of the patients were female. Tumor sequencing identified all 46 known LS cases from the validation cohort and an additional 12 LS cases from the 419-member prospective cohort. Testing with MSI or IHC, followed by BRAF V600E testing missed five and six cases of LS, respectively.

Additionally, researchers noted that tumor sequencing alone had better sensitivity than IHC plus BRAF and MSI plus BRAF. Tumor sequencing had equal specificity to IHC plus BRAF and MSI plus BRAF. Tumor sequencing identified 284 cases with KRAS, NRAS, or BRAF mutations that could affect therapy for stage IV CRC and help to avoid another test. Furthermore, tumor sequencing identified eight patients with germline DPYD mutations that confer toxicity to fluorouracil chemotherapy, which could be useful for treatment selection.

“Up-front tumor sequencing in CRC is simpler and has superior sensitivity to current multi-test approaches to LS screening, while simultaneously providing critical information for treatment selection,” authors of the study concluded.—Janelle Bradley