Hampel H, et al. - Whether up-front tumor sequencing (TS) could replace the current multiple sequential test approach for universal tumor screening for Lynch syndrome (LS) in colorectal cancer (CRC), was determined using a prospective cohort (CRC cases undergoing standard universal tumor screening and germline genetic testing as part of the Ohio Colorectal Cancer Prevention Initiative study) and a validation cohort (CRC cases with LS due to a germline mutation in a mismatch repair gene, undergoing blinded TS). Compared with current multitest approaches to LS screening, up-front TS in CRC affords a simpler approach with superior sensitivity. At the same time, this approach offers critical information for treatment selection.