A Scoring Model and Protocol to Adapt Universal Screening for Lynch Syndrome to Identify Germline Pathogenic Variants by Next Generation Sequencing from Colorectal Cancer Patients and Cascade Screening.

Abstract

Simple SummaryLynch syndrome (LS) is an autosomal-dominantly inherited form of cancer predisposition dominated by colorectal cancer (CRC). LS is caused by germline pathogenic variants (PV) occurring in known mismatch repair genes. For effective cascade screening, it is critical to identify PV for LS predisposition. When limited resources are available, next generation sequencing (NGS) of an entire cohort of colorectal cancer (CRC) patients, even those under 50 or 60 years of age, places a huge burden on the system. Here, we present an innovative LS ascertainment and follow-up program that includes LS molecular analysis, PV screening with NGS technology, and cascade screening. The goal is to improve LS ascertainment in light of the growing burden of early-onset CRC, particularly in low- and middle-income countries.Identification of germline pathogenic variants (PV) predisposing to Lynch syndrome (LS) is an important step for effective use of cascade screening of extended at-risk lineages, leading to reduced morbidity and mortality due to colorectal cancer (CRC). As a general rule, however, next generation sequencing (NGS, either of gene panels or whole exomes) is relatively expensive and unaffordable for general clinical use. In resource-poor settings, performing NGS testing on an entire cohort of CRC patients, even if limited to those under 50 or 60 years of age, still places an enormous burden on limited resources. Although family history can be a good indicator for LS testing, identifying at-risk family members and offering cascade screening may not benefit many patients/probands without an obvious family history. This article presents a novel program called Modified Ascertainment and follow-up Program (MAP) with a scoring model for LS ascertainment and molecular screening by NGS with diagnosis confirmation of PV and cascade screening. The goal is to improve LS ascertainment in light of the growing burden of early-onset CRC, particularly in low- and middle-income countries. Through MAP, judiciously applied molecular genetics will improve identification of PV predisposing to LS and cascade screening.