Feasibility of Screening for Lynch Syndrome Among Patients With Colorectal Cancer

TLDR

Identifying Lynch syndrome is highly beneficial, yet it remains unclear whether microsatellite instability or immunohistochemistry should be used to screen all colorectal cancer patients or only high‑risk subgroups. The study performed MSI and IHC testing on 500 colorectal cancer tumors, and any abnormal result prompted comprehensive mismatch‑repair gene mutation analysis. Across 1,566 colorectal cancer patients, 2.8% had Lynch syndrome—every case was MSI‑high and 94% detected by IHC; screening all patients rather than only those meeting Bethesda criteria would identify 28% more cases, and each proband typically has three mutation‑positive relatives.

Abstract

Identifying individuals with Lynch syndrome (LS) is highly beneficial. However, it is unclear whether microsatellite instability (MSI) or immunohistochemistry (IHC) should be used as the screening test and whether screening should target all patients with colorectal cancer (CRC) or those in high-risk subgroups.MSI testing and IHC for the four mismatch repair proteins was performed on 500 tumors from unselected patients with CRC. If either MSI or IHC was abnormal, complete mutation analysis for the mismatch repair genes was performed.Among the 500 patients, 18 patients (3.6%) had LS. All 18 patients detected with LS (100%) had MSI-high tumors; 17 (94%) of 18 patients with LS were correctly predicted by IHC. Of the 18 probands, only eight patients (44%) were diagnosed at age younger than 50 years, and only 13 patients (72%) met the revised Bethesda guidelines. When these results were added to data on 1,066 previously studied patients, the entire study cohort (N = 1,566) showed an overall prevalence of 44 of 1,566 patients (2.8%; 95% CI, 2.1% to 3.8%) for LS. For each proband, on average, three additional family members carried MMR mutations.One of every 35 patients with CRC has LS, and each has at least three relatives with LS; all of whom can benefit from increased cancer surveillance. For screening, IHC is almost equally sensitive as MSI, but IHC is more readily available and helps to direct gene testing. Limiting tumor analysis to patients who fulfill Bethesda criteria would fail to identify 28% (or one in four) cases of LS.