Use of Molecular Tumor Characteristics to Prioritize Mismatch Repair Gene Testing in Early-Onset Colorectal Cancer

TLDR

The study aimed to evaluate, on a population basis, the relationships among mismatch repair protein expression, microsatellite instability, family history, and germline MMR gene mutation status in early‑onset colorectal cancer. Researchers examined 131 unselected colorectal cancer patients under 45, performing immunohistochemistry for MLH1, MSH2, MSH6, PMS2 and microsatellite instability testing on 105 available tumors. They identified germline mutations in 18 patients, with all tumors showing loss of MMR protein expression; IHC had 100 % sensitivity, MSI 94 %, and Amsterdam Criteria 50 %, making tumor‑based IHC and MSI a highly sensitive, efficient screening strategy that would have missed half of mutation carriers using family history alone.

Abstract

Purpose The relationships between mismatch repair (MMR) protein expression, microsatellite instability (MSI), family history, and germline MMR gene mutation status have not been studied on a population basis. Methods We studied 131 unselected patients with colorectal cancer diagnosed younger than age 45 years. For the 105 available tumors, MLH1, MSH2, MSH6, and PMS2 protein expression using immunohistochemistry (IHC) and MSI were measured. Results Germline mutations were found in 18 patients (nine hMLH1, four hMSH2, four hMSH6, and one hPMS2); all tumors exhibited loss of MMR protein expression, all but one were high MSI or low MSI, and nine were from a family fulfilling Amsterdam Criteria. Sensitivities of IHC testing, MSI (high or low), and Amsterdam Criteria for MMR gene mutation were 100%, 94%, and 50%, respectively. Corresponding positive predictive values were 69%, 50%, and 75%. Conclusions Tumor IHC analysis of four MMR proteins and MSI testing provide a highly sensitive strategy for identifying MMR gene mutation–carrying, early-onset colorectal cancer patients, half of whom would have been missed using Amsterdam Criteria alone. Tumor-based approaches for triaging early-onset colorectal cancer patients for MMR gene mutation testing, irrespective of family history, appear to be an efficient screening strategy for HNPCC.