Identifying mismatch repair-deficient colon cancer: near-perfect concordance between immunohistochemistry and microsatellite instability testing in a large, population-based series.

Maurice B Loughrey,Stephanie G Craig,Perry Maxwell,Victoria Bingham,Claire Mcgready,Jacqueline A James,Helen G Coleman,Matthew P Humphries,Manuel Salto‐Tellez,Stephen Mcquaid,Jason Mcgrath,Peter Bankhead

doi:10.1111/his.14233

Abstract

Establishing the mismatch repair (MMR) status of colorectal cancers is important to enable the detection of underlying Lynch syndrome and inform prognosis and therapy. Current testing typically involves either polymerase chain reaction (PCR)-based microsatellite instability (MSI) testing or MMR protein immunohistochemistry (IHC). The aim of this study was to compare these two approaches in a large, population-based cohort of stage 2 and 3 colon cancer cases in Northern Ireland. The study used the Promega pentaplex assay to determine MSI status and a four-antibody MMR IHC panel. IHC was applied to tumour tissue microarrays with triplicate tumour sampling, and assessed manually. Of 593 cases with available MSI and MMR IHC results, 136 (22.9%) were MSI-high (MSI-H) and 135 (22.8%) showed abnormal MMR IHC. Concordance was extremely high, with 97.1% of MSI-H cases showing abnormal MMR IHC, and 97.8% of cases with abnormal IHC showing MSI-H status. Under-representation of tumour epithelial cells in samples from heavily inflamed tumours resulted in misclassification of several cases with abnormal MMR IHC as microsatellite-stable. MMR IHC revealed rare cases with unusual patterns of MMR protein expression, unusual combinations of expression loss, or secondary clonal loss of expression, as further illustrated by repeat immunostaining on whole tissue sections. MSI PCR testing and MMR IHC can be considered to be equally proficient tests for establishing MMR/MSI status, when there is awareness of the potential pitfalls of either method. The choice of methodology may depend on available services and expertise.

Highlights

The molecular classification of colorectal cancer (CRC) has, in recent years, been the subject of rapid interest and scientific progress.[1]
Given health economic assessments indicating the cost-effectiveness of testing all new CRC diagnoses for underlying Lynch syndrome, and the growing importance of immune checkpoint inhibitor therapy for treating advanced-stage dMMR/microsatellite instability (MSI)-H CRC, the mismatch repair (MMR)/MSI status of CRC is established as a matter of routine.[6,8,13,15,18,19,20,38]
We conducted a thorough comparison of MSI testing and MMR IHC in a large population-based series of colon cancers, to help determine the suitability of one methodology or the other as a primary screening test

Summary

Introduction

The molecular classification of colorectal cancer (CRC) has, in recent years, been the subject of rapid interest and scientific progress.[1] The microsatellite instability (MSI) pathway remains the most consistent and best-characterised molecular pathogenic process leading to the development of CRC.[2,3] The identification of MSI-high (MSI-H) CRC is important for two distinct reasons. Biallelic somatic mutations in MMR genes account for a significant proportion of MSI-H CRCs lacking constitutive mutation in MMR genes, somatic BRAF mutation, or MLH1 promoter hypermethylation, especially among patients in older age groups.[10,11,12]

Methods

Results

Conclusion