Genomic Alterations in DNA Mismatch Repair Genes Across Different Cancer Types

Overview

Journal JCO Precis Oncol

Specialty Oncology

Date 2024 Nov 22

PMID 39576951

Authors

Vijaykumar R Holla

Michael P Kahle

Sun-Hee Kim

Arash Ronaghy

Richard K Yang

Keyur P Patel

Mark J Routbort

Michael J Overman

Ecaterina E Dumbrava

Kenna R Mills Shaw

Daniel D Karp

Funda Meric-Bernstam

Affiliations

Soon will be listed here.

Abstract

Purpose: PD-1 inhibition is effective in patients with mismatch repair deficient (dMMR) solid tumors in a tumor-agnostic fashion. However, dMMR testing by immunohistochemistry (IHC) is not routinely performed across tumor types. By contrast, next-generation sequencing (NGS) for somatic genomic alterations is frequently performed across tumor types. We hypothesized that NGS would identify patients with alterations in mismatch repair (MMR) genes and that these patients would have higher rates of MMR protein loss by IHC. This would support the utility of IHC reflex testing after NGS and potential matching to approved therapeutic options.

Methods: From January 2016 to December 2021, 15,701 patients with solid tumors received NGS covering the MMR genes, and 4,994 patients had both IHC and NGS. Sequencing results were analyzed for mutations in MMR genes, tumor type distribution, and concordance with IHC results when available.

Results: Six hundred and ninety-eight (4.4%) of 15,701 patients had mutations in one of the MMR genes. Mutations were found across tumor types. Three hundred and seventeen (6.3%) of 4,994 patients displayed IHC loss for at least one MMR protein. 33.8% patients (110/325) patients with MMR mutations had dMMR, compared with just 4.4% (207/4,669) patients without mutations ( < .001); dMMR rate varied by mutation type.

Conclusion: Mutations in MMR genes are found in multiple tumor types where IHC testing is not routine. Reflex IHC testing of patients carrying MMR gene mutations, especially those known or inferred to be inactivating, may identify more patients with dMMR and matched treatment options. However, dedicated IHC screening is needed to capture majority of the patients.

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