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Identifying DNA Mutations in Purified Hematopoietic Stem/Progenitor Cells
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Genomic Alterations in DNA Mismatch Repair Genes Across Different Cancer Types

Vijaykumar R Holla1, Michael P Kahle1, Sun-Hee Kim1

  • 1Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, Houston, TX.

JCO Precision Oncology
|November 22, 2024
PubMed
Abstract

Insights

Next-generation sequencing (NGS) can identify mismatch repair (MMR) gene mutations in solid tumors, indicating potential for MMR protein loss. This supports using NGS to guide immunohistochemistry (IHC) testing for dMMR patients.

Area of Science:

  • Oncology
  • Genomics
  • Cancer Biomarkers

Background:

  • Mismatch repair deficient (dMMR) solid tumors respond to PD-1 inhibition.
  • Immunohistochemistry (IHC) for dMMR is not universally applied.
  • Next-generation sequencing (NGS) for genomic alterations is common.

Purpose of the Study:

  • To determine if NGS can identify patients with mismatch repair (MMR) gene alterations.
  • To assess the correlation between NGS-identified MMR gene mutations and MMR protein loss by IHC.
  • To support reflex IHC testing after NGS for dMMR identification.

Main Methods:

  • Analysis of 15,701 solid tumor patients undergoing NGS for MMR genes (2016-2021).
  • Comparison of NGS results with IHC data for 4,994 patients.
  • Evaluation of mutation types and tumor distribution.

Main Results:

  • MMR gene mutations were identified in 4.4% of patients across various tumor types.
  • 33.8% of patients with MMR mutations showed MMR protein loss by IHC, versus 4.4% without mutations.
  • IHC loss varied based on specific MMR gene mutation type.

Conclusions:

  • NGS can detect MMR gene mutations in diverse tumor types lacking routine IHC.
  • Reflex IHC testing post-NGS may increase dMMR patient identification for targeted therapies.
  • Dedicated IHC screening remains essential for comprehensive dMMR detection.

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