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Organisms are capable of detecting and fixing nucleotide mismatches that occur during DNA replication. This sophisticated process requires identifying the new strand and replacing the erroneous bases with correct nucleotides. Mismatch repair is coordinated by many proteins in both prokaryotes and eukaryotes.
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One of the common DNA damages is the chemical alteration of single bases by alkylation, oxidation, or deamination. The altered bases cause mispairing and strand breakage during replication. This type of damage causes minimal change to the DNA double helix structure and can be repaired by the base excision repair (BER) pathways. BER corrects damaged DNA sequences by removing the damaged base and restoring the original base sequence using the complementary strand as a template.
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Mismatch repair-based stratification for immune checkpoint blockade therapy.

Lihong Zhang1, Yang Peng2, Guang Peng2

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American Journal of Cancer Research
|November 13, 2018
PubMed
Summary

Mismatch repair deficiency (MMR-D) drives microsatellite instability (MSI) in cancers, impacting treatment response. Next-generation sequencing (NGS) offers a promising pan-cancer strategy for identifying MMR-D tumors, improving patient selection for therapies.

Keywords:
Mismatch repairgene signatureimmune checkpoint blockademicrosatellite instabilitynext-generation sequencingprogrammed cell death protein 1

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Area of Science:

  • Genomic stability and cancer biology
  • Molecular diagnostics and personalized medicine

Background:

  • Mismatch repair (MMR) is crucial for maintaining genomic stability.
  • MMR deficiency (MMR-D) leads to microsatellite instability (MSI), a hallmark of various cancers, including Lynch syndrome.
  • MMR-D cancers show promising responses to immune checkpoint blockade therapy.

Purpose of the Study:

  • To review the genetic basis and clinical implications of MMR-D.
  • To evaluate current diagnostic methods and their limitations for MMR-D detection.
  • To explore next-generation sequencing (NGS) as a novel pan-cancer diagnostic strategy for MMR-D.

Main Methods:

  • Review of current literature on MMR-D, MSI, and cancer.
  • Analysis of standard diagnostic techniques: immunohistochemistry (IHC) and polymerase chain reaction (PCR)-based MSI analysis.
  • Evaluation of next-generation sequencing (NGS) as a diagnostic tool for MMR-D detection.

Main Results:

  • Current standard methods (IHC, PCR) have limitations for pan-cancer MMR-D testing.
  • NGS presents a mature and advantageous approach for MMR-D detection across various cancer types.
  • Identifying MMR-D is critical for predicting response to immune checkpoint blockade therapy.

Conclusions:

  • Accurate identification of MMR-D is essential for effective cancer treatment, particularly with immunotherapy.
  • NGS offers a superior and versatile strategy for diagnosing MMR-D in a pan-cancer context.
  • Future strategies may integrate MMR-D detection with anti-cancer immunity biomarker assessment.