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A Genetically Engineered Mouse Model of Sporadic Colorectal Cancer
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Published on: July 6, 2017

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WRN-Mutated Colorectal Cancer Is Characterized by a Distinct Genetic Phenotype

Kai Zimmer1, Alberto Puccini2, Joanne Xiu3

  • 1Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck, Innsbruck Medical University, 6020 Innsbruck, Austria.

Cancers
|May 28, 2020
PubMed

Insights

Werner syndrome gene (WRN) mutations are linked to higher tumor mutational burden (TMB) and PD-L1 expression in colorectal cancer (CRC). This suggests WRN-mut CRC may benefit from immune checkpoint inhibitor therapies.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • The Werner syndrome gene (WRN) plays a role in DNA repair.
  • WRN mutations (WRN-mut) are associated with genomic instability and are a potential target in cancers with microsatellite instability (MSI).

Purpose of the Study:

  • To investigate the molecular profile of WRN-mut in colorectal cancer (CRC).
  • To assess the potential of WRN as a therapeutic target in CRC, particularly in tumors with microsatellite instability.

Main Methods:

  • Analysis of tumor samples using next-generation sequencing (NGS), in-situ hybridization, and immunohistochemistry.
  • Calculation of tumor mutational burden (TMB) based on somatic nonsynonymous missense mutations.
  • Determination of mismatch repair (MMR) or microsatellite instability (MSI) status via fragment analysis.

Main Results:

  • WRN-mut were identified in 1.2% of CRC samples, more frequently in right-sided CRC.
  • WRN-mut tumors exhibited significantly higher TMB, PD-L1 expression, and MSI-H/dMMR status compared to WRN wild-type (WRN-wt) tumors.
  • WRN-mut was associated with higher TMB in both MSI-H/dMMR and microsatellite-stable (MSS) subgroups.
  • Observed genetic differences included lower frequencies of TP53, KRAS, and APC mutations in WRN-mut CRC.

Conclusions:

  • WRN-mut CRC is characterized by a high prevalence of MSI-H/dMMR, elevated TMB, and increased PD-L1 expression.
  • These findings suggest WRN-mut status could be a predictive biomarker for response to immune checkpoint inhibitors in CRC.
  • This study provides a comprehensive molecular profile of WRN-mut CRC, supporting its potential as a target for novel therapies.
Keywords:
BRCAnessMSI-H/dMMRPD-L1TMBWRNcolorectal cancerimmunotherapymolecular profiling

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