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<p>Pathogenic mutations in the DNA polymerase ε <i>(POLE)</i> exonuclease domain define a rare but clinically distinct subset of microsatellite-stable (MSS) colorectal cancers (CRCs) characterized by hypermutation and exceptional immune checkpoint blockade sensitivity. Yet <i>POLE</i> testing is not routinely performed, leaving immunotherapy-eligible patients undetected. Because most diagnostic multigene panels do not include <i>POLE</i>, strategies enabling its recognition from routine molecular data are needed. We analyzed 675 CRC cases sequenced using a small targeted NGS panel. Tumors with ≥6 non-synonymous SNVs were flagged as potentially hypermutated. Confirmatory <i>POLE</i> sequencing and comprehensive genomic profiling (CGP) were performed in preselected cases. Findings were validated using two external <i>POLE</i>-mutant CRCs and TCGA-COAD/READ cohorts (&gt;1000 CRCs in total). All <i>POLE-</i>mutant CRCs (<i>n</i> = 5 of 15 flagged cases; two external validation cases) showed exonuclease domain hotspot mutations, pMMR/MSS status, yet MSI-like histopathology. These tumors exhibited predominantly ultra-high TMB, low dbSNP overlap, C&gt;T transition bias, and disrupted co-mutation patterns - canonical <i>POLE-</i>driven hypermutation features. In TCGA, 41/43 <i>POLE</i>-mutant CRCs carried panel-detectable co-mutations. Routine small-panel NGS data can flag candidate <i>POLE</i>-mutant MSS CRCs for confirmatory testing, enabling detection of immunotherapy-responsive tumors otherwise missed. Integrated with AI-based <i>POLE</i>/MSI prediction from H&amp;E slides, this supports multimodal diagnostic workflows enhancing precision immuno-oncology in CRC. Trial registration: NA.</p>

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Mutation enrichment in targeted panels flags immunotherapy-responsive POLE-driven hypermutated microsatellite-stable colorectal cancers

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月3日

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  • Nic Gabriel Reitsam,
  • Kathrin Anna Schneider,
  • Bianca Grosser,
  • Andreas Jung,
  • Daniel Kazdal,
  • Marco Gustav,
  • Jakob Nikolas Kather,
  • Albrecht Stenzinger,
  • Bruno Märkl,
  • Sebastian Dintner

摘要

Pathogenic mutations in the DNA polymerase ε (POLE) exonuclease domain define a rare but clinically distinct subset of microsatellite-stable (MSS) colorectal cancers (CRCs) characterized by hypermutation and exceptional immune checkpoint blockade sensitivity. Yet POLE testing is not routinely performed, leaving immunotherapy-eligible patients undetected. Because most diagnostic multigene panels do not include POLE, strategies enabling its recognition from routine molecular data are needed. We analyzed 675 CRC cases sequenced using a small targeted NGS panel. Tumors with ≥6 non-synonymous SNVs were flagged as potentially hypermutated. Confirmatory POLE sequencing and comprehensive genomic profiling (CGP) were performed in preselected cases. Findings were validated using two external POLE-mutant CRCs and TCGA-COAD/READ cohorts (>1000 CRCs in total). All POLE-mutant CRCs (n = 5 of 15 flagged cases; two external validation cases) showed exonuclease domain hotspot mutations, pMMR/MSS status, yet MSI-like histopathology. These tumors exhibited predominantly ultra-high TMB, low dbSNP overlap, C>T transition bias, and disrupted co-mutation patterns - canonical POLE-driven hypermutation features. In TCGA, 41/43 POLE-mutant CRCs carried panel-detectable co-mutations. Routine small-panel NGS data can flag candidate POLE-mutant MSS CRCs for confirmatory testing, enabling detection of immunotherapy-responsive tumors otherwise missed. Integrated with AI-based POLE/MSI prediction from H&E slides, this supports multimodal diagnostic workflows enhancing precision immuno-oncology in CRC. Trial registration: NA.