ArticleNPJ precision oncology2026
Mutation enrichment in targeted panels flags immunotherapy-responsive POLE-driven hypermutated microsatellite-stable colorectal cancers.
Article in NPJ precision oncology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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10 authors.
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Abstract
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.
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