POLE校正機能欠損大腸がんの臨床的・ゲノム学的特徴および予測モデル

このたびは奨励賞に選出いただき、誠にありがとうございました。ご指導いただいた先生方、そして患者さんに深く感謝申し上げます。

私は研修医時代、がんを患う方々を身体的・精神的・社会的側面まで含めて支えたいと考え、腫瘍内科を志しました。

診療を重ねる中で「治療がなぜ効くのか／効かなくなるのか」を細胞・分子レベルで理解したいという思いが強くなり、大学院での研究を経て、現在も臨床と研究を往復しながら取り組んでいます。

JSMOは臨床と研究の距離が近く、臨床医が自らの問いを研究として育て、仲間とつながり、世界へ発信できる場だと感じています。

腫瘍内科学は急速に発展する一方で、未解決の課題も多い分野です。だからこそ、自身の研究ががん医療をより良く変え得ると信じ、今後も患者さんに還元できる成果を目指して精進していきたいと思います。

Clinicogenomic features and prediction model of POLE proofreading-deficient colorectal cancer

Background: Proofreading-deficient (pd) mutations in DNA polymerase epsilon (POLE) cause ultramutated colorectal cancer (CRC) characterized by high tumor mutational burden (TMB) and marked sensitivity to immune checkpoint inhibitors (ICIs). As POLEpd CRC is extremely rare and most cases are microsatellite-stable (MSS), they are unlikely to receive ICI in routine care unless genomic profiling with TMB assessment is performed. We aimed to clarify the clinicogenomic features of POLEpd CRC and to develop a prediction model to minimize missed opportunities for ICI therapy.

Methods: We retrospectively analyzed clinical and genomic data from the C-CAT registry of cases sequenced with FoundationOne between June 2019 and August 2025. Pathogenicity of POLE variants was annotated with OncoKB. Exploratory analysis of single base substitution (SBS) signature contributions was performed in cases with TMB ≥10 muts/Mb, calculated from panel sequencing data using MutationalPatterns fitted to COSMIC SBS signature v3.4.

Results: Among 9,974 CRC cases, 21 (0.2%) harbored oncogenic POLE mutations (POLEmut), while 483 (4.8%) carried variants of uncertain significance (VUS). POLEmut CRC occurred in younger, predominantly male, enriched for MSS and RAS/BRAF wild-type (WT). Mean TMB was 153 mut/Mb (95%CI 110-195), significantly higher than in POLE-VUS and POLE-WT (8.8 and 3.9 muts/Mb). The mean contributi