Distinct mutational profile and immune microenvironment in microsatellite-unstable and POLE-mutated tumors

微卫星不稳定性 索引 DNA错配修复 结直肠癌 癌症研究 突变 癌症 生物 ARID1A型 INDEL突变 遗传学 基因 微卫星 基因型 单核苷酸多态性 等位基因
作者
Hee Sang Hwang,Deokhoon Kim,Jene Choi
出处
期刊:Journal for ImmunoTherapy of Cancer [BMJ]
卷期号:9 (10): e002797-e002797 被引量:27
标识
DOI:10.1136/jitc-2021-002797
摘要

Introduction Mismatch repair (MMR)-deficient and DNA polymerase epsilon ( POLE )-mutated tumors exhibit a high tumor mutation burden (TMB) and have been proven to be associated with good responses to immune checkpoint inhibitor treatments. However, the relationship between mutational characteristics of MMR-deficient and POLE -mutated tumors and the spatial architecture of tumor-infiltrating lymphocytes (TILs) has not been fully evaluated. Methods We retrieved microsatellite instability-high (MSI-high, N=20) and POLE -mutated (N=47) cases from the clinical next-generation sequencing cohort at Asan Medical Center. Whole-slide immunostaining for CD3, CD4, CD8, FoxP3 and PD-1 were performed with tissue samples of colorectal and gastric cancer (N=24) and the tumor-positive TIL cell densities were correlated with the tumor’s mutational features. The findings were compared with the results of similar analyses in The Cancer Genome Atlas-Colorectal Adenocarcinoma (TCGA-COADREAD) cohort (N=592). Results The MSI-high group showed significantly higher overall TMBs with a number of insertion/deletion (indel) mutations relative to the POLE -mutated group (median TMB; 83.6 vs 12.5/Mb). Oncogenic/likely-oncogenic POLE mutations were identified with ultrahypermutations (≥100 mutations/Mb) (2/47, 4.3%). Concurrent POLE mutations of unknown significance and MSI-high cases were identified in eight cases (8/67, 11%), and two of these colorectal cancers had multiple POLE mutations, showing an ultramutated phenotype (378.1 and 484.4/Mb) and low indel mutation burdens with complete loss of MSH-6 or PMS-2, which was similar to the mutational profile of the POLE -inactivated tumors. Intratumoral CD3-positive, CD4-positive, CD8-positive, FoxP3-positive and PD-1-positive TIL cell densities were more strongly correlated with the indel mutation burden than with the total TMB (correlation coefficient, 0.61–0.73 vs 0.23–0.38). In addition, PI3K/AKT/mTOR pathway mutations were commonly found in MSI-high tumors (75%) but not in POLE -mutated tumors. Conclusions Indel mutation burden rather than total TMB could serve as a predictor of high TILs in both MSI-high and POLE -mutated tumors. Multiple uncharacterized/non-pathogenic POLE mutations occurring via MMR deficiency within MSI-high tumors may have combined pathogenic roles. A mutated PI3K/AKT/mTOR pathway may be a biomarker that can be used to stratify patients with advanced MSI-high tumors for immune therapy.

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