PTCH1 mutation as a potential predictive biomarker for immune checkpoint inhibitors in gastrointestinal cancer.

IF 3.3 3区 医学 Q2 ONCOLOGY
Shuangya Deng, Haoran Gu, ZongYao Chen, Yaqin Liu, Qin Zhang, Dongsheng Chen, Shengen Yi
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Abstract

Immune checkpoint inhibitors (ICIs) have become prominent therapies for gastrointestinal cancer (GC). However, it is urgent to screen patients who can benefit from ICIs. Protein patched homolog 1 (PTCH1) is a frequently altered gene in GC. We attempt to explore the association between PTCH1 mutation and immunotherapy efficacy. The Memorial Sloan Kettering Cancer Center (MSKCC) cohort (n = 236) with GC (esophageal, gastric and colorectal cancers) patients receiving ICIs was used for discovery and the Peking University Cancer Hospital (PUCH) GC cohort (n = 92) was used for validation. Overall survival (OS) and tumor mutational burden (TMB) of the PTCH1 mutant-type (PTCH1-MUT) and PTCH1 wild-type (PTCH1-WT) groups were compared. Furthermore, GC data were collected from The Cancer Genome Atlas to assess the potential mechanisms. In the MSKCC cohort, PTCH1-MUT group showed significantly better OS (P = 0.017) and higher TMB. Multivariate analysis showed that PTCH1 mutation was associated with better OS. In the PUCH cohort, PTCH1-MUT group showed significantly longer OS (P = 0.036) and progression-free survival, and higher durable clinical benefit and TMB. Immune cell infiltration analysis revealed that PTCH1-MUT group had significantly higher distributions of CD8 T cells, CD4 T cells, NK cells, mast cells and M1 cells. The PTCH1-MUT group showed significantly higher expression of most immune-related genes. Gene set enrichment analysis showed that the PTCH1-MUT group had enriched INF-γ response, INF-α response, glycolysis and reactive oxygen species pathway gene sets. PTCH1 mutation may represent a potential biomarker for predicting ICIs response in GC. Nevertheless, prospective cohort studies should be performed to further validate our results.

PTCH1突变作为胃肠癌免疫检查点抑制剂的潜在预测生物标记物。
免疫检查点抑制剂(ICIs)已成为胃肠癌(GC)的主要疗法。然而,筛选能从 ICIs 中获益的患者已迫在眉睫。蛋白斑块同源物1(PTCH1)是胃肠癌中经常发生变化的基因。我们试图探索 PTCH1 基因突变与免疫疗法疗效之间的关联。接受 ICIs 的 GC(食管癌、胃癌和结直肠癌)患者的 MSKCC 队列(n = 236)用于发现,北京大学肿瘤医院(PUCH)GC 队列(n = 92)用于验证。比较了PTCH1突变型(PTCH1-MUT)组和PTCH1野生型(PTCH1-WT)组的总生存期(OS)和肿瘤突变负荷(TMB)。此外,还从TCGA收集了GC数据,以评估潜在的机制。在MSKCC队列中,PTCH1-MUT组的OS明显更好(P = 0.017),TMB也更高。多变量分析显示,PTCH1突变与更好的OS相关。在PUCH队列中,PTCH1-MUT组的OS(P = 0.036)和PFS明显更长,DCB和TMB更高。免疫细胞浸润分析显示,PTCH1-MUT组的CD8 T细胞、CD4 T细胞、NK细胞、肥大细胞和M1细胞分布明显较高。PTCH1-MUT组大多数免疫相关基因的表达量明显更高。GSEA显示,PTCH1-MUT组富集了INF-γ反应、INF-α反应、糖酵解和活性氧通路基因组。PTCH1突变可能是预测GC中ICIs反应的潜在生物标志物。尽管如此,仍需进行前瞻性队列研究来进一步验证我们的结果。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Carcinogenesis
Carcinogenesis 医学-肿瘤学
CiteScore
9.20
自引率
2.10%
发文量
95
审稿时长
1 months
期刊介绍: Carcinogenesis: Integrative Cancer Research is a multi-disciplinary journal that brings together all the varied aspects of research that will ultimately lead to the prevention of cancer in man. The journal publishes papers that warrant prompt publication in the areas of Biology, Genetics and Epigenetics (including the processes of promotion, progression, signal transduction, apoptosis, genomic instability, growth factors, cell and molecular biology, mutation, DNA repair, genetics, etc.), Cancer Biomarkers and Molecular Epidemiology (including genetic predisposition to cancer, and epidemiology), Inflammation, Microenvironment and Prevention (including molecular dosimetry, chemoprevention, nutrition and cancer, etc.), and Carcinogenesis (including oncogenes and tumor suppressor genes in carcinogenesis, therapy resistance of solid tumors, cancer mouse models, apoptosis and senescence, novel therapeutic targets and cancer drugs).
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