多区域基因组与转录组特征分析支持CASP8变异介导的场域癌变证据

Multi-regional genomic and transcriptomic characterization of a melanoma-associated oral cavity cancer provide evidence for CASP8 alteration-mediated field cancerization

Human Genomics

影响因子:4.3

分区:医学2区 / 遗传学2区

发表日期:2024 Sep 07

作者: Shouvik Chakravarty, Arnab Ghosh, Chitrarpita Das, Subrata Das, Subrata Patra, Arindam Maitra, Sandip Ghose, Nidhan K Biswas

DOI: 10.1186/s40246-024-00668-8

摘要

癌前和恶性肿瘤在口腔内由暴露于致癌刺激的上皮细胞“场”中发生。该现象被称为“场域癌变”。在印度口腔鳞状细胞癌（OSCC）患者中，导致场域癌变和肿瘤进展的分子基因组和转录组变化尚不清楚。我们对五个肿瘤及异常增生病变（取样自不同解剖部位——颊前、颊后骨、舌背粘膜黑色素瘤、唇及左颊粘膜）及一名罕见OSCC患者的血液样本进行了全外显子测序、拷贝数变异芯片和全转录组测序。结果发现，CASP8基因的错义突变（p.S375F）为口腔肿瘤场发展中的起始事件。APOBEC突变特征、臂级拷贝数变异、CD8+ T细胞及活化NK细胞的耗竭，以及促炎性肥大细胞的丰富，是早期起源肿瘤的特征。用药抑制CASP8蛋白在CASP8野生型OSCC细胞系中表现出增强的细胞迁移和存活能力。CASP8的变异是口腔场域癌变的最早驱动事件，其他体细胞突变、拷贝数变化和转录组变化最终导致OSCC的形成和进展。

Abstract

Precancerous and malignant tumours arise within the oral cavity from a predisposed "field" of epithelial cells upon exposure to carcinogenic stimulus. This phenomenon is known as "Field Cancerization". The molecular genomic and transcriptomic alterations that lead to field cancerization and tumour progression is unknown in Indian Oral squamous cell carcinoma (OSCC) patients.We have performed whole exome sequencing, copy-number variation array and whole transcriptome sequencing from five tumours and dysplastic lesions (sampled from distinct anatomical subsites - one each from buccal anterior and posterior alveolus, dorsum of tongue-mucosal melanoma, lip and left buccal mucosa) and blood from a rare OSCC patient with field cancerization.A missense CASP8 gene mutation (p.S375F) was observed to be the initiating event in oral tumour field development. APOBEC mutation signatures, arm-level copy number alterations, depletion of CD8 + T cells and activated NK cells and enrichment of pro-inflammatory mast cells were features of early-originating tumours. Pharmacological inhibition of CASP8 protein in a CASP8-wild type OSCC cell line showed enhanced levels of cellular migration and viability.CASP8 alterations are the earliest driving events in oral field carcinogenesis, whereas additional somatic mutational, copy number and transcriptomic alterations ultimately lead to OSCC tumour formation and progression.