黑色素瘤相关的口腔癌的多区域基因组和转录组表征为CASP8改变介导的场癌化提供了证据
Multi-regional genomic and transcriptomic characterization of a melanoma-associated oral cavity cancer provide evidence for CASP8 alteration-mediated field cancerization
影响因子:4.30000
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
摘要
癌前和恶性肿瘤在暴露于致癌刺激的上皮细胞的易感性“场”内出现。这种现象被称为“场癌”。 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,观察到，一个罕见的OSCC患者患有现场癌症的舌粘膜黑色素瘤，唇部和左颊粘膜）的背部。一个失误CASP8基因突变（P.S375F）是口腔肿瘤场发育中的起始事件。 APOBEC突变特征，臂级拷贝数改变，CD8+T细胞的耗竭以及活化的NK细胞以及促炎性肥大细胞的富集是早期原始肿瘤的特征。 CASP8野生型OSCC细胞系中CASP8蛋白的药理抑制作用显示出增强的细胞迁移和生存能力。CASP8改变是口腔田间致癌作用中最早的驱动事件，而其他的体细胞突变，拷贝数，拷贝数和转录变量最终导致OSCC肿瘤的形成和进展。
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.