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

IF 3.8 3区 医学 Q2 GENETICS & HEREDITY
Shouvik Chakravarty, Arnab Ghosh, Chitrarpita Das, Subrata Das, Subrata Patra, Arindam Maitra, Sandip Ghose, Nidhan K Biswas
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引用次数: 0

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

黑色素瘤相关口腔癌的多区域基因组和转录组特征分析为 CASP8 改变介导的野外癌化提供了证据。
背景:口腔内的癌前病变和恶性肿瘤是在暴露于致癌刺激时,由上皮细胞的 "场 "产生的。这种现象被称为 "场癌变"。在印度口腔鳞状细胞癌(OSCC)患者中,导致场癌化和肿瘤进展的分子基因组和转录组改变尚不清楚:我们对五例肿瘤和发育不良病变(取样于不同的解剖亚部位--口腔前后肺泡、舌背粘膜黑色素瘤、唇部和左侧口腔粘膜各一例)以及一名罕见的OSCC患者的血液进行了全外显子组测序、拷贝数变异阵列和全转录组测序:结果:观察到错义 CASP8 基因突变(p.S375F)是口腔瘤场发展的起始事件。APOBEC突变特征、臂水平拷贝数改变、CD8 + T细胞和活化的NK细胞耗竭以及促炎肥大细胞富集是早期起源肿瘤的特征。在CASP8野生型OSCC细胞系中对CASP8蛋白进行药理抑制,结果显示细胞迁移和存活率均有所提高:结论:CASP8改变是口腔领域癌变的最早驱动事件,而其他体细胞突变、拷贝数和转录组改变最终会导致OSCC肿瘤的形成和进展。
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来源期刊
Human Genomics
Human Genomics GENETICS & HEREDITY-
CiteScore
6.00
自引率
2.20%
发文量
55
审稿时长
11 weeks
期刊介绍: Human Genomics is a peer-reviewed, open access, online journal that focuses on the application of genomic analysis in all aspects of human health and disease, as well as genomic analysis of drug efficacy and safety, and comparative genomics. Topics covered by the journal include, but are not limited to: pharmacogenomics, genome-wide association studies, genome-wide sequencing, exome sequencing, next-generation deep-sequencing, functional genomics, epigenomics, translational genomics, expression profiling, proteomics, bioinformatics, animal models, statistical genetics, genetic epidemiology, human population genetics and comparative genomics.
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