口腔内暴露于致癌刺激物后，上皮细胞的易感“区域”会产生癌前肿瘤和恶性肿瘤。这种现象被称为“现场癌化”。在印度口腔鳞状细胞癌 (OSCC) 患者中，导致局部癌化和肿瘤进展的分子基因组和转录组改变尚不清楚。我们对五个肿瘤和发育异常病变进行了全外显子组测序、拷贝数变异阵列和全转录组测序（采样自不同的解剖亚位点 - 颊前牙槽和后牙槽、舌粘膜黑色素瘤背面、唇部和左颊粘膜各一个，以及来自一名罕见的癌变 OSCC 患者的血液。错义 CASP8 基因突变 (p.S375F)观察到这是口腔肿瘤领域发展的起始事件。 APOBEC 突变特征、臂水平拷贝数改变、CD8  T 细胞和活化 NK 细胞的耗竭以及促炎性肥大细胞的富集是早期起源肿瘤的特征。 CASP8 野生型 OSCC 细胞系中 CASP8 蛋白的药理学抑制显示细胞迁移和活力水平增强。CASP8 改变是口腔癌发生的最早驱动事件，而额外的体细胞突变、拷贝数和转录组改变最终导致 OSCC 肿瘤形成和进展。© 2024。作者。

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.© 2024. The Author(s).