Cigarette smoking is a risk factor for the development of head and neck squamous cell carcinoma (HNSCC), partially due to tobacco-induced large-scale chromosomal copy-number alterations (CNAs). Identifying CNAs caused by smoking is essential in determining how gene expression from such regions impact tumor progression and patient outcome. We utilized The Cancer Genome Atlas (TCGA) whole genome sequencing data for HNSCC to directly identify amplified or deleted genes correlating with smoking pack-year based on linear modeling. Internal cross-validation identified 35 CNAs that significantly correlated with patient smoking, independent of human papillomavirus (HPV) status. The most abundant CNAs were chromosome 11q13.3-q14.4 amplification and 9p23.1/9p24.1 deletion. Evaluation of patient amplicons reveals four different patterns of 11q13 gene amplification in HNSCC resulting from breakage-fusion-bridge (BFB) events. . Predictive modeling identified 16 genes from these regions that denote poorer overall and disease-free survival with increased pack-year use, constituting a smoking-associated expression signature (SAES). Patients with altered expression of signature genes have increased risk of death and enhanced cervical lymph node involvement. The identified SAES can be utilized as a novel predictor of increased disease aggressiveness and poor outcome in smoking-associated HNSCC.

吸烟是头颈鳞状细胞癌（HNSCC）发展的危险因素，部分原因是烟草引起的大规模染色体拷贝数改变（CNA）。识别吸烟引起的 CNAs 对于确定这些区域的基因表达如何影响肿瘤进展和患者预后至关重要。我们利用 HNSCC 的癌症基因组图谱 (TCGA) 全基因组测序数据，基于线性模型直接识别与吸烟年数相关的扩增或删除基因。内部交叉验证确定了 35 个 CNA 与患者吸烟显着相关，且与人乳头瘤病毒 (HPV) 状态无关。最丰富的 CNA 是染色体 11q13.3-q14.4 扩增和 9p23.1/9p24.1 缺失。对患者扩增子的评估揭示了 HNSCC 中断裂融合桥 (BFB) 事件导致的 11q13 基因扩增的四种不同模式。。预测模型从这些区域中识别出 16 个基因，这些基因表示随着包年使用量的增加，总体生存率和无病生存率较差，构成吸烟相关表达特征(SAES)。特征基因表达改变的患者死亡风险增加，颈部淋巴结受累增加。所确定的 SAES 可用作与吸烟相关的 HNSCC 疾病侵袭性增加和预后不良的新预测因子。