Department of Otolaryngology - Head and Neck Surgery, University of Western Ontario, London, Ontario, Canada.
Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Oral Oncol. 2020 May;104:104614. doi: 10.1016/j.oraloncology.2020.104614. Epub 2020 Mar 5.
Survival in head and neck squamous cell carcinoma (HNSCC) has been associated with patient sex, typically with males experiencing poorer outcomes. It is unclear if this disparity is based in divergent tumor biology. We analyzed the TCGA HNSCC cohort to uncover disparities in the somatic single nucleotide variation (SNV), copy number alteration (CNA) and mRNA abundance profiles between males and females. Critically, we stratified our results by tumor HPV status to control for this significant confounder.
SNV, CNA and mRNA abundance differences between males and females were compared separately for the HPV-positive (n = 67) and negative (n = 431) TCGA HNSCC cohorts. Overall survival outcomes were compared in males and females in both HPV-positive and HPV-negative subsets of patients.
Females were found to have poorer overall survival than males (p = 0.048), largely due to higher rates of HPV-positive disease among men. SNV analysis revealed that in HPV-positive disease, there were no differences by sex after accounting for the false discovery rate (FDR). In HPV-negative tumors, BRWD3 mutations occurred more frequently in the tumors of female patients compared to males after adjusting for the FDR (p = 0.02). Further, HPV-negative BRWD3 mutant tumors were found to have significantly worse 5-year overall survival compared to wildtype on multivariate analysis (p = 0.02). There were 88 heterozygous deletions and 14 amplifications that were differentially altered between male and female HPV-negative tumors and associated with expression changes. Pathway analysis of these genes revealed that tumors from males were enriched in five pathways including chemokine and phosphophatidylinositol signaling.
Reanalysis of the TCGA HNSCC dataset stratified by sex revealed that males in this cohort had a significant survival advantage, due to a higher proportion of HPV-positive disease. Mutations in BRWD3 were more frequent in HPV-negative tumors of females and were associated with poorer overall survival. BRWD3 may represent a novel biomarker of patient outcomes, but will require additional validation.
头颈部鳞状细胞癌（HNSCC）患者的存活率与患者性别相关，通常男性的预后较差。目前尚不清楚这种差异是否基于肿瘤生物学的差异。我们分析了 TCGA HNSCC 队列，以揭示男性和女性之间体细胞单核苷酸变异（SNV）、拷贝数改变（CNA）和 mRNA 丰度谱的差异。关键的是，我们根据肿瘤 HPV 状态对结果进行分层，以控制这一重要的混杂因素。
我们分别比较了 HPV 阳性（n=67）和 HPV 阴性（n=431）TCGA HNSCC 队列中男性和女性之间的 SNV、CNA 和 mRNA 丰度差异。比较了 HPV 阳性和 HPV 阴性亚组中男性和女性的总生存结局。
女性的总生存率低于男性（p=0.048），这主要是由于男性 HPV 阳性疾病的比例较高。SNV 分析显示，在 HPV 阳性疾病中，在考虑了错误发现率（FDR）后，性别之间没有差异。在 HPV 阴性肿瘤中，BRWD3 突变在女性患者的肿瘤中比男性更常见，调整 FDR 后差异有统计学意义（p=0.02）。进一步的多因素分析显示，HPV 阴性 BRWD3 突变型肿瘤的 5 年总生存率明显低于野生型（p=0.02）。有 88 个杂合性缺失和 14 个扩增在男性和女性 HPV 阴性肿瘤之间存在差异，并与表达变化相关。对这些基因的通路分析显示，男性肿瘤中富含包括趋化因子和磷酸磷脂酰肌醇信号在内的五条通路。
对 TCGA HNSCC 数据集按性别重新分析显示，由于 HPV 阳性疾病的比例较高，该队列中的男性具有显著的生存优势。BRWD3 突变在女性 HPV 阴性肿瘤中更为常见，与总生存率降低相关。BRWD3 可能是一种新的患者预后生物标志物，但需要进一步验证。
