Integrated Head and Neck Oncology Program, Mazumdar Shaw Centre for Translational Research, Mazumdar Shaw Medical Foundation, Narayana Health, Bangalore, Karnataka, India.
Head and Neck Oncology, Mazumdar Shaw Medical Centre, Narayana Health, Bangalore, Karnataka, India.
PLoS One. 2019 Jul 16;14(7):e0218989. doi: 10.1371/journal.pone.0218989. eCollection 2019.
Head and neck squamous cell carcinomas (HNSCC) includes multiple subsites that exhibit differential treatment outcome, which is in turn reflective of tumor stage/histopathology and molecular profile. This study hypothesized that the molecular profile is an accurate prognostic adjunct in patients triaged based on clinico-pathological characteristics. Towards this effect, publically available micro-array datasets (n = 8), were downloaded, classified based on HPV association (n = 83) and site (tongue n = 88; laryngopharynx n = 53; oropharynx n = 51) and re-analyzed (Genespring; v13.1). The significant genes were validated in respective cohorts in The Cancer Genome Atlas (TCGA) for correlation with clinico-pathological parameters/survival. The gene entities (n = 3258) identified from HPV based analysis, when validated in TCGA identified the subset specifically altered in HPV+ HNSCC (n = 63), with three genes showing survival impact (RPP25, NUDCD2, NOVA1). Site-specific meta-analysis identified respective differentials (tongue: 3508, laryngopharynx: 4893, oropharynx: 2386); validation in TCGA revealed markers with high incidence (altered in >10% of patients) in tongue (n = 331), laryngopharynx (n = 701) and oropharynx (n = 404). Assessment of these genes in clinical sub-cohorts of TCGA indicated that early stage tongue (MTFR1, C8ORF33, OTUD6B) and laryngeal cancers (TWISTNB, KLHL13 and UBE2Q1) were defined by distinct prognosticators. Similarly, correlation with perineural/angiolymophatic invasion, identified discrete marker panels with survival impact (tongue: NUDCD1, PRKC1; laryngopharynx: SLC4A1AP, PIK3CA, AP2M1). Alterations in ANO1, NUDCD1, PIK3CA defined survival in tongue cancer patients with nodal metastasis (node+ECS-), while EPS8 is a significant differential in node+ECS- laryngopharyngeal cancers. In oropharynx, wherein HPV is a major etiological factor, distinct prognosticators were identified in HPV+ (ECHDC2, HERC5, GGT6) and HPV- (GRB10, EMILIN1, FNDC1). Meta-analysis in combination with TCGA validation carried out in this study emphasized on the molecular heterogeneity inherent within HNSCC; the feasibility of leveraging this information for improving prognostic efficacy is also established. Subject to large scale clinical validation, the marker panel identified in this study can prove to be valuable prognostic adjuncts.
头颈部鳞状细胞癌（HNSCC）包括多个亚部位，这些亚部位的治疗效果不同，这反过来反映了肿瘤的分期/组织病理学和分子特征。本研究假设分子特征是基于临床病理特征进行分类的患者的准确预后辅助手段。为此，我们下载了公开的微阵列数据集（n=8），根据 HPV 相关性（n=83）和部位（舌 n=88；喉咽 n=53；口咽 n=51）进行分类，并在 Genespring（v13.1）中重新进行了分析。在癌症基因组图谱（TCGA）中，我们分别在各自的队列中验证了具有显著意义的基因与临床病理参数/生存的相关性。从 HPV 分析中确定的基因实体（n=3258），在 TCGA 中进行验证时，确定了 HPV+ HNSCC 中特定改变的亚组（n=63），其中三个基因显示出生存影响（RPP25、NUDCD2、NOVA1）。基于部位的荟萃分析确定了各自的差异（舌：3508；喉咽：4893；口咽：2386）；在 TCGA 中的验证揭示了在舌（n=331）、喉咽（n=701）和口咽（n=404）中发生率较高（>10%的患者发生改变）的标志物。在 TCGA 的临床亚队列中评估这些基因表明，早期舌（MTFR1、C8ORF33、OTUD6B）和喉癌（TWISTNB、KLHL13 和 UBE2Q1）由不同的预后标志物定义。同样，与神经周围/血管淋巴侵袭的相关性，确定了具有生存影响的离散标志物面板（舌：NUDCD1、PRKC1；喉咽：SLC4A1AP、PIK3CA、AP2M1）。ANO1、NUDCD1 和 PIK3CA 的改变定义了无淋巴结转移（淋巴结阴性 ECM）的舌癌患者的生存情况，而 EPS8 是淋巴结阳性 ECM 的喉咽癌的重要差异。在口咽癌中，HPV 是主要的病因因素，在 HPV+（ECHDC2、HERC5、GGT6）和 HPV-（GRB10、EMILIN1、FNDC1）中确定了不同的预后标志物。本研究中进行的荟萃分析与 TCGA 验证相结合，强调了 HNSCC 固有的分子异质性；也证实了利用这些信息来提高预后效果的可行性。在经过大规模临床验证后，本研究中确定的标志物组合将成为有价值的预后辅助手段。
