Table_1_Immunohistochemical Expression of Five Protein Combinations Revealed as Prognostic Markers in Asian Oral Cancer.pdf

Oral squamous cell carcinoma (OSCC) has a high mortality rate (∼50%), and the 5-year overall survival rate is not optimal. Cyto- and histopathological examination of cancer tissues is the main strategy for diagnosis and treatment. In the present study, we aimed to uncover immunohistochemical (IHC) markers for prognosis in Asian OSCC. From the collected 742 synthetic lethal gene pairs (of various cancer types), we first filtered genes relevant to OSCC, performed 29 IHC stains at different cellular portions and combined these IHC stains into 398 distinct pairs. Next, we identified novel IHC prognostic markers in OSCC among Taiwanese population, from the single and paired IHC staining by univariate Cox regression analysis. Increased nuclear expression of RB1 [RB1(N)↑], CDH3(C)↑-STK17A(N)↑ and FLNA(C)↑-KRAS(C)↑were associated with survival, but not independent of tumor stage, where C and N denote cytoplasm and nucleus, respectively. Furthermore, multivariate Cox regression analyses revealed that CSNK1E(C)↓-SHC1(N)↓ (P = 5.9 × 10–5; recommended for clinical use), BRCA1(N)↓-SHC1(N)↓ (P = 0.030), CSNK1E(C)↓-RB1(N)↑ (P = 0.045), [CSNK1E(C)-SHC1(N), FLNA(C)-KRAS(C)] (P = 0.000, rounded to three decimal places) and [BRCA1(N)-SHC1(N), FLNA(C)-KRAS(C)] (P = 0.020) were significant factors of poor prognosis, independent of lymph node metastasis, stage and alcohol consumption. An external dataset from The Cancer Genome Atlas HNSCC cohort confirmed that CDH3↑-STK17A↑ was a significant predictor of poor survival. Our approach identified prognostic markers with components involved in different pathways and revealed IHC marker pairs while neither single IHC was a marker, thus it improved the current state-of-the-art for identification of IHC markers.

口腔鳞状细胞癌（Oral squamous cell carcinoma, OSCC）死亡率高达约50%，5年总生存率仍未达到理想水平。癌症组织的细胞与组织病理学检查是当前临床诊断及治疗的核心策略。本研究旨在挖掘亚洲人群OSCC预后相关的免疫组织化学（Immunohistochemical, IHC）标志物。
研究团队从收集到的涵盖多种癌症类型的742对合成致死基因对中，首先筛选出与OSCC相关的基因，针对不同细胞区域完成了29项IHC染色，并将这些染色结果组合为398组独立的标志物对。
随后，通过单因素Cox回归分析对单个及组合IHC染色结果进行分析，在中国台湾人群的OSCC样本中鉴定出新型IHC预后标志物。其中，RB1(N)↑、CDH3(C)↑-STK17A(N)↑以及FLNA(C)↑-KRAS(C)↑与患者生存显著相关，但该相关性并不独立于肿瘤分期；此处C与N分别代表胞质与胞核。
进一步的多因素Cox回归分析显示，CSNK1E(C)↓-SHC1(N)↓（P=5.9×10–5；推荐用于临床）、BRCA1(N)↓-SHC1(N)↓（P=0.030）、CSNK1E(C)↓-RB1(N)↑（P=0.045）、[CSNK1E(C)-SHC1(N), FLNA(C)-KRAS(C)]（P=0.000，保留三位小数）以及[BRCA1(N)-SHC1(N), FLNA(C)-KRAS(C)]（P=0.020）均为独立于淋巴结转移、肿瘤分期及饮酒史的不良预后显著因素。
来自癌症基因组图谱头颈鳞状细胞癌队列（The Cancer Genome Atlas HNSCC）的外部验证数据集证实，CDH3↑-STK17A↑可作为不良生存结局的显著预测因子。
本研究的分析方法鉴定出的预后标志物组分涉及多条不同信号通路，且发现了单个IHC染色无法作为独立标志物的组合IHC标志物对，从而提升了IHC标志物鉴定领域的当前最优标准。