口腔鱗狀細胞癌（OSCC）為台灣最常見的惡性腫瘤之一，其發生主要與檳榔、菸、酒的長期共同暴露密切相關。儘管頭頸部鱗狀細胞癌（HNSCC）的驅動突變已逐漸被闡明，台灣 OSCC 族群特有的突變景觀及其預後意義仍未獲完整界定。本研究之目的為透過與TCGA癌症基因體圖譜比對界定台灣 OSCC 之族群特異性基因體變異，探討其與臨床病理特徵之關聯，並於晚期疾病中建立及驗證預後特徵。
本研究納入 106 位於國立成功大學附設醫院（NCKUH）接受根治性手術之台灣 OSCC 患者，採用涵蓋 161 個癌症相關基因之 Oncomine Comprehensive Assay v3 標靶次世代定序平台進行分析。經嚴謹之生物資訊篩選出高可信度之外顯子非同義突變，並與 TCGA-OSCC 族群進行比較。在83個晚期病患中，我們進一步將基因層級變異與路徑層級變異與臨床病理特徵及存活預後進行關聯分析以獲得預後相關的生物標記。並利用TCGA 晚期 OSCC（TCGA-aOSCC）族群之對應資料來進一步進行驗證。
研究結果共鑑定出分布於 73 個基因之 317 個外顯子非同義突變，其中 52 個基因為已知癌症驅動基因。最常見之突變基因依序為 TP53、NOTCH1、CDKN2A、HRAS 及 PIK3CA；MSH6（24%）與 PIK3R1（16%）之突變頻率遠高於 TCGA-OSCC（0.4% 與 1.5%）。個別腫瘤所帶突變基因數目越多，與較差之局部無復發存活呈顯著關聯（風險比 1.17，95% 信賴區間 1.04–1.31，p = 0.01）。於 83 例晚期腫瘤中(第三、四期)，TP53 突變與頸部淋巴結轉移呈強烈正相關（p < 0.001），而 NOTCH1、HRAS 及 PIK3CA 突變則呈負相關且富集於 TP53 野生型腫瘤；PIK3CA變異與頸部淋巴結轉移的負相關性在TCGA的晚期OSCC族群(TCGA-aOSCC)中也得到證實。由 PIK3R1、TSC2、FANCD2、NOTCH2 及 RAD51C 組成之五基因特徵，為 NCKUH 族群中之獨立不良預後因子，但於TCGA族群中亦未獲得驗證。然而，致癌性細胞週期基因路徑之變異於 NCKUH 族群與無復發存活率顯著相關，且於 TCGA-aOSCC 族群中亦為疾病特異性存活之獨立預後因子（n = 89，風險比 3.2，95% 信賴區間 1.05–9.75，p = 0.040）。在標靶治療的潛在應用性探討中，我們發現約 95% 之腫瘤帶有至少一個變異，發生於目前暨有的基因靶向型藥物中。
概括而言，本研究描繪了台灣特有之 OSCC 基因突變圖譜，其中 MSH6 與 PIK3R1 之高變異率為與其他研究明顯不同之族群特異性基因變異特徵。相關的基因及基因路徑的變異研究亦找出了與台灣口腔鱗狀細胞癌預後相關的潛在生物標記。本研究所獲得的基因變異圖譜及預後生物標記，將有利於未來進行前瞻性、生物標記導向的臨床試驗研究。

Oral squamous cell carcinoma (OSCC) is among the most prevalent malignancies in Taiwan, where its development is driven largely by the combined, long-term use of betel quid, tobacco, and alcohol. Although driver mutations in head and neck squamous cell carcinoma (HNSCC) have been increasingly characterized, the mutational landscape specific to Taiwanese OSCC, and its prognostic significance, remain incompletely defined. This study aimed to delineate the population-specific genomic alterations in Taiwanese OSCC.
Archival tumor specimens from 106 Taiwanese OSCC patients who underwent curative surgery at National Cheng Kung University Hospital (NCKUH) were profiled with the Oncomine Comprehensive Assay v3, a targeted next-generation sequencing panel covering 161 cancer-related genes. High-confidence exonic, nonsynonymous variants were identified through a stringent bioinformatic filtering workflow and compared with the TCGA-OSCC cohort. Gene- and pathway-level alterations were correlated with clinicopathological characteristics and survival outcomes in 83 advanced-stage OSCC patients. Candidate gene- and pathway-level biomarkers obtained from our analysis were further validated with the retrieved public domain data from the TCGA advanced-stage OSCC (TCGA-aOSCC) cohort.
A total of 317 exonic, nonsynonymous variants were identified in 73 genes, 52 of which are established cancer drivers. As expected, TP53, NOTCH1, CDKN2A, HRAS, and PIK3CA were the most frequently mutated genes noted in OSCC. Notably, we found that MSH6 (24%) and PIK3R1 (16%) were more frequently altered compared to the TCGA-OSCC cohort (0.4% and 1.5%, respectively). A higher number of mutated genes per tumor was significantly associated with poorer local relapse-free survival (hazard ratio [HR], 1.17; 95% confidence interval [CI], 1.04–1.31; p = 0.01). Among the 83 advanced-stage tumors, TP53 mutation was strongly associated with cervical lymph-node metastasis (p < 0.001), whereas NOTCH1, HRAS, and PIK3CA mutations were inversely associated with it and were enriched among TP53 wild-type tumors. The negative association between PIK3CA mutation and lymph node metastasis was also validated in the TCGA-aOSCC cohort. A five-gene signature (PIK3R1, TSC2, FANCD2, NOTCH2, and RAD51C) was found to be independently associated with poor survivorship within the NCKUH cohort (p < 0.001) but was not successfully validated in the TCGA-aOSCC cohort. Alteration of oncogenic cell-cycle gene pathway was associated with recurrence-free survival in the NCKUH cohort and similarly proved to be an independent predictor of disease-specific survival in the TCGA-aOSCC cohort (n = 89; HR, 3.2; 95% CI, 1.05–9.75; p = 0.040). For potential therapeutic applications, we noticed that about 95% of tumors harbored at least one variant in currently actionable genes.
In summary, our study delineates an OSCC mutational landscape shaped by the carcinogen-exposure profile characteristic of Taiwan, in which the enrichment of MSH6 and PIK3R1 alterations is the clearest population-specific feature of genomic alteration. The genomic mutational landscape, with candidate clinicopathological and prognostic biomarkers obtained in this study could pave the way to future targeted therapeutic trials in Taiwanese OSCC.

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