Siriraj Center of Research Excellence in Systems Pharmacology, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Center of Excellence of Otolaryngology Head and Neck Surgery, Rajavithi Hospital, Bangkok, Thailand.
Cancer Rep (Hoboken). 2024 Mar;7(3):e2004. doi: 10.1002/cnr2.2004.
A high recurrent rate of oral squamous cell carcinoma (OSCC) is a major concern in head and neck cancer treatment. The study of the genetic mutation landscape in recurrent OSCC may provide information on certain mutations associated with the pathobiology and treatment response of the OSCC.
We investigated the mutation landscape of matched pretreatment and recurrent tumors to understand the influence of genetic mutations on the pathobiology and clinical outcomes in OSCC.
We sequenced 33 formalin-fixed paraffin-embedded (FFPE) recurrent tumors, primary tumors, and primary tumors before recurrence that matched the recurrent tumors collected from Rajavithi Hospital during 2019-2021. We identified recurrent mutations from these samples by the Oncomine Ion Torrent-based next-generation sequencing on the 517 cancer-associated gene panel. From the results, we found that the most commonly mutated gene in the cohort is a histone methyltransferase KMT2D (54.55%), implicating that aberrance in epigenetic regulation may play a role in oral cancer tumorigenesis. Functional protein association network analysis of the gene frequently mutated in the recurrent tumors showed enrichment of genes that regulate the cancer cell cycle, that is, MRE11A, CDKN2A, and CYLD. This finding was confirmed in the primary-recurring matched pair. We found that recurrent tumors possess a small but recurring group of genes, with presumably the subclonal mutations driving the recurrence of the tumor, suggesting that the recurrent disease originated from a small fraction of the cancer cell that survives standard treatment. These genes were absent in the primary tumor with a good response to the standard treatment. On the other hand, we found an enrichment of DNA repair genes, namely ATR, BRCA1, BRCA2, RAD50, and MUTYH, in nonrecurrent tumors suggesting that the mutations in the DNA repair pathway may at least partially explain the different response to the standard treatment.
Our pilot study identified pathways of carcinogenesis in oral cancer and specific gene sets that indicate treatment responses and prognoses in this group of patients.
口腔鳞状细胞癌（OSCC）的高复发率是头颈部癌症治疗的主要关注点。研究复发性 OSCC 的遗传突变图谱可能为与 OSCC 的病理生物学和治疗反应相关的某些突变提供信息。
我们研究了复发性肿瘤与原发性肿瘤之间的突变图谱，以了解遗传突变对 OSCC 病理生物学和临床结果的影响。
我们对 2019-2021 年从拉加维蒂医院收集的复发性肿瘤、原发性肿瘤和复发前原发性肿瘤的 33 个福尔马林固定石蜡包埋（FFPE）样本进行了测序。我们通过 Oncomine Ion Torrent 基于 517 个癌症相关基因panel 的下一代测序从这些样本中鉴定出复发性突变。结果显示，该队列中最常见的突变基因是组蛋白甲基转移酶 KMT2D（54.55%），这表明表观遗传调控的异常可能在口腔癌肿瘤发生中发挥作用。对复发性肿瘤中经常突变的基因进行功能蛋白关联网络分析，发现了调节癌细胞周期的基因富集，即 MRE11A、CDKN2A 和 CYLD。这一发现在原发性-复发性配对中得到了证实。我们发现，复发性肿瘤具有一小部分但反复出现的基因，这些基因的亚克隆突变可能驱动肿瘤的复发，这表明复发性疾病起源于一小部分在标准治疗中存活的癌细胞。这些基因在对标准治疗反应良好的原发性肿瘤中不存在。另一方面，我们发现非复发性肿瘤中 DNA 修复基因（ATR、BRCA1、BRCA2、RAD50 和 MUTYH）的富集，这表明 DNA 修复途径的突变至少部分解释了对标准治疗的不同反应。
我们的初步研究确定了口腔癌的致癌途径和特定的基因集，这些基因集可用于预测该患者群体的治疗反应和预后。
