Oral squamous cell carcinoma (OSCC) is the predominant type of oral cancer, while some patients may develop oral multiple primary cancers (MPCs) with unclear etiology. This study aimed to investigate the clinicopathological characteristics and genomic alterations of oral MPCs. Clinicopathological data from patients with oral single primary carcinoma (SPC, n = 202) and oral MPCs (n = 34) were collected and compared. Copy number alteration (CNA) analysis was conducted to identify chromosomal-instability differences among oral MPCs, recurrent OSCC cases, and OSCC patients with lymph node metastasis. Whole-exome sequencing was employed to identify potential unique gene mutations in oral MPCs patients. Additionally, CNA and phylogenetic tree analyses were used to gain preliminary insights into the molecular characteristics of different primary tumors within individual patients. Our findings revealed that, in contrast to oral SPC, females predominated the oral MPCs (70.59%), while smoking and alcohol use were not frequent in MPCs. Moreover, long-term survival outcomes were poorer in oral MPCs. From a CNA perspective, no significant differences were observed between oral MPCs patients and those with recurrence and lymph node metastasis. In addition to commonly mutated genes such as CASP8, TP53 and MUC16, in oral MPCs we also detected relatively rare mutations, such as HS3ST6 and RFPL4A. Furthermore, this study also demonstrated that most MPCs patients exhibited similarities in certain genomic regions within individuals, and distinct differences of the similarity degree were observed between synchronous and metachronous oral MPCs.

口腔鳞状细胞癌（OSCC）是口腔癌的主要类型，而一些患者可能会发展为病因不明的口腔多原发癌（MPC）。本研究旨在探讨口腔 MPC 的临床病理特征和基因组改变。 收集并比较口腔单原发癌（SPC，n  = 202）和口腔 MPC（n = 34）患者的临床病理学数据。进行拷贝数改变 (CNA) 分析，以确定口腔 MPC、复发 OSCC 病例和淋巴结转移 OSCC 患者之间的染色体不稳定性差异。采用全外显子组测序来识别口腔 MPC 患者中潜在的独特基因突变。此外，CNA 和系统发育树分析用于初步了解个体患者不同原发肿瘤的分子特征。我们的研究结果显示，与口腔 SPC 相比，女性在口腔 MPC 中占主导地位（70.59%），而吸烟和饮酒在 MPC 中并不常见。此外，口腔 MPC 的长期生存结果较差。从CNA的角度来看，口腔MPCs患者与复发和淋巴结转移的患者之间没有观察到显着差异。除了CASP8、TP53和MUC16等常见突变基因外，在口腔MPC中我们还检测到了相对罕见的突变，如HS3ST6和RFPL4A。此外，本研究还表明，大多数MPC患者在个体内的某些基因组区域表现出相似性，并且在同步和异时口腔MPC之间观察到相似程度的明显差异。