Genome sequencing reveals molecular subgroups in oral epithelial dysplasia

Abstract This study aimed to analyze the molecular characteristics of oral epithelial dysplasia (OED), highlighting the pathways and variants of genes that are frequently mutated in oral squamous cell carcinoma (OSCC) and other cancers. Ten archival OED cases were retrieved for retrospective clinicopathological analysis and exome sequencing. Comparative genomic analysis was performed between high-grade dysplasia (HGD) and low-grade dysplasia (LGD), focusing on 57 well-known cancer genes, of which 10 were previously described as the most mutated in OSCC. HGD cases had significantly more variants; however, a similar mutational landscape to OSCC was observed in both groups. CASP8+FAT1/HRAS, TP53, and miscellaneous molecular signatures were also present. FAT1 is the gene that is most affected by pathogenic variants. Hierarchical divisive clustering showed division between the two groups: “HGD-like cluster” with 4HGD and 2LGD and “LGD-like cluster” with 4 LGD. MLL4 pathogenic variants were exclusively in the “LGD-like cluster”. TP53 was affected in one case of HGD; however, its pathway was usually altered. We describe new insights into the genetic basis of epithelial malignant transformation by genomic analysis, highlighting those associated with FAT1 and TP53. Some LGDs presented a similar mutational landscape to HGD after cluster analysis. Perhaps molecular alterations have not yet been reflected in histomorphology. The relative risk of malignant transformation in this molecular subgroup should be addressed in future studies.

摘要 本研究旨在分析口腔上皮异常增生（oral epithelial dysplasia, OED）的分子特征，重点探讨在口腔鳞状细胞癌（oral squamous cell carcinoma, OSCC）及其他癌症中频发突变的基因通路与变异体。本研究检索了10例存档OED标本，开展回顾性临床病理分析与外显子组测序。针对高级别上皮异常增生（high-grade dysplasia, HGD）与低级别上皮异常增生（low-grade dysplasia, LGD）进行比较基因组分析，聚焦于57个经典癌基因，其中10个此前被报道为OSCC中突变频率最高的基因。HGD组的变异载荷显著更高；不过两组均呈现出与OSCC相似的突变谱。研究还检出CASP8+FAT1/HRAS、TP53及其他多种分子特征。FAT1是受致病变异影响最显著的基因。分层分裂聚类结果显示样本可划分为两类：包含4例HGD与2例LGD的“HGD样聚类簇”，以及包含4例LGD的“LGD样聚类簇”。MLL4致病变异仅存在于“LGD样聚类簇”中。TP53在1例HGD病例中发生变异，但其相关通路常出现异常。本研究通过基因组分析揭示了上皮恶性转化遗传基础的新见解，重点突出了与FAT1及TP53相关的分子改变。聚类分析结果显示，部分LGD病例呈现出与HGD相似的突变谱，提示分子层面的改变或许尚未在组织形态学上体现出来。该分子亚型的恶性转化相对风险有待未来研究进一步探讨。