Supplementary Material for: Somatic variants and exon-level copy number changes in five hyperplastic-stage oral leukoplakias.

Oral leukoplakia (OL), an oral potentially malignant disorder begins with a hyperplastic/hyperkeratotic stage at which no genome-scale somatic single nucleotide variant profiles have been described so far. We performed exome sequencing of five cases at this stage with no evidence of dysplasia to identify genetic alterations (exon-level copy number alterations, indels, and single nucleotide variants), their association with transcript levels and relationship with oral cancer susceptibility. Pathway enrichment analysis of genes associated with tobacco chewing and age-related mutation signatures, transcripts with variants predicted to be functionally damaging and those with significantly altered levels have all indicated the involvement of focal adhesion, ECM–receptor interactions, regulation of cytoskeleton and DNA repair. Two novel mutations identified in FAT1 tumor suppressor gene were associated with decreased transcript levels. In addition, 16 expressed cancer driver genes contained functionally damaging variants. Many of the affected genes were also reported in dysplastic OL lesions. The presence of variants in cancer driver genes and those shared with oral dysplasias possibly provide a basis for further progression and increased susceptibility to oral cancer.

口腔白斑病（Oral leukoplakia, OL）是一种口腔潜在恶性疾患，其病程起始于增生/角化过度阶段，截至目前尚无该阶段的全基因组范围体细胞单核苷酸变异谱相关报道。本研究对5例无异型增生证据的该阶段病例开展外显子组测序，以鉴定遗传改变（外显子水平拷贝数变异、插入缺失变异及单核苷酸变异），探究其与转录水平的关联，以及与口腔癌易感性的关系。对与咀嚼烟草、年龄相关突变特征相关的基因，以及携带功能损伤性变异、转录水平显著改变的转录本进行通路富集分析，结果均显示黏着斑、细胞外基质-受体相互作用、细胞骨架调控及DNA修复通路参与其中。研究在FAT1肿瘤抑制基因（FAT1 tumor suppressor gene）中鉴定出2种新型突变，这些突变与转录水平降低相关。此外，16个表达的癌症驱动基因携带功能损伤性变异。诸多受影响的基因也曾在异型增生性OL病变中被报道。癌症驱动基因中存在的变异，以及与口腔异型增生共享的变异，或许为病变进一步进展及口腔癌易感性升高提供了理论基础。