Supplementary Material for: Comparative Somatic Variant Analysis of a Rare Case with Concurrent Oral Leukoplakia and Oral Submucosal Fibrosis

Oral leukoplakia (OL) and oral submucosal fibrosis (OSMF) are precancerous conditions with common etiologies but with different risks for oral cancer (OC) progression. In rare cases, both conditions occur in the same patient and provide an opportunity for understanding the common and distinctive variants upon exposure of genetically identical normal cells to the same carcinogen(s). We performed exome sequencing of a patient with OL (hyperplasia, but no dysplasia) and OSMF (grade II) in the opposite cheeks using blood DNA as the reference genome. The overall somatic variant burden was higher in OSMF than OL, but opposite in the case of copy number alterations. OL-specific variants were enriched in genes associated with DNA repair, cell division/cell cycle checkpoint pathways, whereas in OSMF, extracellular matrix-receptor interaction was mainly affected. The proportions of variants in cancer driver genes and cancer driver mutations were similar in both cases indicating no difference in the potential risk associated with the two conditions at the stages sampled. Future studies on rare cases similar to the one described in this report will help in understanding the molecular basis of differences associated with OL and OSMF and shared processes accompanying OC progression.

口腔白斑病（Oral leukoplakia, OL）与口腔黏膜下纤维化（oral submucosal fibrosis, OSMF）均为癌前病变，二者具有共同的致病病因，但口腔癌（oral cancer, OC）的进展风险存在差异。在罕见情况下，两种病变可同时发生于同一患者，这为探究基因背景一致的正常细胞暴露于相同致癌物后所呈现的共性与特异性变异特征提供了研究契机。
本研究以一名双侧面颊分别罹患口腔白斑病（伴增生但无异型增生）与Ⅱ级口腔黏膜下纤维化的患者的血液DNA作为参考基因组（reference genome），对两处病变组织开展了外显子组测序（exome sequencing）。
整体而言，口腔黏膜下纤维化的体细胞变异负荷高于口腔白斑病，但拷贝数变异（copy number alterations）的分布特征则恰好相反。
口腔白斑病特异性变异显著富集于DNA修复、细胞分裂/细胞周期检验点通路相关基因；而口腔黏膜下纤维化主要受细胞外基质-受体相互作用通路异常影响。
两类病变中癌症驱动基因及癌症驱动突变的变异比例相近，表明在本研究采样的疾病阶段，二者相关的潜在癌变风险并无显著差异。
未来针对本报告所述这类罕见病例开展的研究，将有助于阐明口腔白斑病与口腔黏膜下纤维化之间差异的分子基础，以及伴随口腔癌进展的共同生物学过程。