Background: Studies on somatic mutations in cancer typically report single-nucleotide variants in coding regions, while mutations in short tandem repeats (STRs) are usually overlooked. Homopolymeric regions, a subset of STRs, are stretches of DNA where only a single nucleotide is repeated multiple times (e.g., AAAAA or TTTTT). Only recently have mutations in such STR regions been seen in colorectal cancer, where microsatellite instability (MSI) is common. In non-melanoma skin cancer (NMSC), MSI is rare. In this study, we focus on somatic mutations in such homopolymeric regions in NMSC and their functional implications. Methods: We performed targeted DNA sequencing (paired tissue and blood from the same individual), using more than 400 cancer-related genes from 32 NMSC patients as cases and non-lesional skin tissue from 16 independent individuals as controls. Results: We identified NMSC-associated STR somatic mutations. These are associated with the dysregulation of DNA damage and repair mechanisms. In artificial intelligence (AI) predictive modeling, these markers could successfully differentiate basal cell carcinoma (BCC) and non-lesional skin tissue. To our knowledge, we present the first study focusing on STR somatic mutations in multiple cancer-related genes in NMSC found only in tumor tissue and not in non-lesional skin tissue. Some of them (APC,BRAF) are associated with more pronounced dysregulation of relevant gene pathways (hedgehog, Notch signaling, and Wnt signaling). Conclusions: Our findings suggest that this STR somatic mutation status might potentially be used to select BCC patients who could benefit from certain precision therapy including hedgehog inhibitors, gamma-secretase inhibitors, anti-Vasuclar endothelial growth factor (VEGF), proteasome inhibitors, and immune check-point inhibitors.
背景：癌症体细胞突变研究通常关注编码区的单核苷酸变异，而短串联重复序列（STR）区域的突变常被忽视。同聚物区域作为STR的子集，是指单一核苷酸连续重复的DNA片段（例如AAAAA或TTTTT）。直到近期，此类STR区域突变才在结直肠癌中被发现，而该癌种中微卫星不稳定性（MSI）较为常见。在非黑色素瘤皮肤癌（NMSC）中，MSI较为罕见。本研究聚焦于NMSC中此类同聚物区域的体细胞突变及其功能影响。 方法：我们对32例NMSC患者（采集配对癌组织与血液样本）及16例独立个体的非病变皮肤组织（作为对照）进行靶向DNA测序，覆盖超过400个癌症相关基因。 结果：我们鉴定出NMSC相关的STR体细胞突变，这些突变与DNA损伤修复机制失调相关。在人工智能预测模型中，这些标志物能有效区分基底细胞癌（BCC）与非病变皮肤组织。据我们所知，本研究首次系统揭示了NMSC中仅存在于肿瘤组织、非病变皮肤组织不存在的多癌症相关基因STR体细胞突变。其中部分突变（APC、BRAF）与相关信号通路（刺猬信号、Notch信号、Wnt信号）的显著失调相关。 结论：我们的研究结果表明，STR体细胞突变状态或可用于筛选可能从特定精准治疗中获益的BCC患者，包括刺猬通路抑制剂、γ-分泌酶抑制剂、抗血管内皮生长因子（VEGF）药物、蛋白酶体抑制剂及免疫检查点抑制剂。
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