Background:DNA damage response (DDR) pathway alterations contribute to genomic instability and malignant progression in several cancers.Methods: We retrospectively reviewed molecular profiles from 5309 sarcoma patient samples, including 746 from pediatric/adolescent and young adults (ped/AYA), encompassing 38 histologic subtypes. The gene expression profiles were further analyzed for immunotherapy-related biomarker associations, including analysis of the T cell-inflamed score.Results: Pathogenic/likely pathogenic DDR alterations were detected in 15.9% (N= 842) of samples overall and 9.25% (N= 69) of Ped/AYA tumors, with mutations occurring most frequently inATRX(10.1%). Shorter overall survival was observed for patients with DDR-alterations compared to those with DDR-wildtype tumors (Hazard Ratio = 1.172, 95% CI: 1.068–1.287;p< 0.001). In many subtypes, DDR-mutated tumors were found to have increased rates of immune markers, including PD-L1+, dMMR/MSI-high, and TMB.Conclusions:Our study of somatic DDR-pathway mutations provides a better understanding of the molecular associations across sarcoma subtypes that may aid in developing future prognostic and therapeutic options for these rare cancers.
背景：DNA损伤应答（DDR）通路改变在多种癌症中导致基因组不稳定和恶性进展。 方法：我们回顾性分析了5309例肉瘤患者样本的分子谱数据，其中包含746例儿童/青少年及年轻成人（ped/AYA）样本，涵盖38种组织学亚型。进一步分析了基因表达谱中与免疫治疗相关的生物标志物关联，包括T细胞炎症评分分析。 结果：总体样本中15.9%（N=842）及ped/AYA肿瘤中9.25%（N=69）检测到致病性/可能致病性DDR改变，其中ATRX基因突变频率最高（10.1%）。与DDR野生型肿瘤患者相比，携带DDR改变的患者总生存期更短（风险比=1.172，95%置信区间：1.068–1.287；p<0.001）。在多种亚型中，DDR突变肿瘤的免疫标志物（包括PD-L1阳性、错配修复缺陷/微卫星高度不稳定及肿瘤突变负荷）表达率升高。 结论：本研究通过对体细胞DDR通路突变的分析，深化了对肉瘤各亚型分子关联的理解，可能为这类罕见癌症的未来预后评估和治疗策略开发提供参考。
肿瘤(癌症)患者之家