Table_1_Age-dependent molecular variations in osteosarcoma: implications for precision oncology across pediatric, adolescent, and adult patients.xlsx

BackgroundOsteosarcoma is a leading subtype of bone tumor affecting adolescents and adults. Comparative molecular characterization among different age groups, especially in pediatric, adolescents and adults, is scarce.
MethodsWe collected samples from 194 osteosarcoma patients, encompassing pediatric, adolescent, and adult cohorts. Genomic analyses were conducted to reveal prevalent mutations and compare molecular features in pediatric, adolescent, and adult patients.
ResultsSamples from 194 osteosarcoma patients across pediatric to adult ages were analyzed, revealing key mutations such as TP53, FLCN, NCOR1, and others. Children and adolescents showed more gene amplifications and HRD mutations, while adults had a greater Tumor Mutational Burden (TMB). Mutations in those over 15 were mainly in cell cycle and PI3K/mTOR pathways, while under 15s had more in cell cycle and angiogenesis with higher VEGFA, CCND3, TFEB mutations. CNV patterns varied with age: VEGFA and XPO5 amplifications more in under 25s, and CDKN2A/B deletions in over 25s. Genetic alterations in genes like MCL1 and MYC were associated with poor prognosis, with VEGFA mutations also indicating worse outcomes. 58% of patients had actionable mutations, suggesting opportunities for targeted therapies. Age-specific patterns were observed, with Multi-TKI mutations more common in younger patients and CDK4/6 inhibitor mutations in adults, highlighting the need for personalized treatment approaches in osteosarcoma. In a small group of patients with VEGFR amplification, postoperative treatment with multi-kinase inhibitors resulted in a PR in 3 of 13 cases, especially in patients under 15. A significant case involved a 13-year-old with a notable tumor size reduction achieving PR, even with other genetic alterations present in some patients with PD.
ConclusionThis study delineates the molecular differences among pediatric, adolescent, and adult osteosarcoma patients at the genomic level, emphasizing the necessity for precision diagnostics and treatment strategies, and may offer novel prognostic biomarkers for patients with osteosarcoma. These findings provide a significant scientific foundation for the development of individualized treatment approaches tailored to patients of different age groups.

背景：骨肉瘤（Osteosarcoma）是累及青少年与成人的主要骨肿瘤亚型。目前针对不同年龄组——尤其是儿童、青少年与成人群体——的比较分子特征研究仍较为匮乏。
方法：本研究纳入194例骨肉瘤患者样本，涵盖儿童、青少年及成人队列。通过基因组分析，明确了常见突变类型，并对比不同年龄组患者的分子特征差异。
结果：本研究对194例覆盖儿童至成人年龄段的骨肉瘤患者样本进行了分析，鉴定出TP53、FLCN、NCOR1等关键突变。儿童与青少年群体展现出更多的基因扩增及同源重组缺陷（HRD, Homologous Recombination Deficiency）突变，而成人群体的肿瘤突变负荷（TMB, Tumor Mutational Burden）更高。15岁以上患者的突变主要富集于细胞周期及PI3K/mTOR信号通路，而15岁以下患者则更多出现细胞周期与血管生成相关突变，且VEGFA、CCND3、TFEB突变频率更高。拷贝数变异（CNV, Copy Number Variation）模式随年龄呈现差异：25岁以下患者更易出现VEGFA与XPO5扩增，而25岁以上患者则以CDKN2A/B缺失更为常见。MCL1、MYC等基因的遗传改变与不良预后相关，VEGFA突变同样提示预后不佳。58%的患者存在可靶向治疗突变，提示存在靶向治疗的潜在机会。研究还观察到年龄特异性的突变模式：多靶点酪氨酸激酶抑制剂（Multi-TKI）相关突变在年轻患者中更为常见，而CDK4/6抑制剂相关突变则多见于成人患者，这凸显了骨肉瘤个体化治疗的必要性。在一小部分存在VEGFR扩增的患者中，术后予以多激酶抑制剂治疗后，13例患者中有3例获得部分缓解（PR, Partial Response），其中尤以15岁以下患者获益更为显著。1例13岁患者的肿瘤体积显著缩小并达到PR，尽管部分存在其他遗传改变的患者出现了疾病进展（PD, Progressive Disease）。
结论：本研究从基因组层面阐明了儿童、青少年与成人骨肉瘤患者的分子差异，强调了精准诊断与个体化治疗策略的必要性，并可为骨肉瘤患者提供全新的预后生物标志物。上述研究结果为针对不同年龄群体制定个性化治疗方案提供了重要的科学依据。