Background: Cofactors, biomarkers, and the mutational status of genes such as TP53, EGFR, IDH1/2, or PIK3CA have been used for patient stratification. However, many genes exhibit recurrent mutational positions known as hotspots, specifically linked to varying degrees of survival outcomes. Nevertheless, few hotspots have been analyzed (e.g., TP53 and EGFR). Thus, many other genes and hotspots remain unexplored. Methods: We systematically screened over 1400 hotspots across 33 TCGA cancer types. We compared the patients carrying a hotspot against (i) all cases, (ii) gene-mutated cases, (iii) other mutated hotspots, or (iv) specific hotspots. Due to the limited number of samples in hotspots and the inherent group imbalance, besides Cox models and the log-rank test, we employed VALORATE to estimate their association with survival precisely. Results: We screened 1469 hotspots in 6451 comparisons, where 314 were associated with survival. Many are discussed and linked to the current literature. Our findings demonstrate associations between known hotspots and survival while also revealing more potential hotspots. To enhance accessibility and promote further investigation, all the Kaplan–Meier curves, the log-rank tests, Cox statistics, and VALORATE-estimated null distributions are accessible on our website. Conclusions: Our analysis revealed both known and putatively novel hotspots associated with survival, which can be used as biomarkers. Our web resource is a valuable tool for cancer research.
背景：目前，患者分层常基于TP53、EGFR、IDH1/2或PIK3CA等基因的突变状态以及相关辅助因子和生物标志物。然而，许多基因存在被称为热点突变的反复突变位点，这些位点与不同程度的生存结局存在特定关联。尽管如此，仅有少数热点（如TP53和EGFR）得到深入分析，大量其他基因及其热点突变仍有待探索。方法：我们系统筛查了33种TCGA癌症类型中的1400多个热点突变。通过将携带热点突变的患者分别与（i）所有病例、（ii）基因突变病例、（iii）其他突变热点或（iv）特定热点进行对比分析。针对热点样本量有限及固有的组间不平衡问题，除采用Cox模型和对数秩检验外，我们运用VALORATE方法精确评估其与生存期的关联性。结果：通过对6451组比较中的1469个热点进行筛查，发现314个热点与生存期存在关联。其中多数热点在现有文献中已有讨论和印证。我们的研究不仅证实了已知热点与生存期的关联，还揭示了更多潜在热点。为提升数据可及性并推动深入研究，所有Kaplan-Meier曲线、对数秩检验结果、Cox统计量及VALORATE估计的零分布数据均已公开于研究网站。结论：本研究揭示了已知及潜在的新型生存相关热点突变，这些发现可作为生物标志物应用于临床。我们的网络资源为癌症研究提供了重要工具。
肿瘤(癌症)患者之家