BACKGROUND Inhibitors of apoptosis proteins (IAPs) are a family of antiapoptotic proteins modulating cell cycle, signal transduction and apoptosis. Dysregulated IAPs have been reported to contribute to tumor progression and chemoresistance in various cancers. However, existing studies were sporadic and only focus on one specific cancer with one particular gene in the IAPs family. A systematic investigation on the co-expression pattern, regulation frameworks on various pathways, prognostic utility on patient outcomes, and predictive value on drug sensitivity among all the IAPs across multiple tumor types was lacking. METHODS Leveraging The Cancer Genome Atlas data with comprehensive genomic characterizations on 9714 patients across 32 tumor types and the Genomics of Drug Sensitivity in Cancer data with both genomic characterizations and drug sensitivity data on > 1000 cell lines, we investigated the co-expression pattern of IAPs, their regulations of apoptosis as well as other pathways and clinical relevance of IAPs for therapeutics development. RESULTS We discovered diverse expression pattern among IAPs, varied spectrum of apoptosis regulations through IAPs and extensive regulations beyond apoptosis involving immune response, cell cycle, gene expression and DNA damage repair. Importantly, IAPs were strong prognostic factors for patient survival and tumor stage in several tumor types including brain, liver, kidney, breast and lung cancer. Further, several IAPs were found to be predictive of sensitivity to BCL-2 inhibitors (BIRC3, BIRC5, BIRC6, and BIRC7) as well as RIPK1 inhibitors (BIRC3 and BIRC6). CONCLUSION Together, our work revealed the landscape of regulations, prognostic utilities and therapeutic relevance of IAPs across multiple tumor types.

中文翻译：

---

用于癌症靶向治疗的凋亡蛋白（IAP）抑制剂的全面分子表征。

背景技术凋亡蛋白（IAP）的抑制剂是调节细胞周期，信号转导和凋亡的抗凋亡蛋白家族。据报道，失调的IAPs在多种癌症中有助于肿瘤进展和化学抗性。然而，现有的研究是零星的，并且仅针对IAPs家族中具有一种特定基因的一种特定癌症。缺乏对多种肿瘤类型的所有IAP中共表达模式，各种途径的调控框架，对患者预后的预测效用以及对药物敏感性的预测价值的系统研究。方法利用具有32个肿瘤类型的9714位患者的全面基因组特征的Cancer Genome Atlas数据以及超过1000种细胞系的基因组特征和药物敏感性数据的Cancer药物敏感性基因组学，我们研究了IAP的共表达模式，它们对细胞凋亡的调控以及IAP在治疗发展中的其他途径和临床相关性。结果我们发现IAP之间存在多种表达模式，通过IAP具有不同的凋亡调控谱，以及涉及免疫应答，细胞周期，基因表达和DNA损伤修复的凋亡以外的广泛调控。重要的是，IAPs是包括脑癌，肝癌，肾癌，乳腺癌和肺癌在内的多种肿瘤类型的患者生存和肿瘤分期的强大预后因素。进一步，发现一些IAP可预测对BCL-2抑制剂（BIRC3，BIRC5，BIRC6和BIRC7）以及RIPK1抑制剂（BIRC3和BIRC6）的敏感性。结论我们的工作共同揭示了多种肿瘤类型的IAP的法规，预后效用和治疗相关性。