Background:Defective DNA repair systems result in the accumulation of mutations, loss of genomic integrity, and eventually cancer. Following initial malignant transformation due to specific DNA damage and defective DNA repair, cancer cells become reliant upon other DNA repair pathways for their survival. The co-occurrence of specific repair deficiencies brings catastrophic outcomes such as cell death for cancer cells and thus holds promise as a potential therapeutic strategy. Exploring the co-occurrence and mutual exclusivity of mutational signatures provides valuable knowledge regarding combinations of defective repair pathways that are cooperative and confer selective advantage to cancer cells and those that are detrimental and cannot be tolerated by them.Methods:Taking advantage of mutational signature profiling, we analyzed whole-genome sequences of 1014 breast cancers to reveal the underlying mutational processes and their interrelationships.Results:We found an inverse relationship between deficiencies of homologous recombination (HRd) and non-homologous end joining (NHEJd) with reactive oxygen species (ROS). Moreover, HRd and NHEJd co-occurred with APOBEC but were mutually exclusive with mismatch repair deficiency (MMRd) and ROS. Our analysis revealed that SBS8 and SBS39 signatures of currently unknown etiology correlate with NHEJd. ID1 and ID2 signatures co-occur with ROS and have mutual exclusivity with HRd, SBS8, SBS39 and NHEJd. The ID4 signature, with currently unknown etiology, has mutual exclusivity with HRd and NHEJd and co-occurred with ROS. On the other hand, the ID15 signature, with currently unknown etiology, co-occurred with SBS8, SBS39, HRd, NHEJd and DBS2, while having an inverse relationship with MMRd and ROS. Comparing the mutational signatures of HRd and non-HRd TNBC genomes reveals the unique presence of ROS signatures in non-HRd tumors and the lack of ROS signature in HRd tumors.Conclusion:Taken together, these analyses indicate the possible application of mutation signatures and their interactions in advancing patient stratification and suggest appropriate therapies targeting the make-up of individual tumors’ mutational processes. Ultimately, this information provides the opportunity to discover promising synthetic lethal candidates targeting DNA repair systems.
背景：DNA修复系统缺陷会导致突变积累、基因组完整性丧失，最终引发癌症。在特定DNA损伤和DNA修复缺陷引发初始恶性转化后，癌细胞会依赖其他DNA修复途径维持生存。特定修复缺陷的共现会引发灾难性后果（如癌细胞死亡），这为潜在治疗策略提供了新方向。通过探究突变特征的共现性与互斥性，可深入理解修复通路缺陷的组合模式：哪些组合具有协同效应并赋予癌细胞选择优势，哪些组合具有损害性且无法被癌细胞耐受。 方法：利用突变特征谱分析技术，我们对1014例乳腺癌全基因组序列进行分析，以揭示潜在的突变过程及其相互关系。 结果：研究发现同源重组缺陷（HRd）与非同源末端连接缺陷（NHEJd）与活性氧（ROS）呈负相关。此外，HRd和NHEJd与APOBEC突变特征共现，但与错配修复缺陷（MMRd）及ROS互斥。分析显示目前病因不明的SBS8和SBS39特征与NHEJd相关。ID1和ID2特征与ROS共现，且与HRd、SBS8、SBS39及NHEJd互斥。目前病因不明的ID4特征与HRd和NHEJd互斥，而与ROS共现。另一方面，目前病因不明的ID15特征与SBS8、SBS39、HRd、NHEJd及DBS2共现，但与MMRd和ROS呈负相关。通过比较HRd与非HRd三阴性乳腺癌基因组的突变特征，发现ROS特征仅存在于非HRd肿瘤中，而HRd肿瘤中缺乏ROS特征。 结论：综合分析表明，突变特征及其相互作用可能应用于推进患者分层，并为针对个体肿瘤突变过程构成的精准治疗提供依据。这些信息最终为发现靶向DNA修复系统的合成致死候选方案提供了重要机遇。
肿瘤(癌症)患者之家