The chemotherapeutic CX-5461 is extremely mutagenic and may increase cancer risk

The chemotherapeutic agent CX-5461 or pidnarulex has been fast-tracked by the US FDA for treatment of BRCA1-, BRCA2-, and PALB2-mutated cancers. It is under investigation in Phase I/II clinical trials. Here we find that although CX-5461 exhibits synthetic lethality in BRCA1-/BRCA2-deficient cells, it also causes extensive, non-selective, collateral mutagenesis in all cells, to magnitudes that exceed known environmental carcinogens, raising public health concerns regarding its potential for promoting secondary cancers.

Deposited here are the de novo mutation lists from the experimental samples included in the study. Whole-genome sequencing short reads were aligned to GRCh38/hg38 using BWA-MEM. Post-processing filters were applied to improve the specificity of mutation-calling. Specifically, for single nucleotide variant calls by CaVEMan, we used CLPM == 0 and ASMD >= 140. To reduce false positive calls by Pindel, we used QUAL >= 250 and REP < 10. Rearrangements were not assessed as they were too few to be informative. A filter for variant allele frequency (> 0.2) was applied to substitutions and indels. De novo substitutions and indels in subclones were obtained by subtracting from respective parental clone whenever available, or by removing mutations shared among subclones.

TwinStrand duplex sequencing data were analysed with the TwinStrand DuplexSeq Mutagenesis App, hosted on DNAnexus. The Mutagenesis App performed error-correction and generated Duplex Consensus alignment and variant calls for both germline and ultra-rare somatic variants. Only variants with variant allele frequency < 0.01 were considered to be the result of mutagenesis (i.e., mutation), and included for subsequent mutation burden and signature analysis. Provided here are the mutation calls from both iPS and HAP1 cells.

化疗药物CX-5461（亦称pidnarulex）已由美国食品药品监督管理局（FDA）加速审批，用于治疗BRCA1、BRCA2和PALB2突变型癌症。该药物正处于I/II期临床试验的探究之中。本研究发现，尽管CX-5461在BRCA1-/BRCA2缺陷细胞中表现出合成致死性，但它亦在所有细胞中引起广泛的、非选择性的旁路突变，其程度甚至超过了已知的环环境致癌物质，引发了关于其可能促进继发性癌症的公共卫生担忧。在此处存档的是研究中包含的实验样本的新发突变列表。全基因组测序短读段被使用BWA-MEM与GRCh38/hg38对齐。通过后处理筛选以提升突变检测的特异性。具体而言，对于CaVEMan的单核苷酸变异调用，我们使用了CLPM等于0和ASMD大于等于140。为了减少Pindel的假阳性调用，我们使用了质量值大于等于250和重复数小于10。由于重组数量太少，无法提供信息，因此未对其进行评估。对替换和插入/缺失变异应用了一个变异等位基因频率（大于0.2）的筛选器。通过从相应的亲本克隆中减去，或通过移除子克隆间共有的突变，获得了亚克隆中的新发替换和插入/缺失。TwinStrand双链测序数据使用位于DNAnexus上的TwinStrand DuplexSeq突变分析应用程序进行分析。突变分析应用程序执行了错误校正，并为体细胞和超罕见体细胞变异的基因型及变异调用生成了双链共识对齐。仅考虑变异等位基因频率小于0.01的变异为突变的结果（即，突变），并将其包括在后续的突变负担和特征分析中。在此提供的是iPS和HAP1细胞的突变调用。