癌症基因组中存在大量的遗传变异；这种变异的一个主要结果是半胱氨酸的增加，由于COSMIC中的错义变异，半胱氨酸是最常见的获得性氨基酸。获得性半胱氨酸既是驱动突变，也是精确治疗的目标位点。然而，尽管其普遍性，几乎所有获得性半胱氨酸仍未被表征。在这里，我们使用半胱氨酸化学蛋白组学，这是一种能够在整个蛋白质组中定位功能、氧化敏感和潜在可药用残基的技术，与基因组学结合，揭示半胱氨酸获取的隐藏景观。对于癌症和正常基因组，我们发现半胱氨酸的获取是遗传变异的普遍后果，在减少 DNA 修复的情况下进一步提高。我们的化学蛋白质组学平台集成了化学蛋白质组学、全外显子和RNA-seq数据，采用自定义的两阶段误差控制蛋白质组学搜索，并通过用户友好的FragPipe界面进一步增强。将 CADD 预测的有害性整合到一起，发现可能导致半胱氨酸获取的具有明显富集程度的损害变异。通过在十一个细胞系中应用化学蛋白质组学，我们发现116个半胱氨酸的增加，其中10个与电泳药物样分子结合。靠近错义变异的参考半胱氨酸也被广泛发现，共791个，支持迄今未开发的蛋白质形式特异性化学探针开发活动的机会。由于化学蛋白质组学还具有匹配样品的组合变异数据库，并且与氧化还原蛋白质组学和小分子筛选兼容，我们预计在指导蛋白质形式特异性生物学和治疗发现方面将得到广泛的应用。

Cancer genomes are rife with genetic variants; one key outcome of this variation is gain-of-cysteine, which is the most frequently acquired amino acid due to missense variants in COSMIC. Acquired cysteines are both driver mutations and sites targeted by precision therapies. However, despite their ubiquity, nearly all acquired cysteines remain uncharacterized. Here, we pair cysteine chemoproteomics-a technique that enables proteome-wide pinpointing of functional, redox sensitive, and potentially druggable residues-with genomics to reveal the hidden landscape of cysteine acquisition. For both cancer and healthy genomes, we find that cysteine acquisition is a ubiquitous consequence of genetic variation that is further elevated in the context of decreased DNA repair. Our chemoproteogenomics platform integrates chemoproteomic, whole exome, and RNA-seq data, with a customized 2-stage false discovery rate (FDR) error controlled proteomic search, further enhanced with a user-friendly FragPipe interface. Integration of CADD predictions of deleteriousness revealed marked enrichment for likely damaging variants that result in acquisition of cysteine. By deploying chemoproteogenomics across eleven cell lines, we identify 116 gain-of-cysteines, of which 10 were liganded by electrophilic druglike molecules. Reference cysteines proximal to missense variants were also found to be pervasive, 791 in total, supporting heretofore untapped opportunities for proteoform-specific chemical probe development campaigns. As chemoproteogenomics is further distinguished by sample-matched combinatorial variant databases and compatible with redox proteomics and small molecule screening, we expect widespread utility in guiding proteoform-specific biology and therapeutic discovery.