治疗后的转移性复发是癌症死亡的主要原因，并且对患者接受的大多数治疗缺少已知的耐药机制。为填补这一空白，我们分析了一个包括1,031个难治性转移性肿瘤的全癌症队列（META-PRISM），这些肿瘤进行了全外显子和转录组测序。与原发未治疗肿瘤相比，META-PRISM肿瘤，特别是前列腺、膀胱和胰腺肿瘤，显示了最为转化的基因组。仅在肺癌和结肠癌中鉴定了标准治疗耐药生物标志物，占META-PRISM肿瘤的9.6％，表明有太少的耐药机制已经接受了临床验证。相反，我们证实了多种调查和假设耐药机制在治疗和未治疗患者中的富集，从而确认其在治疗耐药性中的假设作用。此外，我们证明了分子标记可以改进对六个月生存预测的预测，特别是对于晚期乳腺癌患者。我们的分析确定了META-PRISM队列在研究耐药机制和癌症预测分析方面的实用性。

Metastatic relapse after treatment is the leading cause of cancer mortality, and known resistance mechanisms are missing for most treatments administered to patients. To bridge this gap, we analyze a pan-cancer cohort (META-PRISM) of 1,031 refractory metastatic tumors profiled via whole-exome and transcriptome sequencing. META-PRISM tumors, particularly prostate, bladder, and pancreatic types, displayed the most transformed genomes compared to primary untreated tumors. Standard-of-care resistance biomarkers were identified only in lung and colon cancers - 9.6% of META-PRISM tumors, indicating that too few resistance mechanisms have received clinical validation. In contrast, we verified the enrichment of multiple investigational and hypothetical resistance mechanisms in treated compared to non-treated patients, thereby confirming their putative role in treatment resistance. Additionally, we demonstrated that molecular markers improve six-month survival prediction, particularly in patients with advanced breast cancer. Our analysis establishes the utility of META-PRISM cohort for investigating resistance mechanisms and performing predictive analyses in cancer.