膀胱癌
ARID1A型
医学
免疫检查点
肿瘤科
内科学
外显子组测序
微卫星不稳定性
队列
免疫疗法
癌症
突变
基因
生物
遗传学
等位基因
微卫星
作者
Michal Sarfaty,Mahdi Golkaram,Samuel A. Funt,Hikmat Al‐Ahmadie,Shannon Kaplan,Song Fan,Ashley Marie Regazzi,Vladimir Makarov,Fengshen Kuo,Irina Ostrovnaya,Venkatraman Seshan,Chen Zhao,Benjamin Greenbaum,Li Liu,Jonathan E. Rosenberg,Timothy A. Chan
摘要
PURPOSE Immune checkpoint blockade (ICB) therapy has significantly improved clinical outcomes in bladder cancer. Identification of correlates of benefit is critical to select appropriate therapy for individual patients. METHODS To reveal genetic variables associated with benefit from ICB, we performed whole-exome sequencing on tumor specimens from 88 patients with advanced bladder cancer treated with ICB. RESULTS We identified several genetic factors that correlated with progression-free and overall survival after ICB therapy including ARID1A mutation, tumor mutational burden, intratumoral heterogeneity, the ratio of nonsynonymous to synonymous mutations in the immunopeptidome (immune dN/dS), and tumor cell purity. In addition, we noted that neutrophil-to-lymphocyte ratio and smoking history were negatively associated with overall survival. These genetic characteristics define four molecular subtypes demonstrating differential sensitivity to ICB. We validated the association of these four subtypes with clinical benefit from ICB in an independent cohort (IMvigor210). Finally, we showed that these molecular subtypes also correlate with outcome, although with distinct relationships, among patients not treated with ICB using The Cancer Genome Atlas (TCGA) bladder cancer cohort. Using parallel RNA sequencing data, the subtypes were also shown to correlate with immune infiltration and inflammation, respectively, in the IMvigor210 and TCGA cohorts. CONCLUSION Together, our study defines molecular subgroups of bladder cancer that influence benefit from ICB.
科研通智能强力驱动
Strongly Powered by AbleSci AI