Based on genome-scale screening analysis in a discovery cohort and 7 independent validation cohorts, Jia et al. found that mutations in titin (TTN), the gene with the longest exonic length in the genome and harboring the highest number of mutations, were associated with increased tumor mutation burden (TMB) and correlated with objective response to immune checkpoint blockade (ICB). TTN mutations, observed in nearly 25% of a wide range of solid tumors, identified responders who would have otherwise been missed by other validated biomarkers and may serve as a clinically feasible biomarker to evaluate TMB and predict response to ICB.
Immune checkpoint blockade (ICB) immunotherapy induces potent antitumor immunity across multiple solid tumors, although few patients respond well to this therapy. An emerging biomarker for predicting responsiveness to ICB immunotherapy is tumor mutational burden (TMB). Although several surrogate biomarkers, including deficient mismatch repair, TP53/KRAS mutations, and comutations in DNA damage response pathways, have been shown to be effective for predicting the response to checkpoint blockade immunotherapy, each is positive for only a small cohort of candidates, and many potential responders to ICB are inevitably missed. Here, we found that titin (TTN), which is frequently detected in solid tumors, is associated with increased TMB and correlated with objective response to ICB. In 7 public clinical cohorts, all patients with mutated TTN showed longer progression-free survival or overall survival than those with wild-type status. Furthermore, an improved objective response rate and higher TMB were identified in cohorts with accessible information. Identification of TTN mutation as a predictor of improved outcomes in response to ICBs provides a clinically feasible assessment for estimating TMB and ICB therapy outcomes.
Author Info: (1) Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China. (2) Chongqing Key Laboratory of Immunotherapy, Chongqing, China. (3) Department of C
Author Info: (1) Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China. (2) Chongqing Key Laboratory of Immunotherapy, Chongqing, China. (3) Department of Cancer Immunotherapy, Shandong Cancer Hospital Affiliated to Shandong University, Shandong, China. (4) GloriousMed Technology Co., Ltd. Beijing, China. (5) Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
