Titin mutation associated with responsiveness to checkpoint blockades in solid tumors
Qingzhu Jia, … , Ji He, Bo Zhu
Qingzhu Jia, … , Ji He, Bo Zhu
Published May 16, 2019
Citation Information: JCI Insight. 2019;4(10):e127901. https://doi.org/10.1172/jci.insight.127901.
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Research Article Therapeutics

Titin mutation associated with responsiveness to checkpoint blockades in solid tumors

Abstract

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.

Authors

Qingzhu Jia, Jun Wang, Ning He, Ji He, Bo Zhu

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Figure 1

TTN mutation is related to higher TMB and an increased response rate to ICB.

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TTN mutation is related to higher TMB and an increased response rate to...
(A) The ratio of the median TMB between patients with or without mutation for a specific gene is shown. Red dots indicate a lower TMB for patients with the mutation; gray dots indicate a higher TMB for patients with the mutation. Box plot shows median with first and third quantiles. (B) Two-tailed Mann-Whitney U test was performed to compare the TMB between patients with or without the mutation. The frequencies of genes are plotted against their significance in the U test. Color gradient indicates ratio of TMB in A; red curve indicates fitting line in Loess regression. (C) TMB is shown based on TTN mutation status. Statistics based on 2-tailed Mann-Whitney U test. Box plot shows median with min to max range. (D) Frequencies of TTN mutation. Solid blue indicates tumor types approved for treatment with ICB. (E) Frequencies of mutated TTN for each tumor type with their reported ORR to ICB. Treatment settings, such as previously treated or treatment naive, are shown according to the enrolled criteria in clinical trials. R, Pearson’s coefficient of correlation.