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Alteration in TET1 as potential biomarker for immune checkpoint blockade in multiple cancers.

ABSTRACT: BACKGROUND:Immune checkpoint inhibitors (ICIs) have achieved impressive success in different cancer types, yet responses vary and predictive biomarkers are urgently needed. Growing evidence points to a link between DNA methylation and anti-tumor immunity, while clinical data on the association of genomic alterations in DNA methylation-related genes and ICI response are lacking. METHODS:Clinical cohorts with annotated response and survival data and matched mutational data from published studies were collected and consolidated. The predictive function of specific mutated genes was first tested in the discovery cohort and later validated in the validation cohort. The association between specific mutated genes and tumor immunogenicity and anti-tumor immunity was further investigated in the Cancer Genome Altas (TCGA) dataset. RESULTS:Among twenty-one key genes involving in the regulation of DNA methylation, TET1-mutant (TET1-MUT) was enriched in patients responding to ICI treatment in the discovery cohort (P??0.05 in both two non-ICI-treated cohorts). In TCGA dataset, TET1-MUT was strongly associated with higher tumor mutational burden and neoantigen load, and inflamed pattern of tumor-infiltrating T lymphocytes, immune signatures and immune-related gene expressions. CONCLUSIONS:TET1-MUT was strongly associated with higher ORR, better DCB, longer PFS, and improved OS in patients receiving ICI treatment, suggesting that TET1-MUT is a novel predictive biomarker for immune checkpoint blockade across multiple cancer types.

SUBMITTER: Wu HX

PROVIDER: S-EPMC6798429 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Alteration in TET1 as potential biomarker for immune checkpoint blockade in multiple cancers.

Wu Hao-Xiang HX Chen Yan-Xing YX Wang Zi-Xian ZX Zhao Qi Q He Ming-Ming MM Wang Ying-Nan YN Wang Feng F Xu Rui-Hua RH

Journal for immunotherapy of cancer 20191017 1

<h4>Background</h4>Immune checkpoint inhibitors (ICIs) have achieved impressive success in different cancer types, yet responses vary and predictive biomarkers are urgently needed. Growing evidence points to a link between DNA methylation and anti-tumor immunity, while clinical data on the association of genomic alterations in DNA methylation-related genes and ICI response are lacking.<h4>Methods</h4>Clinical cohorts with annotated response and survival data and matched mutational data from publ ...[more]

PMID: 31623662

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Project description:BackgroundWhile there have been encouraging preliminary clinical results for immune checkpoint inhibitors (ICIs) in BTCs, it remains a challenge to identify the subset of patients who may benefit. In this study, we evaluated the efficacy of ICI treatment in patients with advanced BTCs, and explored potential biomarkers that are predictive of response.MethodsThe study enrolled 26 patients with advanced microsatellite stable BTCs (15 with gallbladder cancers [GCs] and 11 with intrahepatic cholangiocarcinoma [ICCs]) who received ICI treatment. Targeted next-generation sequencing (NGS) was performed on tumor tissue samples collected from 17 patients. Clinical and genomic characteristics were assessed for the correlation with clinical outcome.ResultsAnalysis of the baseline clinical characteristics showed that performance score (PS) of 0 was associated with a better prognosis than PS of 1 (HR = 1.08 × 109 ; 95% CI, 0∼Inf; P = .002). No significant correlations were found between clinical outcome and inflammation-related indicators. NGS profiling of the available tumor tissues, revealed largely non-overlapping somatic alterations between GCs and ICCs. Mutations in LRP1B (HR = 0.26; 95% CI, 0.06-1.21; P = .067), ERBB2 (HR = 0.15; 95% CI, 0.02-1.19; P = .04), or PKHD1 (HR < 0.01; 95% CI, 0-Inf; P = .04) showed strong association with increased progression-free survival (PFS) benefit. Subsequent analysis showed that alterations in the RTK-RAS pathway were associated with improved outcomes (HR = 0.12; 95% CI, 0.02-0.63; P = .003). Tumor mutation burden (TMB) was higher in patients with GC than those with ICC, and was associated with LRP1B mutations (P = .032). We found that patients with 19q amplification (19q Amp) and 9p deletion (9p Del) had poor PFS outcome (19q Amp, HR = 15.4; 95% CI, 2.7-88.5; P < .001; 9p Del; HR = 4.88 × 109 ; 95% CI, 0-Inf; P < .001), while those with chromosomal instability derived PFS benefit (HR = 0.24; 95% CI, 0.05-1.17; P = .057).ConclusionOur study identified several potential clinical and genomic features that may serve as biomarkers of clinical response to ICIs in advanced BTCs patients. A larger sample size is required for further verification.

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Alteration in TET1 as potential biomarker for immune checkpoint blockade in multiple cancers.

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Alteration in TET1 as potential biomarker for immune checkpoint blockade in multiple cancers.

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