Integration of comprehensive genomic profiling, tumor mutational burden, and PD‐L1 expression to identify novel biomarkers of immunotherapy in non‐small cell lung cancer

Shi, Yunfei; Lei, Youming; Liu, Li; Zhang, Shiyue; Wang, Wenjing; Zhao, Juan; Zhao, Shuaiguo; Dong, Xiaowei; Yao, Ming; Wang, Kai; Zhou, Qing

doi:10.1002/cam4.3649

Cited by 58 publications

(51 citation statements)

References 56 publications

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“…Together, the role of KMT2D mutations in T cell responses and immunotherapy may need further elucidation in DLBCL, 40 and the biomarker values of T cells, PD-L1/PD-1 expression, and TMB in DLBCL need to be studied in patients treated with PD-1 inhibitors. Also noteworthy, in non-small-cell lung cancer, KMT family member mutations were associated with higher TMB and PD-L1 expression, 41 whereas KMT2D mutation was an unfavorable prognostic factor. 42 Mutations in several epigenetic genes have been reported to be associated with high TMB and/or efficacy of immune checkpoint blockade immunotherapy in solid tumors, including ARID1A , 43–45 TET1 , 46 KMT2A / C , 47 and EP300 .…”

Section: Discussionmentioning

confidence: 98%

Genomic complexity is associated with epigenetic regulator mutations and poor prognosis in diffuse large B-cell lymphoma

You

Xu-Monette

et al. 2021

OncoImmunology

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Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma with high mutation burdens but a low response rate to immune checkpoint inhibitors. In this study, we performed targeted next-generation sequencing and fluorescent multiplex immunohistochemistry, and investigated the clinical significance and immunological effect of mutation numbers in 424 DLBCL patients treated with standard immunochemotherapy. We found that KMT2D and TP53 nonsynonymous mutations (MUT) were significantly associated with increased nonsynonymous mutation numbers, and that high mutation numbers (MUT high ) were associated with significantly poorer clinical outcome in germinal center B-celllike DLBCL with wild-type TP53. To understand the underlying mechanisms, we identified a geneexpression profiling signature and the association of MUT high with decreased T cells in DLBCL patients with wild-type TP53. On the other hand, in overall cohort, MUT high was associated with lower PD-1 expression in T cells and PD-L1 expression in macrophages, suggesting a positive role of MUT high in immune responses. Analysis in a whole-exome sequencing dataset of 304 patients deposited by Chapuy et al. validated the correlation of MUT-KMT2D with genomic complexity and the significantly poorer survival associated with higher numbers of genomic single nucleotide variants in activated B-cell-like DLBCL with wild-type TP53. Together, these results suggest that KMT2D inactivation or epigenetic dysregulation has a role in driving DLBCL genomic instability, and that genomic complexity has adverse impact on clinical outcome in DLBCL patients with wild-type TP53 treated with standard immunochemotherapy. The oncoimmune data in this study have important implications for biomarker and therapeutic studies in DLBCL.

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Section: Discussionmentioning

confidence: 98%

Genomic complexity is associated with epigenetic regulator mutations and poor prognosis in diffuse large B-cell lymphoma

You

Xu-Monette

et al. 2021

OncoImmunology

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“…Among these issues, we stress the need to obtain a high enough quantity of extracted nucleic acid associated with a high amount, to be able to use sensitive and specific molecular tests. In the future, it will be pivotal to be able to compile, in a reasonable turnaround time for personalized patient care, information concerning the different parameters 207 . Therefore, it will certainly be of strong interest to register data concerning all the genomic alterations associated with gene fusions, histological and radiological imaging, the results of IHC, liquid biopsies, etc.…”

Section: Discussionmentioning

confidence: 99%

Fusion‐positive non‐small cell lung carcinoma: Biological principles, clinical practice, and diagnostic implications

Kazdal

Hofman

Christopoulos

et al. 2022

Genes Chromosomes & Cancer

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Based on superior efficacy and tolerability, targeted therapy is currently preferred over chemotherapy and/or immunotherapy for actionable gene fusions that occur in late‐stage non‐small cell lung carcinoma (NSCLC). Consequently, current clinical practice guidelines mandate testing for ALK, ROS1, NTRK, and RET gene fusions in all patients with newly diagnosed advanced non‐squamous NSCLC (NS‐NSCLC). Gene fusions can be detected using different approaches, but today RNA next‐generation sequencing (NGS) or combined DNA/RNA NGS is the method of choice. The discovery of other gene fusions (involving, eg, NRG1, NUT, FGFR1, FGFR2, MET, BRAF, EGFR, SMARC fusions) and their partners has increased progressively in recent years, leading to the development of new and promising therapies and mandating the development and implementation of comprehensive detection methods. The purpose of this review is to focus on recent data concerning the main gene fusions identified in NSCLC, followed by the discussion of major challenges in this domain.

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“…Members of the KMT2 family (e.g., KMT2A, KMT2C, and KMT2D) exhibit a high mutation rate in nonsmall cell lung cancer tumors ( 64 , 65 ), and these mutations were associated with higher tumor mutational burden (TMB) and PD-L1 expression, as well as higher PD-L1+/TMB-high proportions. Importantly, nonsmall cell lung cancer patients with tumor protein p53 (TP53)/KMT2C comutations who underwent treatment with ICBs had significantly longer PFS and greater durable clinical benefit ( 66 ). CTNNB1 is one of the most common mutant genes in HCC, which encodes a β-catenin protein and is involved in the regulation of the Wnt signaling pathway.…”

Section: Chinese Patients With Hcc: Characteristics and Their Correla...mentioning

confidence: 99%

Immune Checkpoint Blockade in Chinese Patients With Hepatocellular Carcinoma: Characteristics and Particularity

Lin

You

et al. 2022

Front. Oncol.

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More than half of new cases of hepatocellular carcinoma (HCC) and associated deaths occurring annually worldwide are recorded in China. Chinese patients with HCC exhibit special characteristics in terms of etiology, leading to differences in prognosis versus Western patients. In recent years, several angiogenesis inhibitors were approved, and immune checkpoint blockers (ICBs) were recommended as second-line therapy for advanced HCC. In addition, the recent success of a combination of atezolizumab with bevacizumab signals resulted in an essential change in the first-line treatment of HCC. We investigated the characteristics of patients with HCC in China and summarized the rapidly emerging relevant clinical data, which relate to the prospects and challenges associated with the use of ICBs in this setting. We further evaluated the efficacy of ICBs in Chinese patients with HCC based on data obtained from global trials, and discussed possible factors influencing the effectiveness of ICBs in patients with HCC in China. Immunotherapy offers new options for the treatment of advanced HCC, though responses varied between patients. Currently, there is a need to discover specific biomarkers for the accurate identification of patients who would more likely benefit from immunotherapy. Furthermore, investigation of patient characteristics in different countries is necessary to provide a clinical practice basis and reference value for the diagnosis and treatment of HCC.

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Integration of comprehensive genomic profiling, tumor mutational burden, and PD‐L1 expression to identify novel biomarkers of immunotherapy in non‐small cell lung cancer

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 58 publications

References 56 publications

Genomic complexity is associated with epigenetic regulator mutations and poor prognosis in diffuse large B-cell lymphoma

Genomic complexity is associated with epigenetic regulator mutations and poor prognosis in diffuse large B-cell lymphoma

Fusion‐positive non‐small cell lung carcinoma: Biological principles, clinical practice, and diagnostic implications

Immune Checkpoint Blockade in Chinese Patients With Hepatocellular Carcinoma: Characteristics and Particularity

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