Titin mutation associated with responsiveness to checkpoint blockades in solid tumors

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

doi:10.1172/jci.insight.127901

Cited by 124 publications

(130 citation statements)

References 54 publications

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“…TMB is one of the most important biomarkers for predicting ICB response in NSCLC (1)(2)(3)7), and it also shows predictive efficacy for ICB therapies in other types of solid tumors (7,36), but it still has some limitations (5,6,14,19). For example, the cut-offs of TMB for identifying ICB responders are different for different tumor types, and the test platform for assessing TMB has also not been standardized (5,14,19). Thus, more studies are turning to develop surrogate biomarkers that highly correlate with the TMB status, such as genetic mutations of DNA damage response pathways and TP53/KRAS (10,19,37).…”

Section: Discussionmentioning

confidence: 99%

“…For example, the cut-offs of TMB for identifying ICB responders are different for different tumor types, and the test platform for assessing TMB has also not been standardized (5,14,19). Thus, more studies are turning to develop surrogate biomarkers that highly correlate with the TMB status, such as genetic mutations of DNA damage response pathways and TP53/KRAS (10,19,37). However, these mutations are positive for only a minority of patients, and the broad detection of these TMB-related gene mutations in clinical practice remains challenging (19).…”

Section: Discussionmentioning

confidence: 99%

“…The potential mechanism is that tumors with MMRd can result in microsatellite instability (MSI) and are a specific subset of high TMB tumors (5). However, in LUAD, the positivity rate of MMRd/MSI assessed by genomic variations is <1% and much lower than the objective response rate to PD-1 blockade in unselected patients (13,19,(30)(31)(32)(33). Given that previous studies were mainly focusing on genomic variations to explore the MMRd mechanism in LUAD (13,33) and our data showed that MSH2 expression was strongly associated with increased TMB in Discovery-LUAD cohort (Figure 3; Figure S3), we further examined the transcriptome-based MMRd status in LUAD patients with high TMB.…”

Section: Msh2 Expression Outperformed Other Mmr-related Genes For Prementioning

confidence: 99%

“…To test our hypothesis, we recruited three well-studied NSCLC immunotherapeutic cohorts (1)(2)(3) and one multidimensional non-immunotherapeutic The Cancer Genome Atlas (TCGA) dataset. As previous studies reported (2,10,(16)(17)(18)(19), TCGA samples without ICB therapies are still informative to explore tumor immune escape and can also derive surrogate biomarkers for ICB therapies. Combining these four cohorts, we revealed that MSH2 expression was the most robust feature associated with increased TMB and smoking signature in multivariate analysis and might be developed as a potential surrogate biomarker of TMB for identifying ICB responders in lung adenocarcinoma (LUAD), one of the commonest types of NSCLC (20,21).…”

Section: Introductionmentioning

confidence: 99%

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Association of MSH2 Expression With Tumor Mutational Burden and the Immune Microenvironment in Lung Adenocarcinoma

et al. 2020

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Immune checkpoint blockade (ICB) therapies that target programmed cell death 1 (PD1) and PD1 ligand 1 (PDL1) have demonstrated promising benefits in lung adenocarcinoma (LUAD), and tumor mutational burden (TMB) is the most robust biomarker associated with the efficacy of PD-1-PD-L1 axis blockade in LUAD, but the assessment of TMB by whole-exome sequencing (WES) is rather expensive and time-consuming. Although targeted panel sequencing has been developed and approved by the US Food and Drug Administration (FDA) to estimate TMB, we found that its predictive accuracy for ICB response was significantly lower than WES in LUAD. Given that previous studies were mainly focusing on genomic variations to explore surrogate biomarkers of TMB, we turned to examine the transcriptome-based correlation with TMB in this study. Combining three immunotherapeutic cohorts with two independent The Cancer Genome Atlas (TCGA) datasets, we revealed that the expression of mutS homolog 2 (MSH2), one of the most crucial genes involved in DNA mismatch repair (MMR) pathway, was the strongest feature associated with increased TMB in multivariate analysis. Furthermore, MSH2 expression also displayed a significantly positive correlation with smoking signature while an inverse association with MMR deficiency (MMRd) signature in LUAD. More importantly, high expression of MSH2 markedly correlated with increased PD-L1 expression and CD8+ T cell infiltration, both suggesting a prominent immunotherapy-responsive microenvironment in LUAD. Notably, detecting MSH2 expression is much easier, faster, and cheaper than TMB in clinical practice. Taken together, this study demonstrates the association of MSH2 expression with TMB and the immune microenvironment in LUAD. MSH2 expression may be developed as a potential surrogate biomarker of TMB to identify ICB responders in LUAD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Msh2 Expression Outperformed Other Mmr-related Genes For Prementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Association of MSH2 Expression With Tumor Mutational Burden and the Immune Microenvironment in Lung Adenocarcinoma

et al. 2020

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“…Apesar do gene TTN mutado se relacionar por diversas vezes a tumores, ainda não se sabe ao certo papel da titina na carcinogênese [106]. Porém quando alterada, essa proteína é relacionada ao desenvolvimento de desordens neuromusculares e cardiopatias, sendo considerada um possível marcador urinário [107,108].…”

Section: • Proteína Titinaunclassified

Proteômica de biopsias líquidas (sérica e urina) como biomarcadores nos adenocarcinomas colorretais

Bulhões¹,

Cavalcanti²,

Martins³

2019

PIC

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O câncer colorretal (CCR) é o terceiro mais prevalente no mundo, sendo que, cerca de 45% das vezes seu diagnóstico é tardio, geralmente apresentando metástase a distância tendo um prognóstico desfavorável. O padrão-ouro para o diagnóstico é a colonoscopia, no entanto esse exame apresenta diversos riscos como sangramento, perfuração, complicações cardiorrespiratórias e questões relacionadas ao pudor e desconforto, resultando em baixa adesão dos pacientes. Atualmente, o principal exame de rastreio do CCR é a pesquisa de sangue oculto nas fezes (SOF), porém esse possui baixa sensibilidade e especificidade. Sendo assim, se faz necessário a criação de novas ferramentas diagnósticas, como métodos menos invasivos usando biopsias líquidas. Neste trabalho foi realizado uma prospecção de proteínas presentes em biópsias líquidas (plasma e urina) por meio da espectrometria de massas entre um grupo de indivíduos portadores de neoplasia colorretal e de indivíduos não-patológicos (controle) visando definir possíveis biomarcadores. No estudo foram coletadas amostras de plasma e urina de 18 indivíduos, 9 pertencentes ao grupo CCR e 9 ao grupo controle, sendo extraídas as proteínas totais das amostras. Em seguida, essas foram submetidas a nanocromatografia usando uHPLC, os picos obtidos foram submetidos à análise do Orbitrap e Progenesis. Durante a análise foram separadas 18 proteínas com relevância estatística, sendo 5 delas provenientes do plasma e 13 da urina, podendo ser utilizadas como possíveis potenciais biomarcadores. Na literatura, algumas destas já foram descritas e relacionadas ao CCR, outras já foram associadas ao processo da carcinogênese, outras, ainda, não foram descritas no CCR ou no processo de carcinogênese. Assim, futuras pesquisas com focona validação dessas proteínas mais relevantes e avaliação de forma personalizada se faz necessário, além de alinhar a proteômica à outras técnicas, como a metabolômica

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Genomic alterations in neuroendocrine prostate cancer: A systematic review and meta‐analysis

et al. 2023

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Background: Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer. We performed a systematic review and meta-analysis to evaluate the prevalence of genomic alterations in NEPC and better understand its molecular features to potentially inform precision medicine.Methods: EMBASE, PubMed, and Cochrane Central Register of Controlled Trials databases were searched for eligible studies until March 2022. Study qualities were assessed using the Q-genie tool. The prevalence of gene mutations and copy number alterations (CNAs) were extracted, and meta-analysis was performed using R Studio with meta package.Results: A total of 14 studies with 449 NEPC patients were included in this metaanalysis. The most frequently mutated gene in NEPC was TP53 (49.8%), and the prevalence of deleterious mutations in ATM/BRCA was 16.8%. Common CNAs in NEPC included RB1 loss (58.3%), TP53 loss (42.8%), PTEN loss (37.0%), AURKA amplification (28.2%), and MYCN amplification (22.9%). RB1/TP53 alterations and concurrent RB1 and TP53 alterations were remarkably common in NEPC, with a prevalence of 83.8% and 43.9%, respectively. Comparative analyses indicated that the prevalence of (concurrent) RB1/TP53 alterations was significantly higher in de novo NEPC than in treatment-emergent NEPC (t-NEPC).Conclusions: This study presents the comprehensive prevalence of common genomic alterations and potentially actionable targets in NEPC and reveals the genomic differences between de novo NEPC and t-NEPC. Our findings highlight the importance of genomic testing in patients for precision medicine and provide insights into future studies exploring different NEPC subtypes.

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Titin mutation associated with responsiveness to checkpoint blockades in solid tumors

Cited by 124 publications

References 54 publications

Association of MSH2 Expression With Tumor Mutational Burden and the Immune Microenvironment in Lung Adenocarcinoma

Association of MSH2 Expression With Tumor Mutational Burden and the Immune Microenvironment in Lung Adenocarcinoma

Proteômica de biopsias líquidas (sérica e urina) como biomarcadores nos adenocarcinomas colorretais

Genomic alterations in neuroendocrine prostate cancer: A systematic review and meta‐analysis

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