<i>SMARCA4</i> mutations in <i>KRAS</i>‐mutant lung adenocarcinoma: a multi‐cohort analysis

Liu, Liang; Ahmed, Tamjeed; Petty, W. Jeffrey; Grant, Stefan C.; Ruiz, Jimmy; Lycan, Thomas; Topaloğlu, Ümit; Chou, Ping-Chieh; Miller, Lance D.; Hawkins, Gregory A.; Alexander-Miller, Martha A.; O’Neill, Stacey S.; Powell, Bayard L.; D’Agostino, Ralph B.; Munden, Reginald F.; Pasche, Boris; Zhang, Wei

doi:10.1002/1878-0261.12831

Cited by 30 publications

(18 citation statements)

References 51 publications

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“…Mutations of SMARCA4 represent a genetic factor leading to adverse clinical outcome in lung adenocarcinoma (17). SMARCA4-mutant lung cancers may be more sensitive to immunotherapy (8), but other studies have contradictory results (18).…”

Section: Discussionmentioning

confidence: 99%

A Pan-Cancer Analysis of SMARCA4 Alterations in Human Cancers

Peng

et al. 2021

Front. Immunol.

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BackgroundSMARCA4, the essential ATPase subunit of SWI/SNF chromatin remodeling complex, regulates transcription through the control of chromatin structure and is increasingly thought to play significant roles in human cancers. This study aims to explore the potential role of SMARCA4 with a view to providing insights on pathologic mechanisms implicated here.MethodsThe potential roles of SMARCA4 in different tumors were explored based on The Cancer Genome Atlas (TCGA), Genotype-tissue expression (GTEx), Tumor Immune Estimation Resource (TIMER), and Gene Set Enrichment Analysis (GSEA) datasets. The expression difference, mutation and phosphorylation status, survival, pathological stage, DNA methylation, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), tumor microenvironment (TME), and immune cell infiltration related to SMARCA4 were analyzed.ResultsHigh expression levels of SMARCA4 were observed in most cancer types. SMARCA4 expression in tumor samples correlates with poor overall survival in several cancers. Lung adenocarcinoma cases with altered SMARCA4 showed a poorer prognosis. Enhanced phosphorylation levels of S613, S695, S699, and S1417 were observed in several tumors, including breast cancer. SMARCA4 correlated with tumor immunity and associated with different immune cells and genes in different cancer types. TMB, MSI, MMR, and DNA methylation correlated with SMARCA4 dysregulation in cancers. SMARCA4 expression was negatively associated with CD8+ T-cell infiltration in several tumors. Furthermore, the SWI/SNF superfamily-type complex and ATPase complex may be involved in the functional mechanisms of SMARCA4, albeit these data require further confirmation.ConclusionsOur study offers a comprehensive understanding of the oncogenic roles of SMARCA4 across different tumors. SMARCA4 may correlate with tumor immunity.

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Section: Discussionmentioning

confidence: 99%

A Pan-Cancer Analysis of SMARCA4 Alterations in Human Cancers

Peng

et al. 2021

Front. Immunol.

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“…On the other hand, a remarkable effect on ICI therapy received by patients with KRAS and TP53 mutation was seen that was compared to KRAS-SMARCA4 mutation or KRAS mutation alone, as this co-mutation facilitates T-cell infiltration and augments tumor immunogenicity, resulting in a high PD-L1 expression. This, in fact, further enhances the need to evaluate BRG1 IHC expression and molecular evaluation of co-mutations to predict the responders with NSCLC to immunotherapy [7,43,44].…”

Section: Prognostic and Predictive Management Issues In Smarca4-deficient Nsclcmentioning

confidence: 99%

“…The special relationship carried by KRAS-driven lung cancers with SMARCA4 loss was studied by some research groups [7,43,44]. As is already known, KRAS is a key oncogenic driver in lung adenocarcinomas, which is frequently observed in ever smokers and it is associated with a high TMB; hence, a subset of cases which carry other mutations may show a better response to ICI therapy.…”

Section: Prognostic and Predictive Management Issues In Smarca4-deficient Nsclcmentioning

confidence: 99%

“…Therefore, it is acknowledged that a precursor lesion with KRAS mutation progresses to malignancy through an acceleration of an intact SMARCA4 gene. This is possible when the SMARCA4 in a KRAS-dependent lung adenocarcinoma is a missense mutation, identified through an intact BRG1 expression or the loss of BRG1 expression caused by a nonsense, frameshift, or splice site mutation in the SMARCA4 gene in a KRAS-independent lung adenocarcinoma [7,43]. In summary, the SMARCA4-deficient tumors with a KRAS oncogenic activation are associated with a better prognosis, as the tumor will be less progressive, low grade, and with lower tumor burden as compared to a SMARCA4 intact KRAS co-mutated NSCLC.…”

Section: Prognostic and Predictive Management Issues In Smarca4-deficient Nsclcmentioning

confidence: 99%

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Perspectives and Issues in the Assessment of SMARCA4 Deficiency in the Management of Lung Cancer Patients

Armon

Hofman

Ilié

2021

Cells

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Lung cancers are ranked third among the cancer incidence in France in the year 2020, with adenocarcinomas being the commonest sub-type out of ~85% of non-small cell lung carcinomas. The constant evolution of molecular genotyping, which is used for the management of lung adenocarcinomas, has led to the current focus on tumor suppressor genes, specifically the loss of function mutation in the SMARCA4 gene. SMARCA4-deficient adenocarcinomas are preponderant in younger aged male smokers with a predominant solid morphology. The importance of identifying SMARCA4-deficient adenocarcinomas has gained interest for lung cancer management due to its aggressive behavior at diagnosis with vascular invasion and metastasis to the pleura seen upon presentation in most cases. These patients have poor clinical outcome with short overall survival rates, regardless of the stage of disease. The detection of SMARCA4 deficiency is possible in most pathology labs with the advent of sensitive and specific immunohistochemical antibodies. The gene mutations can be detected together with other established lung cancer molecular markers based on the current next generation sequencing panels. Sequencing will also allow the identification of associated gene mutations, notably KRAS, KEAP1, and STK11, which have an impact on the overall survival and progression-free survival of the patients. Predictive data on the treatment with anti-PD-L1 are currently uncertain in this high tumor mutational burden cancer, which warrants more groundwork. Identification of target drugs is also still in pre-clinical testing. Thus, it is paramount to identify the SMARCA4-deficient adenocarcinoma, as it carries worse repercussions on patient survival, despite having an exceptionally low prevalence. Herein, we discuss the pathophysiology of SMARCA4, the clinicopathological consequences, and different detection methods, highlighting the perspectives and challenges in the assessment of SMARCA4 deficiency for the management of non-small cell lung cancer patients. This is imperative, as the contemporary shift on identifying biomarkers associated with tumor suppressor genes such as SMARCA4 are trending; hence, awareness of pathologists and clinicians is needed for the SMARCA4-dNSCLC entity with close follow-up on new management strategies to overcome the poor possibilities of survival in such patients.

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“…A relatively new type of thoracic cancer, in particular lung cancer, with a poor prognosis has been identified to have mutations in SMARCA4 [250][251][252][253][254][255][256][257][258]. These mutations have been found in about 5% to 10% of NSCLC patients, mostly NS-NSCLC patients [259].…”

Section: Smarca4 Mutationsmentioning

confidence: 99%

What Is New in Biomarker Testing at Diagnosis of Advanced Non-Squamous Non-Small Cell Lung Carcinoma? Implications for Cytology and Liquid Biopsy

Hofman

2021

JMP

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The discovery and clinical validation of biomarkers predictive of the response of non-squamous non-small-cell lung carcinomas (NS-NSCLC) to therapeutic strategies continue to provide new data. The evaluation of novel treatments is based on molecular analyses aimed at determining their efficacy. These tests are increasing in number, but the tissue specimens are smaller and smaller and/or can have few tumor cells. Indeed, in addition to tissue samples, complementary cytological and/or blood samples can also give access to these biomarkers. To date, it is recommended and necessary to look for the status of five genomic molecular biomarkers (EGFR, ALK, ROS1, BRAFV600, NTRK) and of a protein biomarker (PD-L1). However, the short- and more or less long-term emergence of new targeted treatments of genomic alterations on RET and MET, but also on others’ genomic alteration, notably on KRAS, HER2, NRG1, SMARCA4, and NUT, have made cellular and blood samples essential for molecular testing. The aim of this review is to present the interest in using cytological and/or liquid biopsies as complementary biological material, or as an alternative to tissue specimens, for detection at diagnosis of new predictive biomarkers of NS-NSCLC.

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SMARCA4 mutations in KRAS‐mutant lung adenocarcinoma: a multi‐cohort analysis

Cited by 30 publications

References 51 publications

A Pan-Cancer Analysis of SMARCA4 Alterations in Human Cancers

A Pan-Cancer Analysis of SMARCA4 Alterations in Human Cancers

Perspectives and Issues in the Assessment of SMARCA4 Deficiency in the Management of Lung Cancer Patients

What Is New in Biomarker Testing at Diagnosis of Advanced Non-Squamous Non-Small Cell Lung Carcinoma? Implications for Cytology and Liquid Biopsy

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