KEAP1 and TP53 Frame Genomic, Evolutionary, and Immunologic Subtypes of Lung Adenocarcinoma With Different Sensitivity to Immunotherapy

Scalera, Stefano; Mazzotta, Marco; Corleone, Giacomo; Sperati, Francesca; Terrenato, Irene; Krasniqi, Eriseld; Pizzuti, Laura; Barba, Maddalena; Vici, Patrizia; Gallo, Enzo; Buglioni, Simonetta; Visca, Paolo; Pescarmona, Edoardo; Marinelli, Daniele; Nicola, Francesca De; Ciuffreda, Ludovica; Goeman, Frauke; Fanciulli, Maurizio; Giusti, Raffaele; Vecchione, Andrea; Maria, Ruggero De; Cappuzzo, Federico; Marchetti, Paolo; Ciliberto, Gennaro; Maugeri‐Saccà, Marcello

doi:10.1016/j.jtho.2021.08.010

Cited by 36 publications

(31 citation statements)

References 46 publications

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“…Based on recent findings, worse clinical outcomes were observed in lung cancer patients with mutations in TP53 , 48 KEAP1 , 49 SMARCA4 , 50 or RBM10 51 . In this study, the low‐risk LUAD patients harbored lower mutational frequencies of the above 4 genes, which was consistent with the association between low‐risk scores and improved prognosis.…”

Section: Discussionsupporting

confidence: 89%

An aging‐related signature predicts favorable outcome and immunogenicity in lung adenocarcinoma

Zhang

Lyu

et al. 2022

Cancer Science

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Aging has been demonstrated to play vital roles in the prognosis and treatment efficacy of cancers, including lung adenocarcinoma (LUAD). This novel study aimed to construct an aging‐related risk signature to evaluate the prognosis and immunogenicity of LUAD. Transcriptomic profiles and clinical information were collected from a total of 2518 LUAD patients from 12 independent cohorts. The risk signature was developed by combining specific gene expression with the corresponding regression coefficients. One cohort treated with the immune checkpoint inhibitor (ICI) was also used. Subsequently, a risk signature was developed based on 21 aging‐related genes. LUAD patients with low‐risk scores exhibited improved survival outcomes in both the discovery and validation cohorts. Further immunology analysis revealed elevated lymphocyte infiltration, decreased infiltration of immune‐suppressive cells, immune response‐related pathways, and favorable ICI predictor enrichment in the low‐risk subgroup. Genomic mutation exploration indicated the enhanced mutation burden and higher mutation rates in significantly driver genes of TP53, KEAP1, SMARCA4, and RBM10 were enriched in patients with a low‐risk signature. In the immunotherapeutic cohort, it was observed that low‐risk aging scores were markedly associated with prolonged ICI prognosis. Overall, the estimated aging signature proved capable of evaluating the prognosis, tumor microenvironment, and immunogenicity, which further provided clues for tailoring prognosis prediction and immunotherapy strategies, apart from promoting individualized treatment plans for LUAD patients.

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Section: Discussionsupporting

confidence: 89%

An aging‐related signature predicts favorable outcome and immunogenicity in lung adenocarcinoma

Zhang

Lyu

et al. 2022

Cancer Science

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“…These mutated NSCLC seem to present a long-term response to ICIs [ 175 ]. Finally, different subgroups of tumors can be distinguished, certain tumors showing a KEAP1 mutation in the absence of a TP53 mutation lead to an immune desert, while both KEAP1 and TP53 associated mutations show a rich immune infiltrate [ 172 , 176 ]. Other genes of interest such as SMARCA4 should also be studied, since SMARCA4 and KRAS co-mutations lead to a weak response to ICIs [ 177 ].…”

Section: Impact Of Kras Mutations On the Efficienc...mentioning

confidence: 99%

Section: Opportunities and Challenges For The Thoracic Pathologistsmentioning

confidence: 99%

“…DNA degradation can provide false-negative or false-positive results, notably in the context of assessment of KRAS mutations [ 167 , 176 ]. These false results can be due to poor management of one or several steps of the pre-analytical phase [ 176 , 195 ]. For example, a long period of cold ischemia, a long or short fixative time, can have consequences on false-negative molecular results due to DNA degradation or false-positive molecular results due to DNA deamination [ 176 , 195 ].…”

Section: Opportunities and Challenges For The Thoracic Pathologistsmentioning

confidence: 99%

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Daily Practice Assessment of KRAS Status in NSCLC Patients: A New Challenge for the Thoracic Pathologist Is Right around the Corner

Bontoux

Hofman

Brest

et al. 2022

Cancers

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KRAS mutations are among the most frequent genomic alterations identified in non-squamous non-small cell lung carcinomas (NS-NSCLC), notably in lung adenocarcinomas. In most cases, these mutations are mutually exclusive, with different genomic alterations currently known to be sensitive to therapies targeting EGFR, ALK, BRAF, ROS1, and NTRK. Recently, several promising clinical trials targeting KRAS mutations, particularly for KRAS G12C-mutated NSCLC, have established new hope for better treatment of patients. In parallel, other studies have shown that NSCLC harboring co-mutations in KRAS and STK11 or KEAP1 have demonstrated primary resistance to immune checkpoint inhibitors. Thus, the assessment of the KRAS status in advanced-stage NS-NSCLC has become essential to setting up an optimal therapeutic strategy in these patients. This stimulated the development of new algorithms for the management of NSCLC samples in pathology laboratories and conditioned reorganization of optimal health care of lung cancer patients by the thoracic pathologists. This review addresses the recent data concerning the detection of KRAS mutations in NSCLC and focuses on the new challenges facing pathologists in daily practice for KRAS status assessment.

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“…On the contrary, patients with KEAP1/NFE2L2 mutations had inferior survival compared with wild-type patients in subgroup analyses from several trials regarding immunotherapy [27][28][29]. Concurrent mutations with KEAP1/NFE2L2 may also affect patients' benefits from immunotherapy [30,31]. Moreover, Hellyer et al suggested that KEAP1/ NFE2L2 mutations might represent a mechanism of intrinsic resistance to EGFR-tyrosine kinase inhibitor therapy [32].…”

Section: Introductionmentioning

confidence: 99%

Multi-omics analysis identifies distinct subtypes with clinical relevance in lung adenocarcinoma harboring KEAP1/NFE2L2

Yang¹,

Li²,

Chen³

et al. 2022

J. Cancer

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Backgrounds:Lung adenocarcinoma is one of the most common malignant tumors, in which KEAP1-NFE2L2 pathway is altered frequently. The biological features and intrinsic heterogeneities of KEAP1/NFE2L2-mutant lung adenocarcinoma remain unclear. Methods: Multiplatform data from The Cancer Genome Atlas (TCGA) were acquired to identify two subtypes of lung adenocarcinoma harboring KEAP1/NFE2L2 mutations. Bioinformatic analyses, including immune microenvironment, methylation level and mutational signature, were performed to characterize the intrinsic heterogeneities. Meanwhile, initial results were validated by using in silico assessment of common lung adenocarcinoma cell lines, which revealed consistent features of mutant subtypes. Furthermore, drug sensitivity screening was conducted based on public datasets. Results: Two mutant subtypes (P1 and P2) of 89 patients were identified in TCGA. P2 patients had significantly higher levels of smoking and worse survival compared with P1 patients. The P2 subset was characterized by active immune microenvironment and more smoking-induced genomic alterations with respect to methylation and somatic mutations. Validations of the corresponding features in 20 mutant cell lines were achieved. Several compounds which were sensitive to mutant subtypes of lung adenocarcinoma were identified, such as inhibitors of PI3K/Akt and IGF1R signaling pathways. Conclusions: KEAP1/NFE2L2-mutant lung adenocarcinoma showed potential heterogeneities. The intrinsic heterogeneities of KEAP1/NFE2L2 were associated with immune microenvironment and smoking-related genomic aberrations.

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KEAP1 and TP53 Frame Genomic, Evolutionary, and Immunologic Subtypes of Lung Adenocarcinoma With Different Sensitivity to Immunotherapy

Cited by 36 publications

References 46 publications

An aging‐related signature predicts favorable outcome and immunogenicity in lung adenocarcinoma

An aging‐related signature predicts favorable outcome and immunogenicity in lung adenocarcinoma

Daily Practice Assessment of KRAS Status in NSCLC Patients: A New Challenge for the Thoracic Pathologist Is Right around the Corner

Multi-omics analysis identifies distinct subtypes with clinical relevance in lung adenocarcinoma harboring KEAP1/NFE2L2

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