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

Abstract

INTRODUCTION:

The connection between driver mutations and the efficacy of immune checkpoint inhibitors is the focus of intense investigations. In lung adenocarcinoma (LUAD), KEAP1/STK11 alterations have been tied to immunoresistance. Nevertheless, the heterogeneity characterizing immunotherapy efficacy suggests the contribution of still unappreciated events.

METHODS:

Somatic interaction analysis of top-ranking mutant genes in LUAD was carried out in the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) (N = 6208). Mutational processes, intratumor heterogeneity, evolutionary trajectories, immunologic features, and cancer-associated signatures were investigated, exploiting multiple data sets (AACR GENIE, The Cancer Genome Atlas [TCGA], TRAcking Cancer Evolution through therapy [Rx]). The impact of the proposed subtyping on survival outcomes was assessed in two independent cohorts of immune checkpoint inhibitor-treated patients: the tissue-based sequencing cohort (Rome/Memorial Sloan Kettering Cancer Center/Dana-Farber Cancer Institute, tissue-based next-generation sequencing [NGS] cohort, N = 343) and the blood-based sequencing cohort (OAK/POPLAR trials, blood-based NGS cohort, N = 304).

RESULTS:

Observing the neutral interaction between KEAP1 and TP53, KEAP1/TP53-based subtypes were dissected at the molecular and clinical levels. KEAP1 single-mutant (KEAP1 SM) and KEAP1/TP53 double-mutant (KEAP1/TP53 DM) LUAD share a transcriptomic profile characterized by the overexpression of AKR genes, which are under the control of a productive superenhancer with NEF2L2-binding signals. Nevertheless, KEAP1 SM and KEAP1/TP53 DM tumors differ by mutational repertoire, degree of intratumor heterogeneity, evolutionary trajectories, pathway-level signatures, and immune microenvironment composition. In both cohorts (blood-based NGS and tissue-based NGS), KEAP1 SM tumors had the shortest survival; the KEAP1/TP53 DM subgroup had an intermediate prognosis matching that of pure TP53 LUAD, whereas the longest survival was noticed in the double wild-type group.

CONCLUSIONS:

Our data provide a framework for genomically-informed immunotherapy, highlighting the importance of multimodal data integration to achieve a clinically exploitable taxonomy.

• Authors: Stefano Scalera, Marco Mazzotta, Giacomo Corleone, Francesca Sperati, Irene Terrenato, Eriseld Krasniqi, Laura Pizzuti, Maddalena Barba, Patrizia Vici, Enzo Gallo, Simonetta Buglioni, Paolo Visca, Edoardo Pescarmona, Daniele Marinelli, Francesca De Nicola, Ludovica Ciuffreda, Frauke Goeman, Maurizio Fanciulli, Raffaele Giusti, Andrea Vecchione, Ruggero De Maria, Federico Cappuzzo, Paolo Marchetti, Gennaro Ciliberto, Marcello Maugeri-Saccà
• Journal: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer (J Thorac Oncol) Vol. 16 Issue 12 Pg. 2065-2077 (12 2021) ISSN: 1556-1380 [Electronic] United States
• PMID: 34450259 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Chemical References

• KEAP1 protein, human
• Kelch-Like ECH-Associated Protein 1
• NF-E2-Related Factor 2
• TP53 protein, human
• Tumor Suppressor Protein p53

Topics

• Adenocarcinoma of Lung (genetics, therapy)
• Genomics
• Humans
• Immunotherapy
• Kelch-Like ECH-Associated Protein 1 (genetics, metabolism)
• Lung Neoplasms (genetics, therapy)
• Mutation
• NF-E2-Related Factor 2 (genetics, metabolism)
• Tumor Microenvironment
• Tumor Suppressor Protein p53 (genetics)