Details

Autor(en) / Beteiligte

• 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
• De Nicola, Francesca
• Ciuffreda, Ludovica
• Goeman, Frauke
• Fanciulli, Maurizio
• Giusti, Raffaele
• Vecchione, Andrea
• De Maria, Ruggero
• Cappuzzo, Federico
• Marchetti, Paolo
• Ciliberto, Gennaro
• Maugeri-Saccà, Marcello

Titel

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

Ist Teil von

• Journal of thoracic oncology, 2021-12, Vol.16 (12), p.2065-2077

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

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