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

被引：39

作者：

Scalera, Stefano ^{[1
]}

Mazzotta, Marco ^{[2
]}

Corleone, Giacomo ^{[1
]}

Sperati, Francesca ^{[3
]}

Terrenato, Irene ^{[4
]}

Krasniqi, Eriseld ^{[2
]}

Pizzuti, Laura ^{[2
]}

Barba, Maddalena ^{[2
]}

Vici, Patrizia ^{[2
]}

Gallo, Enzo ^{[5
]}

Buglioni, Simonetta ^{[5
]}

Visca, Paolo ^{[5
]}

Pescarmona, Edoardo ^{[5
]}

Marinelli, Daniele ^{[6
]}

De Nicola, Francesca ^{[1
]}

Ciuffreda, Ludovica ^{[1
]}

Goeman, Frauke ^{[1
]}

Fanciulli, Maurizio ^{[1
]}

Giusti, Raffaele ^{[7
]}

Vecchione, Andrea ^{[8
]}

De Maria, Ruggero ^{[9
,10
]}

Cappuzzo, Federico

Marchetti, Paolo ^{[6
,11
]}

Ciliberto, Gennaro ^{[12
]}

Maugeri-Sacca, Marcello ^{[2
]}

机构：

[1] Ist Ricovero & Cura Carattere Sci IRCCS, Regina Elena Natl Canc Inst, Dept Res Adv Diagnost & Technol Innovat, SAFU Lab, Rome, Italy

[2] Ist Ricovero & Cura Carattere Sci IRCCS, Regina Elena Natl Canc Inst, Div Med Oncol 2, Via Elio Chianesi 53, I-00144 Rome, Italy

[3] Ist Ricovero Cura Carattere Sci IRCCS, San Gallicano Dermatol Inst, Biostat Unit, Rome, Italy

[4] Ist Ricovero & Cura Carattere Sci IRCCS, Regina Elena Natl Canc Inst, Biostat Sci Direct, Rome, Italy

[5] Ist Ricovero & Cura Carattere Sci IRCCS, Regina Elena Natl Canc Inst, Dept Pathol, Rome, Italy

[6] Sapienza Univ, Policlin Umberto 1, Med Oncol Unit B, Rome, Italy

[7] StAndrea Hosp, Med Oncol Unit, Rome, Italy

[8] Sapienza Univ, StAndrea Hosp, Dept Clin & Mol Med, Pathol Unit, Rome, Italy

[9] Univ A Gemelli, Fdn Policlin, Ist Ricovero & Cura Carattere Sci IRCCS, Rome, Italy

[10] Univ Cattolica Sacro Cuore, Inst Gen Pathol, Rome, Italy

[11] Sapienza Univ, StAndrea Hosp, Dept Clin & Mol Med, Oncol Unit, Rome, Italy

[12] Ist Ricovero & Cura Carattere Sci IRCCS, Regina Elena Natl Canc Inst, Sci Direct, Rome, Italy

来源：

JOURNAL OF THORACIC ONCOLOGY | 2021年 / 16卷 / 12期

关键词：

KEAP1; TP53; Lung adenocarcinoma; Immunotherapy; PD-1; BLOCKADE; OPEN-LABEL; CANCER; MUTATIONS; ATEZOLIZUMAB; MULTICENTER; RESISTANCE; LANDSCAPE; DOCETAXEL;

D O I：

10.1016/j.jtho.2021.08.010

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 immu-noresistance. 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/DanaFarber 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 NEF2L2binding 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 genomicallyinformed immunotherapy, highlighting the importance of multimodal data integration to achieve a clinically exploitable taxonomy. (C) 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

引用

页码：2065 / 2077

页数：13

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