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Published on: January 19, 2019
KEAP1 and TP53 Frame Genomic, Evolutionary, and Immunologic Subtypes of Lung Adenocarcinoma With Different
Stefano Scalera1, Marco Mazzotta2, Giacomo Corleone1
1SAFU Laboratory, Department of Research, Advanced Diagnostic, and Technological Innovation, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Regina Elena National Cancer Institute, Rome, Italy.
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.
Insights
Investigating KEAP1/TP53 mutations in lung adenocarcinoma reveals distinct subtypes with varying survival outcomes. KEAP1 single-mutant tumors show the shortest survival, while double wild-type offers the longest, guiding immunotherapy strategies.
Area of Science:
- Oncology
- Genomics
- Immunotherapy
Background:
- Driver mutations significantly influence immune checkpoint inhibitor (ICI) efficacy in lung adenocarcinoma (LUAD).
- KEAP1 and STK11 alterations are linked to immunoresistance in LUAD.
- Tumor heterogeneity suggests unappreciated factors impact immunotherapy response.
Purpose of the Study:
- To investigate the molecular and clinical impact of KEAP1/TP53 alterations in LUAD.
- To define novel LUAD subtypes based on KEAP1 and TP53 mutational status.
- To assess the prognostic value of these subtypes in ICI-treated patients.
Main Methods:
- Somatic interaction analysis of LUAD mutations using AACR Project GENIE data (N=6208).
- Integration of multiple datasets (AACR GENIE, TCGA, TRACERx) for mutational processes, heterogeneity, evolution, and immune features.
- Prognostic evaluation in independent tissue-based (N=343) and blood-based (N=304) ICI-treated LUAD cohorts.
Main Results:
- KEAP1/TP53-based subtypes were identified, sharing AKR gene overexpression but differing in mutational repertoire, heterogeneity, and immune microenvironment.
- KEAP1 single-mutant (KEAP1 SM) LUAD exhibited the shortest survival.
- KEAP1/TP53 double-mutant (KEAP1/TP53 DM) LUAD showed intermediate survival, similar to TP53-mutant LUAD, while double wild-type had the longest survival.
Conclusions:
- Genomic subtyping of LUAD based on KEAP1/TP53 interactions provides a framework for immunotherapy.
- Multimodal data integration is crucial for developing clinically actionable cancer taxonomies.
- Distinct LUAD subtypes have differential prognoses in response to ICI therapy.
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