Transcriptional phenocopies of deleterious<i>KEAP1</i>mutations dictate survival outcomes in lung cancer treated with immunotherapy
Abstract Mutational models denoting KEAP1-NRF2 pathway activation have emerged as determinants of survival outcomes in non-small cell lung cancer (NSCLC). Hypothesizing that genetically distinct tumors recapitulate the transcriptional footprint ofKEAP1mutations (KEAPness), we identified a KEAP1-NRF2-related gene set shared by tumors with and without pathway mutations. KEAPness-dominant tumors were associated with poor survival outcomes and immune exclusion in two independent cohorts of immunotherapy-treated NSCLC (SU2C and OAK/POPLAR). Moreover, patients with KEAPness tumors had survival outcomes comparable to theirKEAP1-mutant counterparts. In the TRACERx421, KEAPness exhibited limited transcriptional intratumoral heterogeneity and an immune-excluded microenvironment, as highlighted by orthogonal methods for T cell estimation. This phenotypic state widely occurred across genetically divergent tumors, exhibiting shared and private cancer genes under positive selection when compared toKEAP1-mutant tumors. Collectively, we discovered the pervasive nature of the KEAPness phenotypic driver across evolutionary divergent tumors. This model outperforms mutation-based classifiers in predicting survival outcomes..
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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 18. Dez. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Scalera, Stefano [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2023.10.30.23297743 |
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| PPN (Katalog-ID): |
XBI041364724 |
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| 520 | |a Abstract Mutational models denoting KEAP1-NRF2 pathway activation have emerged as determinants of survival outcomes in non-small cell lung cancer (NSCLC). Hypothesizing that genetically distinct tumors recapitulate the transcriptional footprint ofKEAP1mutations (KEAPness), we identified a KEAP1-NRF2-related gene set shared by tumors with and without pathway mutations. KEAPness-dominant tumors were associated with poor survival outcomes and immune exclusion in two independent cohorts of immunotherapy-treated NSCLC (SU2C and OAK/POPLAR). Moreover, patients with KEAPness tumors had survival outcomes comparable to theirKEAP1-mutant counterparts. In the TRACERx421, KEAPness exhibited limited transcriptional intratumoral heterogeneity and an immune-excluded microenvironment, as highlighted by orthogonal methods for T cell estimation. This phenotypic state widely occurred across genetically divergent tumors, exhibiting shared and private cancer genes under positive selection when compared toKEAP1-mutant tumors. Collectively, we discovered the pervasive nature of the KEAPness phenotypic driver across evolutionary divergent tumors. This model outperforms mutation-based classifiers in predicting survival outcomes. | ||
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| 700 | 1 | |a Marinelli, Daniele |4 aut | |
| 700 | 1 | |a Mazzotta, Marco |4 aut | |
| 700 | 1 | |a Cipriani, Laura |4 aut | |
| 700 | 1 | |a Bon, Giulia |4 aut | |
| 700 | 1 | |a Schiavoni, Giulia |4 aut | |
| 700 | 1 | |a Terrenato, Irene |4 aut | |
| 700 | 1 | |a Federico, Alessandro Di |4 aut | |
| 700 | 1 | |a Alessi, Joao V. |4 aut | |
| 700 | 1 | |a Fanciulli, Maurizio |4 aut | |
| 700 | 1 | |a Ciuffreda, Ludovica |4 aut | |
| 700 | 1 | |a Nicola, Francesca De |4 aut | |
| 700 | 1 | |a Goeman, Frauke |4 aut | |
| 700 | 1 | |a Caravagna, Giulio |4 aut | |
| 700 | 1 | |a Santini, Daniele |4 aut | |
| 700 | 1 | |a Maria, Ruggero De |4 aut | |
| 700 | 1 | |a Cappuzzo, Federico |4 aut | |
| 700 | 1 | |a Ciliberto, Gennaro |4 aut | |
| 700 | 1 | |a Jamal-Hanjani, Mariam |4 aut | |
| 700 | 1 | |a Awad, Mark M. |4 aut | |
| 700 | 1 | |a McGranahan, Nicholas |4 aut | |
| 700 | 1 | |a Maugeri-Saccà, Marcello |4 aut | |
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