ArticleCell2025
Pan-cancer analysis of biallelic inactivation in tumor suppressor genes identifies KEAP1 zygosity as a predictive biomarker in lung cancer.
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Article in Cell, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Tumor cell-intrinsic stress states drive sensitivity to CAR T cell therapy in pancreatic cancer.Science advances · 2026Article
- SMARCA4, STK11, and KEAP1 co-inactivation associates with poor prognosis and upregulation of the TGF-β pathway in lung adenocarcinoma.Translational oncology · 2026Article
- Gene mutant dosage is associated with prognosis and metastatic tropism in 60,000 clinical cancer samples.Nature genetics · 2026Article
- Histone deacetylase enzyme activity is not the universal anticancer target of HDAC inhibitors.Signal transduction and targeted therapy · 2026Article
- Cancer type-specific variation in patterns of driver alterations across 50,000 tumors.Cancer cell · 2026Article
- Genomic Features and Response to Poly(ADP-ribose) Polymerase Inhibition in Metastatic Castration-Resistant Prostate Cancer.JCO precision oncology · 2026Observational
- Chronic stress, gut microbiota, and immunity: interconnections and implications for health.Molecular and cellular biochemistry · 2025Review
- Somatic DICER1 pathogenic variants detected in a well-differentiated fetal lung adenocarcinoma diagnosed in a man with familial adenomatous polyposis.BJC reports · 2025Article
- A functional map of CDK-drug interactions at single amino acid resolution.bioRxiv : the preprint server for biology · 2025Article
- Involvement of KEAP1/NRF2 pathway in non-BRAF mutated squamous cell carcinoma of the thyroid.The Journal of pathology · 2025Article
- Half the Chromosome It Used to Be: Identifying Cancer Treatments Targeting Aneuploid Losses.Genes · 2025Article
- MultiplexedbioRxiv : the preprint server for biology · 2025Article
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Authors and funding
28 authors.
Mark ZuckerComputational Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Maria A PerryMarie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Samuel I GouldDepartment of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
Arielle ElkriefDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Anton SafonovDepartment of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Rohit ThummalapalliDepartment of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Miika MehineDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Debyani ChakravartyMarie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
A Rose BrannonDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Marc LadanyiDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Pedram RazaviDepartment of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Mark T A DonoghueMarie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Yonina R Murciano-GoroffDepartment of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Kristiana GrigoriadisCancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London, London, UK; Cancer Genome Evolution Research Group, University College London Cancer Institute, London, UK.
Nicholas McGranahanCancer Research UK Lung Cancer Centre of Excellence, University College London, London, UK; Cancer Genome Evolution Research Group, University College London Cancer Institute, London, UK.
Mariam Jamal-HanjaniCancer Research UK Lung Cancer Centre of Excellence, University College London, London, UK; Cancer Metastasis Laboratory, University College London Cancer Institute, London, UK; Department of Medical Oncology, University College London Hospitals, London, UK.
Charles SwantonCancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London, London, UK; Department of Medical Oncology, University College London Hospitals, London, UK.
Yuan ChenDepartment of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Ronglai ShenDepartment of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Sarat ChandarlapatyDepartment of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
David B SolitMarie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nikolaus SchultzComputational Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
Michael F BergerComputational Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
Jason ChangDepartment of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Adam J SchoenfeldDepartment of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Francisco J Sánchez-RiveraDepartment of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
Ed ReznikComputational Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: reznike@mskcc.org.
Chaitanya BandlamudiMarie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: bandlamc@mskcc.org.
Funding
X-RAY CRYSTALLOGRAPHYP30CA008748 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI Hongbiao Carl Lekaye · 1985 to 2026
$347.4MVIRUS PRODUCTION COREP30CA014051 · NCI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI Paula T Hammond · 1985 to 2026
$93.9MTargeting Polθ to Overcome PARP Inhibitor Resistance in Homologous Recombination Deficient Breast CancerP50CA247749 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI Simon N. Powell · 2020 to 2026
$16.3MInvestigational Cancer Therapeutics Training Program (ICTTP)T32CA009207 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI Omar Abdel-Wahab, Alexander Drilon · 1985 to 2026
$13.7MPre-doctoral Training in Fundamental Approaches to Biochemistry and Cell and Molecular BiologyT32GM136540 · NIGMS · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI Mary Gehring, Michael Laub · 2021 to 2026
$9.5MMSK Paul Calabresi Career Development Award for Clinical OncologyK12CA184746 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI Omar Abdel-Wahab, Simon N. Powell · 2015 to 2026
$8.3MMutant p53 in Tumorigenesis, Invasion, and MetastasisP01CA291694 · NCI · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI James J Manfredi · 2025 to 2026
$7.9MDefining the function of Complex I truncating mutations in cancerR37CA276200 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI Payam Gammage, Eduard Reznik · 2023 to 2026
$2.5MDefining mechanisms of resistance to hormonal therapy in breast cancerR01CA234361 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI CHANDARLAPATY, SARAT, SOLIT, DAVID B. · 2019 to 2023
$2.0MNCI NIH HHS K12 CA184746NCI NIH HHS P01 CA291694NCI NIH HHS P30 CA008748NCI NIH HHS P30 CA014051NCI NIH HHS P50 CA247749NCI NIH HHS R01 CA234361NCI NIH HHS R37 CA276200NCI NIH HHS T32 CA009207NIGMS NIH HHS T32 GM136540
Abstract
The canonical model of tumor suppressor gene (TSG)-mediated oncogenesis posits that loss of both alleles is necessary for inactivation. Here, through allele-specific analysis of sequencing data from 48,179 cancer patients, we define the prevalence, selective pressure for, and functional consequences of biallelic inactivation across TSGs. TSGs largely assort into distinct classes associated with either pan-cancer (Class 1) or lineage-specific (Class 2) patterns of selection for biallelic loss, although some TSGs are predominantly monoallelically inactivated (Class 3/4). We demonstrate that selection for biallelic inactivation can be utilized to identify driver genes in non-canonical contexts, including among variants of unknown significance (VUSs) of several TSGs such as KEAP1. Genomic, functional, and clinical data collectively indicate that KEAP1 VUSs phenocopy established KEAP1 oncogenic alleles and that zygosity, rather than variant classification, is predictive of therapeutic response. TSG zygosity is therefore a fundamental determinant of disease etiology and therapeutic sensitivity.
Indexed as
Biomarkers, TumorGenes, Tumor SuppressorKelch-Like ECH-Associated Protein 1Lung NeoplasmsAllelesHumansBiomarkers, TumorKEAP1 protein, humanKelch-Like ECH-Associated Protein 1biallelic inactivationbiallelic losscancer genomicsclinical sequencingKEAP1Knudson's two-hitlung cancerpancancerpredictive biomarkerstumor suppressor genes
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