ArticleCell2025
Precision proteogenomics reveals pan-cancer impact of germline variants.
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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 5 papers.
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5citing papers in PubMed
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Who cites it
5 citing papers in PubMed.
- Targeting Phosphatidylserine Synthesis for Tumor Cell Suppression in Esophageal Squamous Cell Carcinoma and Glioblastoma.International journal of molecular sciences · 2026Article
- Global impact of germline structural variation on the cancer proteome.Nature communications · 2026Article
- Identification of Potential Biomarkers and Drugs for Papillary Thyroid Carcinoma Using Computational Analysis and Molecular Docking.Current medicinal chemistry · 2026Article
- Translating Liquid Biopsy into Practice- The Promise and Challenges of Circulating Tumor Cells in Ovarian and Lung Cancer Management.Biomarker insights · 2026Review
- Review
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Authors and funding
42 authors.
Fernanda Martins RodriguesDepartment of Medicine, Washington University in St. Louis, Saint Louis, MO, USA; McDonnell Genome Institute, Washington University in St. Louis, Saint Louis, MO, USA; Department of Genetics, Washington University in St. Louis, St. Louis, MO 63110, USA.
Nadezhda V TerekhanovaDepartment of Medicine, Washington University in St. Louis, Saint Louis, MO, USA; McDonnell Genome Institute, Washington University in St. Louis, Saint Louis, MO, USA; Department of Genetics, Washington University in St. Louis, St. Louis, MO 63110, USA.
Kathleen J ImbachJosep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Spain; Universitat Autonoma de Barcelona, Barcelona, Spain.
Karl R ClauserBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Myvizhi Esai SelvanDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Thoracic Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Isabel MendizabalCenter for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain; Translational Prostate Cancer Research Lab, CIC bioGUNE-Basurto, Biocruces Bizkaia Health Research Institute, Derio, Spain.
Yifat GeffenBroad Institute of MIT and Harvard, Cambridge, MA, USA; Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
Yo AkiyamaBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Myranda MaynardBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Tomer M YaronMeyer Cancer Center, Department of Medicine, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA.
Yize LiDepartment of Medicine, Washington University in St. Louis, Saint Louis, MO, USA; McDonnell Genome Institute, Washington University in St. Louis, Saint Louis, MO, USA; Department of Genetics, Washington University in St. Louis, St. Louis, MO 63110, USA.
Song CaoDepartment of Medicine, Washington University in St. Louis, Saint Louis, MO, USA; McDonnell Genome Institute, Washington University in St. Louis, Saint Louis, MO, USA; Department of Genetics, Washington University in St. Louis, St. Louis, MO 63110, USA.
Erik P StorrsDepartment of Medicine, Washington University in St. Louis, Saint Louis, MO, USA; McDonnell Genome Institute, Washington University in St. Louis, Saint Louis, MO, USA; Department of Genetics, Washington University in St. Louis, St. Louis, MO 63110, USA.
Olivia S GondaDepartment of Biology, Brigham Young University, Salt Lake City, UT, USA.
Adrian Gaite-RegueroCenter for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain.
Akshay GovindanDepartment of Medicine, Washington University in St. Louis, Saint Louis, MO, USA; McDonnell Genome Institute, Washington University in St. Louis, Saint Louis, MO, USA; Department of Genetics, Washington University in St. Louis, St. Louis, MO 63110, USA.
Emily A KawalerApplied Bioinformatics Laboratories, New York University Langone Health, New York City, NY, USA.
Matthew A WyczalkowskiDepartment of Medicine, Washington University in St. Louis, Saint Louis, MO, USA; McDonnell Genome Institute, Washington University in St. Louis, Saint Louis, MO, USA; Department of Genetics, Washington University in St. Louis, St. Louis, MO 63110, USA.
Robert J KleinDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Berk TurhanDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Karsten KrugBroad Institute of MIT and Harvard, Cambridge, MA, USA.
D R ManiBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Felipe da Veiga LeprevostDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
Alexey I NesvizhskiiDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
Steven A CarrBroad Institute of MIT and Harvard, Cambridge, MA, USA.
David FenyöInstitute for Systems Genetics, NYU Grossman School of Medicine, New York, NY, USA.
Michael A GilletteBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Antonio ColapricoDepartment of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, USA; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
Antonio IavaroneSylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Neurological Surgery, Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, Miami, FL, USA.
Ana I RoblesOffice of Cancer Clinical Proteomics Research, National Cancer Institute, Rockville, MD, USA.
Kuan-Lin HuangDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Transformative Disease Modeling, Tisch Cancer Institute, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Chandan Kumar-SinhaDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
François AguetBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Alexander J LazarDepartments of Pathology and Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Lewis C CantleyDana Farber Cancer Institute, Boston, MA, USA.
Urko M MarigortaCenter for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
Zeynep H GümüşDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Thoracic Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: zeynep.gumus@mssm.edu.
Matthew H BaileyDepartment of Biology, Brigham Young University, Salt Lake City, UT, USA. Electronic address: matthew.bailey@byu.edu.
Gad GetzBroad Institute of MIT and Harvard, Cambridge, MA, USA; Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: gadgetz@broadinstitute.org.
Eduard Porta-PardoJosep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Spain; Barcelona Supercomputing Center (BSC), Barcelona, Spain. Electronic address: eporta@carrerasresearch.org.
Li DingDepartment of Medicine, Washington University in St. Louis, Saint Louis, MO, USA; McDonnell Genome Institute, Washington University in St. Louis, Saint Louis, MO, USA; Department of Genetics, Washington University in St. Louis, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University in St. Louis, Saint Louis, MO, USA. Electronic address: lding@wustl.edu.
Clinical Proteomic Tumor Analysis Consortium
Funding
Role of Phosphoinositides and Protein Kinases in the control of Cancer MetabolismR35CA197588 · NCI · WEILL MEDICAL COLL OF CORNELL UNIV · PI LEWIS C. CANTLEY · 2016 to 2026
$10.2MProteogenomic Studies aimed at understanding ovarian tumor responses to agents targeting the DNA damage response and translating this knowledge into clinical benefitU01CA214114 · NCI · FRED HUTCHINSON CANCER RESEARCH CENTER · PI BIRRER, MICHAEL, PAULOVICH, AMANDA G · 2017 to 2021
$8.4MMICROSCALED PROTEOGENOMICS FOR CANCER CLINICAL TRIALSU01CA214125 · NCI · BAYLOR COLLEGE OF MEDICINE · PI ANURAG, MEENAKSHI, CARR, STEVEN A · 2017 to 2021
$7.0MProteogenomic Translational Research Center for Clinical ProteomicU01CA214116 · NCI · BATTELLE PACIFIC NORTHWEST LABORATORIES · PI DRUKER, BRIAN J, RODLAND, KARIN D · 2017 to 2021
$6.8MCenter for Advanced Multi-Omic Characterization of CancerU24CA271012 · NCI · BATTELLE PACIFIC NORTHWEST LABORATORIES · PI Tao Liu · 2022 to 2026
$6.6MCenter of Excellence for High Throughput Proteogenomic CharacterizationU24CA210986 · NCI · BROAD INSTITUTE, INC. · PI CARR, STEVEN A, GILLETTE, MICHAEL A · 2016 to 2020
$6.4MCenter of Excellence for High Throughput Proteogenomic CharacterizationU24CA270823 · NCI · BROAD INSTITUTE, INC. · PI STEVEN A CARR, MICHAEL A GILLETTE · 2022 to 2026
$5.3MThe Comprehensive Proteome Characterization Center at Johns Hopkins: High Precision Discovery and Confirmation of Genoproteomic TargetsU24CA210985 · NCI · JOHNS HOPKINS UNIVERSITY · PI CHAN, DANIEL WANYUI, ZHANG, HUI · 2016 to 2020
$5.3MPNNL Proteome Characterization CenterU24CA210955 · NCI · BATTELLE PACIFIC NORTHWEST LABORATORIES · PI LIU, TAO, SMITH, RICHARD D · 2016 to 2020
$5.3MOncogenic mechanisms, molecular stratification and therapeutic targets of brain tumorsR35CA253183 · NCI · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI Antonio Iavarone · 2021 to 2026
$5.2MProteogenomic translator for cancer biomarker discovery towards precision medicineU24CA271114 · NCI · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI Avi Ma'ayan, Pei Wang · 2022 to 2026
$5.0MiPGDAC, An Integrative Proteogenomic Data Analysis Center for CPTACU24CA210954 · NCI · BAYLOR COLLEGE OF MEDICINE · PI ZHANG, BING · 2016 to 2020
$4.9MNCI NIH HHS HHSN261201500003CNCI NIH HHS HHSN261201500003INCI NIH HHS R33 CA263705NCI NIH HHS R35 CA197588NCI NIH HHS R35 CA253183NCI NIH HHS U01 CA214114NCI NIH HHS U01 CA214116NCI NIH HHS U01 CA214125NCI NIH HHS U24 CA210954NCI NIH HHS U24 CA210955NCI NIH HHS U24 CA210967NCI NIH HHS U24 CA210972NCI NIH HHS U24 CA210979NCI NIH HHS U24 CA210985NCI NIH HHS U24 CA210986NCI NIH HHS U24 CA210993NCI NIH HHS U24 CA211006NCI NIH HHS U24 CA270823NCI NIH HHS U24 CA271012NCI NIH HHS U24 CA271075NCI NIH HHS U24 CA271114NHGRI NIH HHS R01 HG009711NIGMS NIH HHS R35 GM138113NIH HHS S10 OD030463
Abstract
We investigate the impact of germline variants on cancer patients' proteomes, encompassing 1,064 individuals across 10 cancer types. We introduced an approach, "precision peptidomics," mapping 337,469 coding germline variants onto peptides from patients' mass spectrometry data, revealing their potential impact on post-translational modifications, protein stability, allele-specific expression, and protein structure by leveraging the relevant protein databases. We identified rare pathogenic and common germline variants in cancer genes potentially affecting proteomic features, including variants altering protein abundance and structure and variants in kinases (ERBB2 and MAP2K2) impacting phosphorylation. Precision peptidome analysis predicted destabilizing events in signal-regulatory protein alpha (SIRPA) and glial fibrillary acid protein (GFAP), relevant to immunomodulation and glioblastoma diagnostics, respectively. Genome-wide association studies identified quantitative trait loci for gene expression and protein levels, spanning millions of SNPs and thousands of proteins. Polygenic risk scores correlated with distal effects from risk variants. Our findings emphasize the contribution of germline genetics to cancer heterogeneity and high-throughput precision peptidomics.
Indexed as
Germ-Line MutationNeoplasmsProteogenomicsErb-b2 Receptor Tyrosine KinasesGenome-Wide Association StudyHumansPolymorphism, Single NucleotideProtein Processing, Post-TranslationalProteomeQuantitative Trait LociErb-b2 Receptor Tyrosine KinasesProteomeCPTACgermlinepan-cancerprecision peptidomicsproteogenomics
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