Precision proteogenomics reveals pan-cancer impact of germline variants
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.
Authors
- Gad A. Getz (ORCID: https://orcid.org/0000-0002-0936-0753)
- Yifat Geffen (ORCID: https://orcid.org/0000-0003-3692-4689)
- Karl R. Clauser (ORCID: https://orcid.org/0000-0002-1052-9456)
- Myvizhi Esai Selvan (ORCID: https://orcid.org/0000-0003-4640-5727)
- Berk Turhan (ORCID: https://orcid.org/0000-0002-6471-0357)
- Song Cao (ORCID: https://orcid.org/0000-0002-3231-6136)
- Karsten Krug
- Robert J. Klein (ORCID: https://orcid.org/0000-0003-3539-5391)
- D.R. Mani (ORCID: https://orcid.org/0000-0003-3914-133X)
- Yo Akiyama (ORCID: https://orcid.org/0000-0001-6662-1289)
- Felipe da Veiga Leprevost (ORCID: https://orcid.org/0000-0002-8228-5374)
- Kuan‐lin Huang (ORCID: https://orcid.org/0000-0002-5537-5817)
- Isabel Mendizabal (ORCID: https://orcid.org/0000-0002-9018-3474)
- Steven A. Carr (ORCID: https://orcid.org/0000-0002-7203-4299)
- Antonio Colaprico (ORCID: https://orcid.org/0000-0003-1044-4361)
- Erik Storrs (ORCID: https://orcid.org/0000-0002-8041-0864)
- Emily Kawaler (ORCID: https://orcid.org/0000-0002-7438-7282)
- Zeynep H. Gümüş (ORCID: https://orcid.org/0000-0002-7364-2202)
- Akshay Govindan (ORCID: https://orcid.org/0009-0000-7582-6198)
- A Gaite-Reguero (ORCID: https://orcid.org/0009-0004-4885-3472)
- Nadezhda V. Terekhanova (ORCID: https://orcid.org/0000-0001-8711-4649)
- Alexander J. Lazar (ORCID: https://orcid.org/0000-0002-6395-4499)
- Matthew H. Bailey (ORCID: https://orcid.org/0000-0003-4526-9727)
- Lewis C. Cantley (ORCID: https://orcid.org/0000-0002-1298-7653)
- Tomer M. Yaron (ORCID: https://orcid.org/0000-0001-6574-7314)
- Michael A. Gillette (ORCID: https://orcid.org/0000-0001-9300-1448)
- David Fenyö (ORCID: https://orcid.org/0000-0001-5049-3825)
- Kathleen J. Imbach (ORCID: https://orcid.org/0000-0002-3861-7845)
- Yize Li (ORCID: https://orcid.org/0000-0003-1074-281X)
- Ana I. Robles (ORCID: https://orcid.org/0000-0001-5019-4374)
- Fernanda Martins Rodrigues (ORCID: https://orcid.org/0000-0002-2140-0690)
- François Aguet (ORCID: https://orcid.org/0000-0001-9414-300X)
- Antonio Iavarone (ORCID: https://orcid.org/0000-0002-0683-4634)
- Eduard Porta‐Pardo (ORCID: https://orcid.org/0000-0001-7900-4239)
- Myranda Maynard
- Alexey I. Nesvizhskii (ORCID: https://orcid.org/0000-0002-2806-7819)
- Urko M. Marigorta (ORCID: https://orcid.org/0000-0002-9087-6609)
- Jun Li (ORCID: https://orcid.org/0000-0002-1171-7141)
- Chandan Kumar‐Sinha (ORCID: https://orcid.org/0000-0002-8696-3400)
- Matthew A. Wyczalkowski
- Olivia S Gonda
Institutions
- Brigham Young University (US)
- Broad Institute (US)
- Ikerbasque (ES)
- The University of Texas MD Anderson Cancer Center (US)
- University of Miami (US)
- Washington University in St. Louis (US)
- Cornell University (US)
- University of Michigan (US)
- Institute for Systems Biology (US)
- NYU Langone Health (US)
- Josep Carreras Leukaemia Research Institute (ES)
- University of Miami Health System (US)
- CIC bioGUNE (ES)
- Michigan Medicine (US)
- Dana-Farber Cancer Institute (US)
- Michigan Center for Translational Pathology (US)
- Cancer Clinic (US)
- National Cancer Institute (US)
- Sylvester Comprehensive Cancer Center (US)
- Universitat Politècnica de Catalunya (ES)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Cell
- Published
- 2025-04-14
- DOI
- https://doi.org/10.1016/j.cell.2025.03.026
- Citations
- 4
- Primary Topic
- Cancer Genomics and Diagnostics
- Type
- article
- Field-Weighted Citation Impact
- 3.75
Funders
- National Institutes of Health
- National Human Genome Research Institute
- National Cancer Institute