Precision proteogenomics reveals pan-cancer impact of germline variants

doi:10.1016/j.cell.2025.03.026

. 2025 May 1;188(9):2312-2335.e26.

doi: 10.1016/j.cell.2025.03.026. Epub 2025 Apr 14.

Precision proteogenomics reveals pan-cancer impact of germline variants

Fernanda Martins Rodrigues¹, Nadezhda V Terekhanova¹, Kathleen J Imbach², Karl R Clauser³, Myvizhi Esai Selvan⁴, Isabel Mendizabal⁵, Yifat Geffen⁶, Yo Akiyama³, Myranda Maynard³, Tomer M Yaron⁷, Yize Li¹, Song Cao¹, Erik P Storrs¹, Olivia S Gonda⁸, Adrian Gaite-Reguero⁹, Akshay Govindan¹, Emily A Kawaler¹⁰, Matthew A Wyczalkowski¹, Robert J Klein¹¹, Berk Turhan¹¹, Karsten Krug³, D R Mani³, Felipe da Veiga Leprevost¹², Alexey I Nesvizhskii¹³, Steven A Carr³, David Fenyö¹⁴, Michael A Gillette³, Antonio Colaprico¹⁵, Antonio Iavarone¹⁶, Ana I Robles¹⁷, Kuan-Lin Huang¹⁸, Chandan Kumar-Sinha¹⁹, François Aguet³, Alexander J Lazar²⁰, Lewis C Cantley²¹, Urko M Marigorta²², Zeynep H Gümüş²³, Matthew H Bailey²⁴, Gad Getz²⁵, Eduard Porta-Pardo²⁶, Li Ding²⁷; Clinical Proteomic Tumor Analysis Consortium

Collaborators, Affiliations

Collaborators

Clinical Proteomic Tumor Analysis Consortium:
Eunkyung An, Meenakshi Anurag, Jasmin Bavarva, Chet Birger, Michael J Birrer, Anna P Calinawan, Michele Ceccarelli, Daniel W Chan, Arul M Chinnaiyan, Hanbyul Cho, Shrabanti Chowdhury, Marcin P Cieslik, Daniel Cui Zhou, Corbin Day, Marcin J Domagalski, Yongchao Dou, Brian J Druker, Nathan Edwards, Matthew J Ellis, Steven M Foltz, Alicia Francis, Tania J Gonzalez Robles, Sara J C Gosline, Runyu Hong, Galen Hostetter, Yingwei Hu, Tara Hiltke, Chen Huang, Emily Huntsman, Eric J Jaehnig, Scott D Jewell, Jiayi Ji, Wen Jiang, Lizabeth Katsnelson, Karen A Ketchum, Iga Kolodziejczak, Jonathan T Lei, Yuxing Liao, Caleb M Lindgren, Tao Liu, Weiping Ma, Wilson McKerrow, Chelsea J Newton, Robert Oldroyd, Gilbert S Omenn, Amanda G Paulovich, Francesca Petralia, Boris Reva, Karin D Rodland, Henry Rodriguez, Kelly V Ruggles, Dmitry Rykunov, Sara R Savage, Eric E Schadt, Michael Schnaubelt, Tobias Schraink, Zhiao Shi, Richard D Smith, Xiaoyu Song, Yizhe Song, Jimin Tan, Ratna R Thangudu, Nicole Tignor, Joshua M Wang, Pei Wang, Ying Wang, Bo Wen, Maciej Wiznerowicz, Xinpei Yi, Bing Zhang, Hui Zhang, Xu Zhang, Zhen Zhang, David I Heiman, Jared L Johnson, Liang-Bo Wang, Lijun Yao, Mathangi Thiagarajan, Mehdi Mesri, Özgün Babur, Pietro Pugliese, Qing Zhang, Samuel H Payne, Saravana M Dhanasekaran, Shankara Anand, Shankha Satpathy, Stephan Schürer, Vasileios Stathias, Wen-Wei Liang, Wenke Liu, Yige Wu

Affiliations

¹ Department 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.
² Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Spain; Universitat Autonoma de Barcelona, Barcelona, Spain.
³ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Department 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.
⁵ Center 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.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
⁷ Meyer Cancer Center, Department of Medicine, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA.
⁸ Department of Biology, Brigham Young University, Salt Lake City, UT, USA.
⁹ Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain.
¹⁰ Applied Bioinformatics Laboratories, New York University Langone Health, New York City, NY, USA.
¹¹ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹² Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
¹³ Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
¹⁴ Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY, USA.
¹⁵ Department 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.
¹⁶ Sylvester 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.
¹⁷ Office of Cancer Clinical Proteomics Research, National Cancer Institute, Rockville, MD, USA.
¹⁸ Department 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.
¹⁹ Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
²⁰ Departments of Pathology and Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
²¹ Dana Farber Cancer Institute, Boston, MA, USA.
²² Center 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.
²³ Department 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.
²⁴ Department of Biology, Brigham Young University, Salt Lake City, UT, USA. Electronic address: matthew.bailey@byu.edu.
²⁵ Broad 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.
²⁶ Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Spain; Barcelona Supercomputing Center (BSC), Barcelona, Spain. Electronic address: eporta@carrerasresearch.org.
²⁷ Department 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.

PMID: 40233739
PMCID: PMC12326532 (available on 2026-05-01)
DOI: 10.1016/j.cell.2025.03.026

Precision proteogenomics reveals pan-cancer impact of germline variants

Fernanda Martins Rodrigues et al. Cell. 2025.

. 2025 May 1;188(9):2312-2335.e26.

doi: 10.1016/j.cell.2025.03.026. Epub 2025 Apr 14.

Authors

Collaborators

Clinical Proteomic Tumor Analysis Consortium:
Eunkyung An, Meenakshi Anurag, Jasmin Bavarva, Chet Birger, Michael J Birrer, Anna P Calinawan, Michele Ceccarelli, Daniel W Chan, Arul M Chinnaiyan, Hanbyul Cho, Shrabanti Chowdhury, Marcin P Cieslik, Daniel Cui Zhou, Corbin Day, Marcin J Domagalski, Yongchao Dou, Brian J Druker, Nathan Edwards, Matthew J Ellis, Steven M Foltz, Alicia Francis, Tania J Gonzalez Robles, Sara J C Gosline, Runyu Hong, Galen Hostetter, Yingwei Hu, Tara Hiltke, Chen Huang, Emily Huntsman, Eric J Jaehnig, Scott D Jewell, Jiayi Ji, Wen Jiang, Lizabeth Katsnelson, Karen A Ketchum, Iga Kolodziejczak, Jonathan T Lei, Yuxing Liao, Caleb M Lindgren, Tao Liu, Weiping Ma, Wilson McKerrow, Chelsea J Newton, Robert Oldroyd, Gilbert S Omenn, Amanda G Paulovich, Francesca Petralia, Boris Reva, Karin D Rodland, Henry Rodriguez, Kelly V Ruggles, Dmitry Rykunov, Sara R Savage, Eric E Schadt, Michael Schnaubelt, Tobias Schraink, Zhiao Shi, Richard D Smith, Xiaoyu Song, Yizhe Song, Jimin Tan, Ratna R Thangudu, Nicole Tignor, Joshua M Wang, Pei Wang, Ying Wang, Bo Wen, Maciej Wiznerowicz, Xinpei Yi, Bing Zhang, Hui Zhang, Xu Zhang, Zhen Zhang, David I Heiman, Jared L Johnson, Liang-Bo Wang, Lijun Yao, Mathangi Thiagarajan, Mehdi Mesri, Özgün Babur, Pietro Pugliese, Qing Zhang, Samuel H Payne, Saravana M Dhanasekaran, Shankara Anand, Shankha Satpathy, Stephan Schürer, Vasileios Stathias, Wen-Wei Liang, Wenke Liu, Yige Wu

Affiliations

¹ Department 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.
² Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Spain; Universitat Autonoma de Barcelona, Barcelona, Spain.
³ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Department 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.
⁵ Center 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.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
⁷ Meyer Cancer Center, Department of Medicine, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA.
⁸ Department of Biology, Brigham Young University, Salt Lake City, UT, USA.
⁹ Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Spain.
¹⁰ Applied Bioinformatics Laboratories, New York University Langone Health, New York City, NY, USA.
¹¹ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹² Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
¹³ Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
¹⁴ Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY, USA.
¹⁵ Department 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.
¹⁶ Sylvester 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.
¹⁷ Office of Cancer Clinical Proteomics Research, National Cancer Institute, Rockville, MD, USA.
¹⁸ Department 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.
¹⁹ Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
²⁰ Departments of Pathology and Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
²¹ Dana Farber Cancer Institute, Boston, MA, USA.
²² Center 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.
²³ Department 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.
²⁴ Department of Biology, Brigham Young University, Salt Lake City, UT, USA. Electronic address: matthew.bailey@byu.edu.
²⁵ Broad 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.
²⁶ Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Spain; Barcelona Supercomputing Center (BSC), Barcelona, Spain. Electronic address: eporta@carrerasresearch.org.
²⁷ Department 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.

PMID: 40233739
PMCID: PMC12326532 (available on 2026-05-01)
DOI: 10.1016/j.cell.2025.03.026

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.

Keywords: CPTAC; germline; pan-cancer; precision peptidomics; proteogenomics.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Cited by

The Primary Role of Noncoding RNA in the Pathogenesis of Cancer.
Shah A. Shah A. Genes (Basel). 2025 Jun 30;16(7):771. doi: 10.3390/genes16070771. Genes (Basel). 2025. PMID: 40725427 Free PMC article. Review.

References

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[1] Robson M, Im S-A, Senkus E, Xu B, Domchek SM, Masuda N, Delaloge S, Li W, Tung N, Armstrong A, et al. (2017). Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N. Engl. J. Med 377, 523–533. 10.1056/NEJMoa1706450. - DOI - PubMed

[2] Robson M, Im S-A, Senkus E, Xu B, Domchek SM, Masuda N, Delaloge S, Li W, Tung N, Armstrong A, et al. (2017). Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N. Engl. J. Med 377, 523–533. 10.1056/NEJMoa1706450. - DOI - PubMed

[3] Villani A, Tabori U, Schiffman J, Shlien A, Beyene J, Druker H, Novokmet A, Finlay J, and Malkin D. (2011). Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol. 12, 559–567. 10.1016/S1470-2045(11)70119-X. - DOI - PubMed

[4] Villani A, Tabori U, Schiffman J, Shlien A, Beyene J, Druker H, Novokmet A, Finlay J, and Malkin D. (2011). Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol. 12, 559–567. 10.1016/S1470-2045(11)70119-X. - DOI - PubMed

[5] Robson M, and Offit K. (2007). Clinical practice. Management of an inherited predisposition to breast cancer. N. Engl. J. Med 357, 154–162. 10.1056/NEJMcp071286. - DOI - PubMed

[6] Robson M, and Offit K. (2007). Clinical practice. Management of an inherited predisposition to breast cancer. N. Engl. J. Med 357, 154–162. 10.1056/NEJMcp071286. - DOI - PubMed

[7] Galiatsatos P, and Foulkes WD (2006). Familial adenomatous polyposis. Am. J. Gastroenterol 101, 385–398. 10.1111/j.1572-0241.2006.00375.x. - DOI - PubMed

[8] Galiatsatos P, and Foulkes WD (2006). Familial adenomatous polyposis. Am. J. Gastroenterol 101, 385–398. 10.1111/j.1572-0241.2006.00375.x. - DOI - PubMed

[9] Rahman N. (2014). Realizing the promise of cancer predisposition genes. Nature 505, 302–308. 10.1038/nature12981. - DOI - PMC - PubMed

[10] Rahman N. (2014). Realizing the promise of cancer predisposition genes. Nature 505, 302–308. 10.1038/nature12981. - DOI - PMC - PubMed

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Precision proteogenomics reveals pan-cancer impact of germline variants

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Precision proteogenomics reveals pan-cancer impact of germline variants

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