| Title: | Precision proteogenomics reveals pan-cancer impact of germline variants |
| Journal: | Cell |
| Published: | 14 Apr 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40233739/ |
| DOI: | https://doi.org/10.1016/j.cell.2025.03.026 |
Publication 18702
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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.</p>
10 Keywords
- Erb-b2 Receptor Tyrosine Kinases
- Genome-Wide Association Study
- Germ-Line Mutation
- Humans
- Neoplasms
- Polymorphism, Single Nucleotide
- Protein Processing, Post-Translational
- Proteogenomics
- Proteome
- Quantitative Trait Loci
133 Authors
- Fernanda Martins Rodrigues
- Nadezhda V. Terekhanova
- Kathleen J. Imbach
- Karl R. Clauser
- Myvizhi Esai Selvan
- Isabel Mendizabal
- Yifat Geffen
- Yo Akiyama
- Myranda Maynard
- Tomer M. Yaron
- Yize Li
- Song Cao
- Erik P. Storrs
- Olivia S. Gonda
- Adrian Gaite-Reguero
- Akshay Govindan
- Emily A. Kawaler
- Matthew A. Wyczalkowski
- Robert J. Klein
- Berk Turhan
- Karsten Krug
- D.R. Mani
- Felipe da Veiga Leprevost
- Alexey I. Nesvizhskii
- Steven A. Carr
- David Fenyö
- Michael A. Gillette
- Antonio Colaprico
- Antonio Iavarone
- Ana I. Robles
- Kuan-lin Huang
- Chandan Kumar-Sinha
- François Aguet
- Alexander J. Lazar
- Lewis C. Cantley
- Urko M. Marigorta
- Zeynep H. Gümüş
- Matthew H. Bailey
- Gad Getz
- Eduard Porta-Pardo
- Li Ding
- 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
Enabling scientific discoveries that improve human health