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1. Proteogenomic Landscape of Breast Cancer Tumorigenesis and Targeted Therapy.

Author

Krug K, Jaehnig EJ, Satpathy S, Blumenberg L, Karpova A, Anurag M, Miles G, Mertins P, Geffen Y, Tang LC, Heiman DI, Cao S, Maruvka YE, Lei JT, Huang C, Kothadia RB, Colaprico A, Birger C, Wang J, Dou Y, Wen B, Shi Z, Liao Y, Wiznerowicz M, Wyczalkowski MA, Chen XS, Kennedy JJ, Paulovich AG, Thiagarajan M, Kinsinger CR, Hiltke T, Boja ES, Mesri M, Robles AI, Rodriguez H, Westbrook TF, Ding L, Getz G, Clauser KR, Fenyö D, Ruggles KV, Zhang B, Mani DR, Carr SA, Ellis MJ, and Gillette MA

Subjects
APOBEC Deaminases metabolism, Adult, Aged, Aged, 80 and over, Breast Neoplasms immunology, Breast Neoplasms therapy, Cohort Studies, DNA Damage, DNA Repair, Female, Humans, Immunotherapy, Metabolomics, Middle Aged, Mutagenesis genetics, Phosphorylation, Protein Kinase Inhibitors pharmacology, Protein Kinases metabolism, Receptor, ErbB-2 metabolism, Retinoblastoma Protein metabolism, Tumor Microenvironment immunology, Breast Neoplasms genetics, Breast Neoplasms pathology, Carcinogenesis genetics, Carcinogenesis pathology, Molecular Targeted Therapy, Proteogenomics
Abstract

The integration of mass spectrometry-based proteomics with next-generation DNA and RNA sequencing profiles tumors more comprehensively. Here this "proteogenomics" approach was applied to 122 treatment-naive primary breast cancers accrued to preserve post-translational modifications, including protein phosphorylation and acetylation. Proteogenomics challenged standard breast cancer diagnoses, provided detailed analysis of the ERBB2 amplicon, defined tumor subsets that could benefit from immune checkpoint therapy, and allowed more accurate assessment of Rb status for prediction of CDK4/6 inhibitor responsiveness. Phosphoproteomics profiles uncovered novel associations between tumor suppressor loss and targetable kinases. Acetylproteome analysis highlighted acetylation on key nuclear proteins involved in the DNA damage response and revealed cross-talk between cytoplasmic and mitochondrial acetylation and metabolism. Our results underscore the potential of proteogenomics for clinical investigation of breast cancer through more accurate annotation of targetable pathways and biological features of this remarkably heterogeneous malignancy., Competing Interests: Declaration of Interests M.J.E reports ownership and royalties associated with Bioclassifier LLC through sales by Nanostring LLC and Veracyte for the “Prosigna” breast cancer prognostic test. He also reports ad hoc consulting for AstraZeneca, Foundation Medicine, G1 Therapeutics, Novartis, Sermonix, Abbvie, Lilly and Pfizer. B.Z. has received research funding from Bristol-Myers Squibb. S.A.C. is a scientific advisory board member of Kymera, PTM BioLabs, and Seer and ad hoc consultant to Pfizer and Biogen., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2020
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2. Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma.

Author

Gillette MA, Satpathy S, Cao S, Dhanasekaran SM, Vasaikar SV, Krug K, Petralia F, Li Y, Liang WW, Reva B, Krek A, Ji J, Song X, Liu W, Hong R, Yao L, Blumenberg L, Savage SR, Wendl MC, Wen B, Li K, Tang LC, MacMullan MA, Avanessian SC, Kane MH, Newton CJ, Cornwell M, Kothadia RB, Ma W, Yoo S, Mannan R, Vats P, Kumar-Sinha C, Kawaler EA, Omelchenko T, Colaprico A, Geffen Y, Maruvka YE, da Veiga Leprevost F, Wiznerowicz M, Gümüş ZH, Veluswamy RR, Hostetter G, Heiman DI, Wyczalkowski MA, Hiltke T, Mesri M, Kinsinger CR, Boja ES, Omenn GS, Chinnaiyan AM, Rodriguez H, Li QK, Jewell SD, Thiagarajan M, Getz G, Zhang B, Fenyö D, Ruggles KV, Cieslik MP, Robles AI, Clauser KR, Govindan R, Wang P, Nesvizhskii AI, Ding L, Mani DR, and Carr SA

Subjects
Adenocarcinoma of Lung immunology, Adult, Aged, Aged, 80 and over, Biomarkers, Tumor metabolism, Carcinogenesis genetics, Carcinogenesis pathology, DNA Copy Number Variations genetics, DNA Methylation genetics, Female, Humans, Lung Neoplasms immunology, Male, Middle Aged, Mutation genetics, Oncogene Proteins, Fusion, Phenotype, Phosphoproteins metabolism, Proteome metabolism, Adenocarcinoma of Lung drug therapy, Adenocarcinoma of Lung genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Proteogenomics
Abstract

To explore the biology of lung adenocarcinoma (LUAD) and identify new therapeutic opportunities, we performed comprehensive proteogenomic characterization of 110 tumors and 101 matched normal adjacent tissues (NATs) incorporating genomics, epigenomics, deep-scale proteomics, phosphoproteomics, and acetylproteomics. Multi-omics clustering revealed four subgroups defined by key driver mutations, country, and gender. Proteomic and phosphoproteomic data illuminated biology downstream of copy number aberrations, somatic mutations, and fusions and identified therapeutic vulnerabilities associated with driver events involving KRAS, EGFR, and ALK. Immune subtyping revealed a complex landscape, reinforced the association of STK11 with immune-cold behavior, and underscored a potential immunosuppressive role of neutrophil degranulation. Smoking-associated LUADs showed correlation with other environmental exposure signatures and a field effect in NATs. Matched NATs allowed identification of differentially expressed proteins with potential diagnostic and therapeutic utility. This proteogenomics dataset represents a unique public resource for researchers and clinicians seeking to better understand and treat lung adenocarcinomas., Competing Interests: Declaration of Interests B.Z. has received research funding from Bristol-Myers Squibb. All other authors have no conflict of interests to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Published
2020
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