Proteogenomics of non-small cell lung cancer reveals molecular subtypes associated with specific therapeutic targets and immune evasion mechanisms.
Journal
Nature cancer
ISSN: 2662-1347
Titre abrégé: Nat Cancer
Pays: England
ID NLM: 101761119
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
entrez:
6
12
2021
pubmed:
7
12
2021
medline:
7
12
2021
Statut:
ppublish
Résumé
Despite major advancements in lung cancer treatment, long-term survival is still rare, and a deeper understanding of molecular phenotypes would allow the identification of specific cancer dependencies and immune evasion mechanisms. Here we performed in-depth mass spectrometry (MS)-based proteogenomic analysis of 141 tumors representing all major histologies of non-small cell lung cancer (NSCLC). We identified six distinct proteome subtypes with striking differences in immune cell composition and subtype-specific expression of immune checkpoints. Unexpectedly, high neoantigen burden was linked to global hypomethylation and complex neoantigens mapped to genomic regions, such as endogenous retroviral elements and introns, in immune-cold subtypes. Further, we linked immune evasion with LAG3 via STK11 mutation-dependent HNF1A activation and FGL1 expression. Finally, we develop a data-independent acquisition MS-based NSCLC subtype classification method, validate it in an independent cohort of 208 NSCLC cases and demonstrate its clinical utility by analyzing an additional cohort of 84 late-stage NSCLC biopsy samples.
Identifiants
pubmed: 34870237
doi: 10.1038/s43018-021-00259-9
pmc: PMC7612062
mid: EMS133264
pii: 10.1038/s43018-021-00259-9
doi:
Substances chimiques
FGL1 protein, human
0
Fibrinogen
9001-32-5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
1224-1242Subventions
Organisme : Worldwide Cancer Research
ID : 19-0238
Pays : United Kingdom
Organisme : Medical Research Council
Pays : United Kingdom
Déclaration de conflit d'intérêts
Competing interests J.L. has received grant funding from AstraZeneca, Roche and Novartis (not financing of the current manuscript). J.L. and L.M.O. are share holders of FenoMark Diagnostics. J.L., T.A., I.S., and L.M.O are co-inventors on a patent application related to this work. J.L. and D.T. are associate with Roche financed Cancer Core Europe clinical trial (not associated to current manuscript). Since completing his contribution to the current work, M.Pirmoradian has become an employee of AstraZeneca. All other authors declare no competing interests.
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