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Proteogenomics of non-small cell lung cancer reveals molecular subtypes associated with specific therapeutic targets and immune-evasion mechanisms

Lehtiö, Janne ; Arslan, Taner ; Siavelis, Ioannis ; Pan, Yanbo ; Socciarelli, Fabio ; Berkovska, Olena ; Umer, Husen M. ; Mermelekas, Georgios ; Pirmoradian, Mohammad and Jönsson, Mats LU , et al. (2021) In Nature Cancer 2(11). p.1224-1242
Abstract

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-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... (More)

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-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 LAG-3 via STK11 mutation-dependent HNF1A activation and FGL1 expression. Finally, we develop a data-independent acquisition mass-spectrometry-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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Cancer
volume
2
issue
11
pages
19 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85119654244
  • pmid:34870237
ISSN
2662-1347
DOI
10.1038/s43018-021-00259-9
language
English
LU publication?
yes
id
23c121b6-9125-4cb3-b5a2-e8aeb852a85b
date added to LUP
2021-12-03 14:23:02
date last changed
2024-05-19 19:17:51
@article{23c121b6-9125-4cb3-b5a2-e8aeb852a85b,
  abstract     = {{<p>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-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 LAG-3 via STK11 mutation-dependent HNF1A activation and FGL1 expression. Finally, we develop a data-independent acquisition mass-spectrometry-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.</p>}},
  author       = {{Lehtiö, Janne and Arslan, Taner and Siavelis, Ioannis and Pan, Yanbo and Socciarelli, Fabio and Berkovska, Olena and Umer, Husen M. and Mermelekas, Georgios and Pirmoradian, Mohammad and Jönsson, Mats and Brunnström, Hans and Brustugun, Odd Terje and Purohit, Krishna Pinganksha and Cunningham, Richard and Foroughi Asl, Hassan and Isaksson, Sofi and Arbajian, Elsa and Aine, Mattias and Karlsson, Anna and Kotevska, Marija and Gram Hansen, Carsten and Drageset Haakensen, Vilde and Helland, Åslaug and Tamborero, David and Johansson, Henrik J. and Branca, Rui M. and Planck, Maria and Staaf, Johan and Orre, Lukas M.}},
  issn         = {{2662-1347}},
  language     = {{eng}},
  number       = {{11}},
  pages        = {{1224--1242}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Cancer}},
  title        = {{Proteogenomics of non-small cell lung cancer reveals molecular subtypes associated with specific therapeutic targets and immune-evasion mechanisms}},
  url          = {{http://dx.doi.org/10.1038/s43018-021-00259-9}},
  doi          = {{10.1038/s43018-021-00259-9}},
  volume       = {{2}},
  year         = {{2021}},
}