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

Overview

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 (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.

authors

  • Lehtiö, Janne
  • Arslan, Taner
  • Siavelis, Ioannis
  • Pan, Yanbo
  • Socciarelli, Fabio
  • Berkovska, Olena
  • Umer, Husen M
  • Mermelekas, Georgios
  • Pirmoradian, Mohammad
  • Jönsson, Mats
  • Brunnström, Hans
  • Brustugun, Odd Terje
  • Purohit, Krishna Pinganksha
  • Cunningham, Richard
  • Foroughi Asl, Hassan
  • Isaksson, Sofi
  • Arbajian, Elsa
  • Aine, Mattias
  • Karlsson, Anna
  • Kotevska, Marija
  • Gram Hansen, Carsten
  • Drageset Haakensen, Vilde
  • Helland, Åslaug
  • Tamborero, David
  • Johansson, Henrik J
  • Branca, Rui M
  • Planck, Maria
  • Staaf, Johan
  • Orre, Lukas M

publication date

  • November 22, 2021

Research

keywords

  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms
  • Proteogenomics

Identity

PubMed Central ID

  • PMC7612062

Scopus Document Identifier

  • 85119654244

Digital Object Identifier (DOI)

  • 10.21203/rs.3.pex-1561/v1

PubMed ID

  • 34870237

Additional Document Info

volume

  • 2

issue

  • 11