TY - JOUR
T1 - Proteogenomics of non-small cell lung cancer reveals molecular subtypes associated with specific therapeutic targets and immune-evasion mechanisms
AU - Lehtiö, Janne
AU - Arslan, Taner
AU - Siavelis, Ioannis
AU - Pan, Yanbo
AU - Socciarelli, Fabio
AU - Berkovska, Olena
AU - Umer, Husen M.
AU - Mermelekas, Georgios
AU - Pirmoradian, Mohammad
AU - Jönsson, Mats
AU - Brunnström, Hans
AU - Brustugun, Odd Terje
AU - Purohit, Krishna Pinganksha
AU - Cunningham, Richard
AU - Foroughi Asl, Hassan
AU - Isaksson, Sofi
AU - Arbajian, Elsa
AU - Aine, Mattias
AU - Karlsson, Anna
AU - Kotevska, Marija
AU - Gram Hansen, Carsten
AU - Drageset Haakensen, Vilde
AU - Helland, Åslaug
AU - Tamborero, David
AU - Johansson, Henrik J.
AU - Branca, Rui M.
AU - Planck, Maria
AU - Staaf, Johan
AU - Orre, Lukas M.
PY - 2021/11/22
Y1 - 2021/11/22
N2 - 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.
AB - 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.
U2 - 10.1038/s43018-021-00259-9
DO - 10.1038/s43018-021-00259-9
M3 - Article
SN - 2662-1347
VL - 2
SP - 1224
EP - 1242
JO - nature cancer
JF - nature cancer
IS - 11
ER -