Title | Proteogenomics of non-small cell lung cancer reveals molecular subtypes associated with specific therapeutic targets and immune evasion mechanisms. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Lehtiö J, Arslan T, Siavelis I, Pan Y, Socciarelli F, Berkovska O, Umer HM, Mermelekas G, Pirmoradian M, Jönsson M, Brunnström H, Brustugun OTerje, Purohit KPinganksha, Cunningham R, Asl HForoughi, Isaksson S, Arbajian E, Aine M, Karlsson A, Kotevska M, Hansen CGram, Haakensen VDrageset, Helland Å, Tamborero D, Johansson HJ, Branca RM, Planck M, Staaf J, Orre LM |
Journal | Nat Cancer |
Volume | 2 |
Issue | 11 |
Pagination | 1224-1242 |
Date Published | 2021 Nov |
ISSN | 2662-1347 |
Keywords | Carcinoma, Non-Small-Cell Lung, Fibrinogen, Genomics, Humans, Immune Evasion, Lung Neoplasms, Proteogenomics |
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. |
DOI | 10.1038/s43018-021-00259-9 |
Alternate Journal | Nat Cancer |
PubMed ID | 34870237 |
PubMed Central ID | PMC7612062 |
Grant List | 19-0238 / AICR_ / Worldwide Cancer Research / United Kingdom / MRC_ / Medical Research Council / United Kingdom |
Related Faculty:
Fabio Socciarelli, M.D., Ph.D.