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

Autor: Lehtiö J; Department of Oncology and Pathology, Karolinska Institutet, SciLifeLab, Solna, Sweden. janne.lehtio@ki.se., Arslan T; Department of Oncology and Pathology, Karolinska Institutet, SciLifeLab, Solna, Sweden., Siavelis I; Department of Oncology and Pathology, Karolinska Institutet, SciLifeLab, Solna, Sweden., Pan Y; Department of Oncology and Pathology, Karolinska Institutet, SciLifeLab, Solna, Sweden., Socciarelli F; Department of Oncology and Pathology, Karolinska Institutet, SciLifeLab, Solna, Sweden., Berkovska O; Department of Oncology and Pathology, Karolinska Institutet, SciLifeLab, Solna, Sweden., Umer HM; Department of Oncology and Pathology, Karolinska Institutet, SciLifeLab, Solna, Sweden., Mermelekas G; Department of Oncology and Pathology, Karolinska Institutet, SciLifeLab, Solna, Sweden., Pirmoradian M; Department of Oncology and Pathology, Karolinska Institutet, SciLifeLab, Solna, Sweden., Jönsson M; Division of Oncology, Department of Clinical Sciences, Lund and CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden., Brunnström H; Department of Pathology, Laboratory Medicine Region Skåne, Lund, Sweden.; Division of Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden., Brustugun OT; Section of Oncology, Drammen Hospital, Vestre Viken Health Trust, Drammen, Norway.; Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway., Purohit KP; University of Edinburgh Centre for Inflammation Research, Institute for Regeneration and Repair, Queen's Medical Research Institute, Edinburgh bioQuarter, Edinburgh, UK.; MRC Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK., Cunningham R; University of Edinburgh Centre for Inflammation Research, Institute for Regeneration and Repair, Queen's Medical Research Institute, Edinburgh bioQuarter, Edinburgh, UK.; MRC Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK., Foroughi Asl H; Genomic Medicine Center, Karolinska University Hospital, Stockholm, Sweden.; Clinical Genomics Facility, Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden., Isaksson S; Division of Oncology, Department of Clinical Sciences, Lund and CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden., Arbajian E; Division of Oncology, Department of Clinical Sciences, Lund and CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden., Aine M; Division of Oncology, Department of Clinical Sciences, Lund and CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden., Karlsson A; Division of Oncology, Department of Clinical Sciences, Lund and CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden., Kotevska M; Division of Oncology, Department of Clinical Sciences, Lund and CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.; Department of Respiratory Medicine and Allergology, Skåne University Hospital, Lund, Sweden., Gram Hansen C; University of Edinburgh Centre for Inflammation Research, Institute for Regeneration and Repair, Queen's Medical Research Institute, Edinburgh bioQuarter, Edinburgh, UK.; MRC Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK., Drageset Haakensen V; Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; Department of Oncology, Oslo University Hospital, Oslo, Norway., Helland Å; Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; Department of Oncology, Oslo University Hospital, Oslo, Norway.; Faculty of Medicine, University of Oslo, Oslo, Norway., Tamborero D; Department of Oncology and Pathology, Karolinska Institutet, SciLifeLab, Solna, Sweden., Johansson HJ; Department of Oncology and Pathology, Karolinska Institutet, SciLifeLab, Solna, Sweden., Branca RM; Department of Oncology and Pathology, Karolinska Institutet, SciLifeLab, Solna, Sweden., Planck M; Division of Oncology, Department of Clinical Sciences, Lund and CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.; Department of Respiratory Medicine and Allergology, Skåne University Hospital, Lund, Sweden., Staaf J; Division of Oncology, Department of Clinical Sciences, Lund and CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden., Orre LM; Department of Oncology and Pathology, Karolinska Institutet, SciLifeLab, Solna, Sweden.
Jazyk: angličtina
Zdroj: Nature cancer [Nat Cancer] 2021 Nov; Vol. 2 (11), pp. 1224-1242. Date of Electronic Publication: 2021 Nov 22.
DOI: 10.1038/s43018-021-00259-9
Abstrakt: 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.
Competing Interests: 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.
Databáze: MEDLINE
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