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Gene Expression Profiling of Large Cell Lung Cancer Links Transcriptional Phenotypes to the New Histological WHO 2015 Classification
Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden..
Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden.;Reg Labs Reg Skane, Dept Pathol, Lund, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.ORCID iD: 0000-0003-1210-5961
Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden..
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2017 (English)In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 12, no 8, p. 1257-1267Article in journal (Refereed) Published
Abstract [en]

Introduction: Large cell lung cancer (LCLC) and large cell neuroendocrine carcinoma (LCNEC) constitute a small proportion of NSCLC. The WHO 2015 classification guidelines changed the definition of the debated histological subtype LCLC to be based on immunomarkers for adenocarcinoma and squamous cancer. We sought to determine whether these new guidelines also translate into the transcriptional landscape of lung cancer, and LCLC specifically.

Methods: Gene expression profiling was performed by using Illumina V4 HT12 microarrays (Illumina, San Diego, CA) on samples from 159 cases (comprising all histological subtypes, including 10 classified as LCLC WHO 2015 and 14 classified as LCNEC according to the WHO 2015 guidelines), with complimentary mutational and immunohistochemical data. Derived transcriptional phenotypes were validated in 199 independent tumors, including six WHO 2015 LCLCs and five LCNECs.

Results: Unsupervised analysis of gene expression data identified a phenotype comprising 90% of WHO 2015 LCLC tumors, with characteristics of poorly differentiated proliferatiVe cancer, a 90% tumor protein p53 gene (TP53) mutation rate, and lack of well-known NSCLC oncogene driver alterations. Validation in independent data confirmed aggregation of WHO 2015 LCLCs in the specific phenotype. For LCNEC tumors, the unsupervised gene expression analysis suggested two different transcriptional patterns corresponding to a proposed genetic division of LCNEC tumors into SCLC-like and NSCLC-like cancer on the basis of TP53 and retinoblastoma 1 gene (RB1) alteration patterns.

Conclusions: Refined classification of LCLC has implications for diagnosis, prognostics, and therapy decisions. Our molecular analyses support the WHO 2015 classification of LCLC and LCNEC tumors, which herein follow different tumorigenic paths and can accordingly be stratified into different transcriptional subgroups, thus linking diagnostic immunohistochemical staining driven classification with the transcriptional landscape of lung cancer.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE INC , 2017. Vol. 12, no 8, p. 1257-1267
Keyword [en]
Lung cancer, Large cell lung carcinoma, LCNEC, Mutation, Gene expression, WHO classification
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-333713DOI: 10.1016/j.jtho.2017.05.008ISI: 000407187400009PubMedID: 28535939OAI: oai:DiVA.org:uu-333713DiVA, id: diva2:1158805
Funder
Swedish Cancer SocietyGunnar Nilsson Cancer FoundationThe Crafoord FoundationKing Gustaf V Jubilee Fund
Available from: 2017-11-21 Created: 2017-11-21 Last updated: 2018-02-01Bibliographically approved

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