Gene Expression Profiling of Large Cell Lung Cancer Links Transcriptional Phenotypes to the New Histological WHO 2015 Classification Anna Karlsson, MSc,

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Gene Expression Profiling of Large Cell Lung Cancer Links Transcriptional Phenotypes to the New Histological WHO 2015 Classification Anna Karlsson, MSc, Hans Brunnström, MD, PhD, Patrick Micke, MD, PhD, Srinivas Veerla, PhD, Johanna Mattsson, PhD, Linnea La Fleur, MSc, Johan Botling, MD, PhD, Mats Jönsson, PhD, Christel Reuterswärd, MSc, Maria Planck, MD, PhD, Johan Staaf, PhD Journal of Thoracic Oncology Volume 12, Issue 8, Pages 1257-1267 (August 2017) DOI: 10.1016/j.jtho.2017.05.008 Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 1 Unsupervised gene expression analysis stratifies large cell lung cancer (LCLC) and large cell neuroendocrine carcinoma (LCNEC) into molecular subgroups. Gene expression heatmap of 2730 Illumina probes across 159 lung cancers stratified by 10 specified consensus clusters. The 2730 probes correspond to a log2ratio standard deviation cutoff of more than 0.5 Annotations for histological subtypes, clinicopathological variables, selected mutations, retinoblastoma 1 immunohistochemistry (RB1 IHC), classification according to reported gene expression phenotypes (GEPs) for adenocarcinoma (AC) and squamous cell carcinoma (SqCC), and expression of selected biological metagenes are provided. For annotations, black corresponds to a positive/presence call, gray to a negative call, and white to not applicable or not available. Gene cluster functional annotations are provided for some specific clusters in the heatmap. ECM, extracellular matrix; mut, mutation; RB1 mut, retinoblastoma 1 gene mutation; TP53, tumor protein p53 gene; STK11, serine/threonine kinase 11 gene; TRU, terminal respiratory unit; PP, proximal proliferative; and PI, proximal inflammatory. Journal of Thoracic Oncology 2017 12, 1257-1267DOI: (10.1016/j.jtho.2017.05.008) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 2 Mutations and gene expression characteristics of large cell neuroendocrine carcinoma (LCNEC) tumors with respect to consensus clusters. (A) Mutational map of detected mutations in 26 tumor suppressor and oncogenes for 14 LCNEC tumors stratified by consensus cluster assignment. Only genes with one or more mutations are shown. (B) Average log2ratio expression of a 16-gene serine/threonine kinase 11 gene (STK11) loss gene signature28 for LCNEC tumors. Tumors are colored by their consensus cluster as in (A). Asterisk indicates a case with STK11 mutation (C) Expression of the proliferation metagene for LCNEC tumors stratified by consensus cluster. (D) Expression of the neuroendocrine metagene for LCNEC tumors stratified by consensus cluster. Statistical testing in B–D was not performed on account of the small group sizes. In A–D, consensus cluster 3 cases are labeled green, cluster 6 cases purple, and cluster 7 cases pink. RB1 IHC, retinoblastoma 1 immunohistochemistry; RB1 mutation, retinoblastoma 1 gene mutation; TP53, tumor protein p53 gene; PTEN, phosphatase and tensin homolog gene; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene; KIT, KIT proto-oncogene receptor tyrosine kinase gene; GNAS, GNAS complex locus gene; GNAQ, G Protein Subunit Alpha, Q; APC, adenomatous polyposis coli gene; APC, WNT signaling pathway regulator gene; InsDel, insertion/deletion. Journal of Thoracic Oncology 2017 12, 1257-1267DOI: (10.1016/j.jtho.2017.05.008) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 3 Genomic characteristics of large cell lung cancer (LCLC) marker-null cases. (A) Mutational map of detected mutations among 26 tumor suppressor and oncogenes in the 10 LCLC marker-null cases stratified by the 10 defined consensus clusters. Only genes with one or more mutations are shown. (B) Expression of the napsin A/surfactant biological metagene for the 10 marker-null cases stratified by consensus clusters. Colors of the individual samples correspond to cluster colors in (A). LCLC, large cell lung cancer; TP53, tumor protein p53 gene; PTEN, phosphatase and tensin homolog gene; APC, APC, adenomatous polyposis coli gene; WNT signaling pathway regulator gene. Journal of Thoracic Oncology 2017 12, 1257-1267DOI: (10.1016/j.jtho.2017.05.008) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 4 Validation of the large cell neuroendocrine carcinoma (LCNEC) and large cell lung cancer (LCLC) marker-null gene expression phenotypes (GEPs). Gene expression heatmap of 2196 genes across 199 lung cancers from Djureinovic et al.26 classified by a nearest centroid predictor into 10 consensus clusters. Six cases were set as unclassified and are excluded from the heatmap (n = 193 cases in the heatmap). Annotations for histological subtypes, clinicopathological variables, classification according to reported GEPs, for adenocarcinoma (AC) and squamous cell carcinoma (SqCC), and expression of selected biological metagenes are provided. For annotations, black corresponds to a positive/presence call, gray to a negative call, and white to not applicable or not available. SARC, sarcomatoid, TRU, terminal respiratory unit; PP, proximal proliferative; PI, proximal inflammatory. Journal of Thoracic Oncology 2017 12, 1257-1267DOI: (10.1016/j.jtho.2017.05.008) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions