Innate Genetic Evolution of Lung Cancers and Spatial Heterogeneity: Analysis of Treatment-Naïve Lesions Kenichi Suda, MD, PhD, Jihye Kim, PhD, Isao Murakami,

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Innate Genetic Evolution of Lung Cancers and Spatial Heterogeneity: Analysis of Treatment-Naïve Lesions Kenichi Suda, MD, PhD, Jihye Kim, PhD, Isao Murakami, MD, PhD, Leslie Rozeboom, MS, Masaki Shimoji, MD, PhD, Shigeki Shimizu, MD, PhD, Christopher J. Rivard, PhD, Tetsuya Mitsudomi, MD, PhD, Aik-Choon Tan, PhD, Fred R. Hirsch, MD, PhD Journal of Thoracic Oncology Volume 13, Issue 10, Pages 1496-1507 (October 2018) DOI: 10.1016/j.jtho.2018.05.039 Copyright © 2018 International Association for the Study of Lung Cancer Terms and Conditions

Figure 1 The global unsupervised clustering analysis of expression data of all lesions analyzed. The left and right rows indicate the histology and the individual patient, respectively. LN, lymph node metastases; RML, right middle lobe of the lung; LUL, left upper lobe of the lung; AC, adenocarcinoma; SQ, squamous cell carcinoma. Journal of Thoracic Oncology 2018 13, 1496-1507DOI: (10.1016/j.jtho.2018.05.039) Copyright © 2018 International Association for the Study of Lung Cancer Terms and Conditions

Figure 2 Mutational and pathway analyses of lesions obtained from a never-smoking lung adenocarcinoma patient (case 1). (A) Geographic locations of analyzed lesions are shown. (B) Pathway analysis was performed with Gene Set Enrichment Analysis based on MSigDB C2 curated KEGG gene sets. (Dysregulated pathways in all lesions are summarized in Supplementary Table 1, and are excluded from the figure.) (C) Representative mutations identified in case 1. KIF5B-RET fusion was also identified in all lesions, but not in noncancerous tissue, using TopHat-Fusion on the RNA-seq. Insulin-like growth factor 2 receptor (IGF2R), major histocompatibility complex, class I, A (HLA-A), and erb-b2 receptor tyrosine kinase 2 (ERBB2) mutations were also identified as trunk mutations, whereas NF1 mutation was present only in some metastatic lesions. The phylogenetic tree was constructed using a Neighbor joining method implemented in the R phangom package, based on somatic and deleterious mutations in reliably expressed genes. The genes with asterisk indicate that somatic/deleterious mutations in those genes were identified in lesions obtained from the other lung adenocarcinoma patient (case 2). Journal of Thoracic Oncology 2018 13, 1496-1507DOI: (10.1016/j.jtho.2018.05.039) Copyright © 2018 International Association for the Study of Lung Cancer Terms and Conditions

Figure 2 Mutational and pathway analyses of lesions obtained from a never-smoking lung adenocarcinoma patient (case 1). (A) Geographic locations of analyzed lesions are shown. (B) Pathway analysis was performed with Gene Set Enrichment Analysis based on MSigDB C2 curated KEGG gene sets. (Dysregulated pathways in all lesions are summarized in Supplementary Table 1, and are excluded from the figure.) (C) Representative mutations identified in case 1. KIF5B-RET fusion was also identified in all lesions, but not in noncancerous tissue, using TopHat-Fusion on the RNA-seq. Insulin-like growth factor 2 receptor (IGF2R), major histocompatibility complex, class I, A (HLA-A), and erb-b2 receptor tyrosine kinase 2 (ERBB2) mutations were also identified as trunk mutations, whereas NF1 mutation was present only in some metastatic lesions. The phylogenetic tree was constructed using a Neighbor joining method implemented in the R phangom package, based on somatic and deleterious mutations in reliably expressed genes. The genes with asterisk indicate that somatic/deleterious mutations in those genes were identified in lesions obtained from the other lung adenocarcinoma patient (case 2). Journal of Thoracic Oncology 2018 13, 1496-1507DOI: (10.1016/j.jtho.2018.05.039) Copyright © 2018 International Association for the Study of Lung Cancer Terms and Conditions

Figure 3 Mutational and pathway analyses of lesions obtained from a lung squamous cell carcinoma patient with heavy smoking history (case 3). (A) Geographic locations of analyzed lesions. (B) Pathway analysis was performed with Gene Set Enrichment Analysis based on MSigDB C2 curated KEGG gene sets. (C) Representative mutations identified in case 3. Nuclear factor, erythroid 2 like 2 (NFE2L2) and integrin subunit beta 4 (ITGB4) mutations were identified in all lesions except for the hilar lymph node metastasis. The phylogenetic tree was constructed using a Neighbor joining method implemented in the R phangom package, based on somatic and deleterious mutations in reliably expressed genes. The genes with asterisks indicate that somatic/deleterious mutations in those genes were identified in lesions obtained from the other lung squamous cell carcinoma patient (case 4). Journal of Thoracic Oncology 2018 13, 1496-1507DOI: (10.1016/j.jtho.2018.05.039) Copyright © 2018 International Association for the Study of Lung Cancer Terms and Conditions

Figure 3 Mutational and pathway analyses of lesions obtained from a lung squamous cell carcinoma patient with heavy smoking history (case 3). (A) Geographic locations of analyzed lesions. (B) Pathway analysis was performed with Gene Set Enrichment Analysis based on MSigDB C2 curated KEGG gene sets. (C) Representative mutations identified in case 3. Nuclear factor, erythroid 2 like 2 (NFE2L2) and integrin subunit beta 4 (ITGB4) mutations were identified in all lesions except for the hilar lymph node metastasis. The phylogenetic tree was constructed using a Neighbor joining method implemented in the R phangom package, based on somatic and deleterious mutations in reliably expressed genes. The genes with asterisks indicate that somatic/deleterious mutations in those genes were identified in lesions obtained from the other lung squamous cell carcinoma patient (case 4). Journal of Thoracic Oncology 2018 13, 1496-1507DOI: (10.1016/j.jtho.2018.05.039) Copyright © 2018 International Association for the Study of Lung Cancer Terms and Conditions

Figure 4 The intertumor heterogeneity of potential “predictive” biomarkers for PD-1/PD-L1 targeted immunotherapy. (A) The relative expression of CD274 (PD-L1) and tumor mutation burden (the numbers of somatic/non-synonymous mutations detected) are shown. Primary lesion from each patient was marked by a dotted circle. Comparison of PD-L1 immunohistochemistry staining in the primary tumor (B), visceral pleura (C), contra-lateral lung metastasis (D), and liver metastasis (E) in case 1 is shown. PD-1, programmed death 1; PD-L1, programmed death ligand 1. Journal of Thoracic Oncology 2018 13, 1496-1507DOI: (10.1016/j.jtho.2018.05.039) Copyright © 2018 International Association for the Study of Lung Cancer Terms and Conditions