LIST OF SUPPLEMENTARY FIGURES Supplementary Figure 1: Example of KRAS-mutated LCNEC: Illustration of NGS and histopathologic features Supplementary Figure 2: Dot plots for total number of genomic alterations in carcinoid-like vs other LCNECs Supplementary Figure 3: OncoPrints for chromatin modifier, neurogenesis/neural function, DNA replication/repair and PI3K-AKT-mTOR pathway genes Supplementary Figure 4: Map of NOTCH mutations Supplementary Figure 5: Expression of NE genes in transcriptional subgroups of lung adenocarcinoma in TCGA series Supplementary Figure 6: Kaplan-Meier survival curves

A. Supplementary Figure 1: Example of KRAS-mutated LCNEC: Illustration of NGS and histopathologic features. Shown is case ID LCNEC-39, harboring KRAS Q61L (c.182A>T) mutation. A. Integrative genomic viewer (IGV) screenshot of NGS reads of KRAS c.182A>T present at 40% (169/422) of total reads in the tumor sample (top) compared to 0% of total reads in the matched normal tissue (bottom). B, C. H&E showing classic LCNEC morphology (nests, rosettes, palisading, high mitotic rate, necrosis, non-small cell cytology). D. IHC for synaptophysin. E. IHC for ASCL1. B.C.D. SYNE. ASCL1

Total number of alterations per case LCNEC- carcinoid-like LCNEC- SCLC/NSCLC-like P=0.007 Supplementary Figure 2: Dot plots for total number of genomic alterations in carcinoid-like vs other LCNECs Total number of genomic alterations (mutations + copy number alterations) per case in carcinoid-like LCNEC vs other LCNECs. Red lines indicate the mean, and error bars indicate standard deviation

ATM11% ATR0 POLE11% ERCC24% ERCC56% BRCA14% BRCA213% CHEK10 CHEK22% RAD502% MSH24% MSH62% PARP16% AKT10 AKT20 AKT32% PTEN8%8% TSC16%6% TSC28%8% MTOR2%2% RICTOR4%4% PIK3C2G8%8% PIK3CB4%4% PIK3CD6%6% PIK3CG6%6% PIK3R22%2% PIK3R30 Case ID Loss Missense mutation Inframe mutation Truncating mutation Case ID MLL8% MLL213% MLL313% KDM5C6% KDM6A4% SETD24% MEN14% EP3000 CREBBP6% BAP16% DNMT10 DNMT3A6% DNMT3B2% TET16% TET24% ARID1A13% ARID1B2% ARID24% ATRX11% SMARCA415% SMARCB12% ASXL12% BCOR6% Histone methylation (mutated in 49%) Histone acetylation DNA methylation (mutated in 18%) SWI/SNF chromatin remodeling (mutated in 40%) Polycomb group Histone ubiquitination Chromatin modifiers Altered in 35 (78%) of 45 cases NOTCH1 1 17% NOTCH2 1 2% NOTCH3 1 8% NOTCH4 1 15% NTRK2 2 2% NTRK3 2 17% EPHA3 3,4 13% EPHA5 3,4 15% EPHB1 3,4 6% PTPRT 5 22% NF1 6 15% ERBB4 7 13% GRIN2A 8 11% Altered in 15 cases (33%) Neurogenesis/neural function Altered in 32 (72%) of 45 cases Case ID DNA replication/repair Altered in 23 (52%) PI3K-AKT-mTOR pathway Altered in 22 (49%) Case ID A.B.B. C.D.D. Supplementary Figure 3: OncoPrints for chromatin modifier (A), neurogenesis/neural function (B), DNA replication/repair (C) and PI3K-AKT-mTOR pathway (D) genes. Case IDs shading corresponds to the following: pink - SCLC-like, blue - NSCLC-like, green - carcinoid-like. (B) References for the role of individual genes in neural development/function: 1. Ball DW. Cancer Lett. 2004;204: Barbacid M. J Neurobiol. 1994;25: Laussu J et al Cell Adh Migr. 2014;8: Klein R. Current opinion in cell biology. 2004;16: Lee JR. BMB reports. 2015;48: Lee da Y et al Genes Dev. 2010;24: Pinkas-Kramarski R et al Oncogene. 1997;15: Marwick K et al Lancet. 2015;385 Suppl 1:S65.

Supplementary Figure 4: Map of NOTCH mutations LNR, Lin/NOTCH repeats; HD-N and HD-C, heterodimerization domain N-terminal and C-terminal, respectively; TM, transmembrane domain; RAM, RAM domain; ANK, ankyrin repeat domain; TAD, transcriptional activation domain. Circle colors encode Missense Mutations (Green) and Truncating Mutations (Red). EGF-like HD N HD C TM RAM Ankyrin TAD PEST NOTCH extracellular domain (N EC ) NOTCH transmembrane subunit (N™) Intracellular domain of NOTCH (ICN) Negative regulatory region (NRR) LNR

Supplementary Figure 5: Expression of NE genes in transcriptional subgroups of lung adenocarcinoma in TCGA series Expression of neuroendocrine genes (ASCL1, Dopa Decarboxylase) in transcriptional subtypes of adenocarcinoma in the Cancer Genome Atlas Research (TCGA) series. RNASeq RSEM normalized data was downloaded from Firehose Broad GDAC version The gene expression values were log2 transformed for further data analysis. Gene expression values (Y axis) are on log2 scale. P=2.3e-07P=1.6e-04 Proximal Proliferative Proximal Inflammatory ASCL1|429 (P overall=6.92E-10) P=1.5e-05P=1.2e-06 DDC|1644 (Dopa Decarboxylase) (P overall=3.86E-14) Terminal Respiratory Unit Proximal Proliferative Proximal Inflammatory Terminal Respiratory Unit

Overall survival Recurrence-free survival nmedian5 yr NSCLC-like SCLC-like nmedian5 yr NSCLC-like SCLC-like Survival (years) P = 0.883P = Survival (years) A.B.B. Supplementary Figure 6: Kaplan-Meier survival curves Overall survival (A) and recurrence-free survival (B). Recurrence-free survival was assessed for a subset of patients with completely-resected stage I-IIIa disease. SCLC-like NSCLC-like SCLC-like NSCLC-like