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Supplementary Table 3: Clinicopathologic characteristics

Supplementary Table 5: Detailed summary of NOTCH gene family mutations

Supplementary Table 6: Complete list of potentially-actionable alterations

Supplementary Table 4: Complete list of mutations and copy number alterations detected by MSK-IMPACT in 45 LCNECs

Supplementary Table 7: Detailed chemosensitivity data

Purpose: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a highly aggressive neoplasm, whose biologic relationship to small cell lung carcinoma (SCLC) versus non-SCLC (NSCLC) remains unclear, contributing to uncertainty regarding optimal clinical management. To clarify these relationships, we analyzed genomic alterations in LCNEC compared with other major lung carcinoma types.Experimental Design: LCNEC (n = 45) tumor/normal pairs underwent targeted next-generation sequencing of 241 cancer genes by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) platform and comprehensive histologic, immunohistochemical, and clinical analysis. Genomic data were compared with MSK-IMPACT analysis of other lung carcinoma histologies (n = 242).Results: Commonly altered genes in LCNEC included TP53 (78%), RB1 (38%), STK11 (33%), KEAP1 (31%), and KRAS (22%). Genomic profiles segregated LCNEC into 2 major and 1 minor subsets: SCLC-like (n = 18), characterized by TP53+RB1 co-mutation/loss and other SCLC-type alterations, including MYCL amplification; NSCLC-like (n = 25), characterized by the lack of coaltered TP53+RB1 and nearly universal occurrence of NSCLC-type mutations (STK11, KRAS, and KEAP1); and carcinoid-like (n = 2), characterized by MEN1 mutations and low mutation burden. SCLC-like and NSCLC-like subsets revealed several clinicopathologic differences, including higher proliferative activity in SCLC-like tumors (P < 0.0001) and exclusive adenocarcinoma-type differentiation marker expression in NSCLC-like tumors (P = 0.005). While exhibiting predominant similarity with lung adenocarcinoma, NSCLC-like LCNEC harbored several distinctive genomic alterations, including more frequent mutations in NOTCH family genes (28%), implicated as key regulators of neuroendocrine differentiation.Conclusions: LCNEC is a biologically heterogeneous group of tumors, comprising distinct subsets with genomic signatures of SCLC, NSCLC (predominantly adenocarcinoma), and rarely, highly proliferative carcinoids. Recognition of these subsets may inform the classification and management of LCNEC patients. Clin Cancer Res; 22(14); 3618–29. ©2016 AACR.

Supplementary Table 2: Immunohistochemical antibodies and protocols

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

Supplementary Table 1: Next-generation sequencing (MSK-IMPACT) gene panel