Supplementary Figure 1 A B C CD56 D E F CD56.

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Supplementary Figure 1 A B C CD56 D E F CD56

LCNEC 68c PIK3CA_E545K LCNEC 13c PTEN_S59* G A T C A LCNEC 9c Supplementary Figure 2 LCNEC 68c PIK3CA_E545K LCNEC 13c PTEN_S59* G A T C A LCNEC 9c PTEN_K342* T G C T C A C T G A G C A G A LCNEC 11p MTOR_E2419K LCNEC 4c RICTOR_R910H G G C T T C C A G C A G T G T A C G A A C A T T

OCP: Oncomine® Cancer Research Panel Supplementary Figure 3 Sample Gene symbol Target Seq. OCP Copy number LCNEC 72C FGFR1 20.3 20.6 LCNEC 42C MYCL1 10.5 11.5 LCNEC 1p MYCN 18.3 22.3 KIT 8.0 6.7 PDGFRA 7.2 LCNEC 9p KRAS 28.2 23.9 MYC 16.7 21.3 SCLC_106C 7.8 8.7 SCLC_187C 10.9 11.6 SCLC_143C 52.5 84.3 OCP 84 53 (Copy number) (Copy number) Target Sequence OCP: Oncomine® Cancer Research Panel LCNEC: large cell neuroendocrine carcinoma, SCLC: small cell lung cancer

Supplementary Figure 4 MYC MYCL1 FGFR1

Supplementary Figure 5 RTKs: receptor tyrosine kinases female Sex Smoking History Advanced Case　 Symbol n PI3K/AKT/mTOR pathway MYC family MAPK/ERK pathway Major RTKs Others PI3K /AKT /mTOR pathway PIK3CA 5 PTEN 8 AKT2 3 RICTOR MTOR MYC MYCL1 6 MYCN MAPK　/ERK pathway KRAS HRAS MAP2K1 1 MAP2K2 NF1 4 FGFR1 KIT 2 ERBB2 ROS1 PDGFRA EGFR IGF1R RET MET TP53 110 RB1 56 CREBBP RTKs: receptor tyrosine kinases female never smoker biopsy cases (advanced cases) missense mutation nonsense mutation frame-shift indel inframe indel hotspot mutation copy number gain amplification

M: mutation, scr: Immunohistochemistry (IHC) scoring Supplementary Figure 6 RB1 M RB scr p16 frameshift indel nonsense mutation IHC strong positive IHC weak positive M: mutation, scr: Immunohistochemistry (IHC) scoring

M: mutation, CN: copy number, scr: Immunohistochemistry (IHC) scoring Supplementary Figure 7 KIT M CN scr EGFR IGF1R KDR ERBB2 FGFR1 c-Met RET ROS1 hotspot mutation frameshift indel missense mutation copy number gain amplification IHC strong positive IHC weak positive M: mutation, CN: copy number, scr: Immunohistochemistry (IHC) scoring