Supplemental Figure 1 Tumor samples Normal samples Chromosome.

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Supplemental Figure 1 Tumor samples Normal samples Chromosome

Supplemental Figure 2 A B Number of protein altering mutations Percent Number of mutations* SNV 198 Indel 11 Total 209 Percent Number of protein altering mutations G>T,C>A G>C,C>G G>A,C>T A>T,T>A A>G,T>C A>C,T>G Samples

PIK3CA PTEN Supplemental Figure 3 N202Y T313R E545K **Y155H V317- p85 binding domain Ras binding domain C2 domain Helical domain Kinase domain **Y155H V317- PTEN S287* Phos- phatase domain C2 domain

Supplemental Figure 4 Rev. Rev. Rev. SCLC 042 PIK3CA (Vf*: 46.7%) SCLC genome_mut_syntax: g.3:178919119A>T aa_mut_syntax: p.N202Y (Substitution-Missense) SCLC 038 Rev. PIK3CA COSMICid: 764 (Vf*: 60.7%) genome_mut_syntax: g.3:178936091G>A aa_mut_syntax: p.E545K (Substitution-Missense) SCLC 058 ROS1 (Vf*: 41.2%) genome_mut_syntax: g.6:117641077C>T aa_mut_syntax: p.V1965A (Substitution-Missense) SCLC 018 Rev. ROS1 (Vf*: 11.5%) genome_mut_syntax: g.6:117631325C>A aa_mut_syntax: p.R2118I (Substitution-Missense) SCLC 024 KIT (Vf*: 60.0%) genome_mut_syntax: g.4:55589771_3 ACG del aa_mut_syntax: p.Y418del (Deletion-In frame)

Supplemental Figure 5 A B Chromosome Chromosome GISTIC q score

Supplemental Figure 6 copy number loss nonsense mutation  frame-shift indel in-frame indel missense mutation copy number gain

Supplemental Figure 7 A B C

Supplemental Figure 8 A B C PIK3CA p-AKT AKT p-S6RP S6RP GAPDH siNC #1 #2 #3 siPIK3CA