Epigenome-wide DNA methylation analysis of small cell lung cancer cell lines suggests potential chemotherapy targets

Krushkal, Julia; Silvers, Thomas; Reinhold, William C.; Sonkin, Dmitriy; Vural, Suleyman; Connelly, John; Varma, Sudhir; Meltzer, Paul S.; Kunkel, Mark; Rapisarda, Annamaria; Evans, David; Pommier, Yves; Teicher, Beverly A.

doi:10.1186/s13148-020-00876-8

Table 3 Candidate genes with methylation probes that had correlations with log(IC50) of candidate antitumor agents satisfying p_FDR < 0.1

From: Epigenome-wide DNA methylation analysis of small cell lung cancer cell lines suggests potential chemotherapy targets

Agent	Inhibitor category	Associated gene	Location	Highest \|ρ\| for probe methylation vs log(IC50)	Lowest p_FDR for probe methylation vs log(IC50)	Highest \|r\| for transcript expression vs log(IC50)	Lowest p for transcript expression vs logIC50	Highest \|ρ\| for transcript expression vs probe methylation	Lowest p for transcript expression vs probe methylation	Transcript with lowest p for expression vs log(IC50)
ABT-348	Aurora kinase	EPAS1	2p21	0.5548	0.0515	0.3638	0.0025	0.6800	3.39 × 10⁻¹⁰	NM_001430 (EPAS1)
ABT-737	Bcl-2	DLL3	19q13.2	0.5506	0.0515	− 0.4139	0.0005	− 0.4426	0.0002	NM_016941 (DLL3)
ABT-737	Bcl-2	FHIT	3p14.2	− 0.5502	0.0515	0.1830	0.1382	− 0.3164	0.0097	ENST00000468189 (FHIT)
ABT-737	Bcl-2	KIT	4q12	− 0.5391	0.0580	− 0.5372	2.77 × 10⁻⁶	0.5426	2.52 × 10⁻⁶	NM_000222 (KIT)
ABT-737	Bcl-2	EPAS1	2p21	− 0.5204	0.0937	− 0.0501	0.6873	0.2638	0.0324	NM_001430 (EPAS1)
AMG-900	Aurora kinase	EPAS1	2p21	0.6278	0.0052*	0.3966	0.0009	0.6800	3.39 × 10⁻¹⁰	NM_001430 (EPAS1)
AS-703569	Aurora kinase	CCND1	11q13.3	− 0.5568	0.0515	− 0.3614	0.0027	0.5972	1.20 × 10⁻⁷	NM_053056 (CCND1)
BEZ-235	mTOR	AKT1	14q32.33	− 0.5370	0.0604	0.2562	0.0363	− 0.3499	0.0040	NM_001014432 (AKT1)
BI-2536	PLK-1	KIF24	9p13.3	0.5403	0.0580	0.1740	0.1591	0.0689	0.5828	NM_194313 (KIF24)
CYC-116	Aurora kinase	EZH2	7q36.1	0.5456	0.0515	− 0.0162	0.8966	− 0.1156	0.3554	NM_004456 (EZH2)
ENMD-2076	Aurora kinase	CCND1	11q13.3	− 0.5777	0.0391*	− 0.4201	0.0004	0.5972	1.20 × 10⁻⁷	NM_053056 (CCND1)
ENMD-2076	Aurora kinase	ALK	2p23.2	− 0.5551	0.0515	0.0036	0.9768	0.2331	0.0597	NM_004304 (ALK)
ENMD-2076	Aurora kinase	EPHA2	1p36.13	0.5233	0.0876	− 0.2090	0.0897	− 0.3787	0.0017	NM_004431 (EPHA2)
ENMD-2076	Aurora kinase	RGS7	1q43	0.5191	0.0948	0.4887	2.72 × 10⁻⁵	0.7412	1.11 × 10⁻¹²	NM_002924 (RGS7)
GSK-461364	PLK-1	EPAS1	2p21	0.5165	0.0994	0.3554	0.0032	0.6800	3.39 × 10⁻¹⁰	NM_001430 (EPAS1)
Sapanisertib	mTOR	IGF1R	15q26.3	0.5262	0.0798	− 0.0889	0.4744	− 0.1369	0.2730	NM_000875 (IGF1R)
MLN-8237	Aurora kinase	EPAS1	2p21	0.5462	0.0515	0.3245	0.0074	0.6800	3.39 × 10⁻¹⁰	NM_001430 (EPAS1)
Olaparib	PARP1	SEMA3B	3p21.31	0.5264	0.0798	− 0.0815	0.5120	0.0907	0.4687	NM_004636 (SEMA3B)
SNS-314	Aurora kinase	EPAS1	2p21	0.5880	0.0322*	0.3434	0.0044	0.6800	3.39 × 10⁻¹⁰	NM_001430 (EPAS1)
SNS-314	Aurora kinase	EZH2	7q36.1	0.5464	0.0515	− 0.0444	0.7215	− 0.1156	0.3554	NM_004456 (EZH2)
TAK-901	Aurora kinase	ZNF423	16q12.1	− 0.5360	0.0604	− 0.1859	0.1319	0.5773	3.88 × 10⁻⁷	NM_015069 (ZNF423)
TAK-960	PLK-1	KIF24	9p13.3	0.5571	0.0515	0.2285	0.0630	0.0689	0.5828	NM_194313 (KIF24)
TAK-960	PLK-1	MYC	8q24.21	0.5432	0.0540	− 0.1537	0.2143	0.2652	0.0314	NM_002467 (MYC)
Salinomycin	Apoptotic	FGFR2	10q26.13	− 0.5334	0.0650	− 0.3237	0.0075	0.6785	3.84 × 10⁻¹⁰	NM_000141 (FGFR2)
Salinomycin	Apoptotic	KIF3B	20q11.21	− 0.5202	0.0937	0.1938	0.1162	− 0.4576	0.0001	NM_004798 (KIF3B)

Listed are the gene-drug correlations for candidate genes in which one or more probes had p_FDR < 0.1 for Spearman correlation with agents listed in Supplementary Table 2. Supplementary Table 6 provides the list of candidate gene-drug pairs satisfying a less stringent criterion of p_FDR < 0.15. The list of individual probes and their individual p values are provided in Supplementary Table 7
p_FDR, FDR-adjusted p value, accounting for multiple testing of 10,515 methylation probes in or near candidate genes and 44 agents listed in Supplementary Table 2.
*p_FDR < 0.05
ρ Spearman correlation coefficient, r Pearson correlation coefficient

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