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 1 Individual genes and genome regions containing multiple genes which contained methylation probes with the strongest Spearman correlations (p < 10⁻⁸) with log(IC50) of antitumor agents

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

Agent	Inhibitor category	Associated genes	Chromosomal location	Highest \|ρ\| for probe methylation vs log(IC50)	Lowest p 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)
4SC-202	HDAC	*SNED1*	2q37.3	0.6927	1.16 × 10⁻¹⁰	0.1492	0.2281	0.2178	0.0789	NM_001080437 (SNED1)
BIM-46187	Pan-G-protein	*C8orf74*	8p23.1	− 0.6721	6.47 × 10⁻¹⁰
R-547	CDK	*TREX1*	3p21.31	− 0.6674	9.39 × 10⁻¹⁰
CT-32228	LPAAT-β	*STK39*	2q24.3	0.6620	1.43 × 10⁻⁹	− 0.0575	0.6438	− 0.1757	0.1581	NM_013233 (STK39)
Pyrvinium pamoate		*FBXL18*	7p22.1	0.6612	1.51 × 10⁻⁹	0.0083	0.9471	− 0.0427	0.7333	NM_024963 (FBXL18)
Digoxin		*KLHL26*	19p13.11	0.6606	1.58 × 10⁻⁹	0.0266	0.8309	0.2699	0.0284	NM_018316 (KLHL26)
Astex FGF inhibitor	FGFR	*TRIM2*	4q31.3	0.6580	1.94 × 10⁻⁹	0.0143	0.9085	− 0.1558	0.2117	NM_015271 (TRIM2)
ENMD-2076	Aurora kinase	*NRP1*	10p11.22	0.6566	2.14 × 10⁻⁹	0.1231	0.3212	0.3968	0.0010	NM_003873 (NRP1)
Olaparib	PARP1	*LHX4*	1q25.2	0.6559	2.26 × 10⁻⁹	0.0803	0.5184	0.4303	0.0003	NM_033343 (LHX4)
Depsipeptide	HDAC	*VWF*	12p13.31	− 0.6535	2.70 × 10⁻⁹	− 0.1586	0.1999	0.3311	0.0066	NM_000552 (VWF)
Tamoxifen	SERM	*CABIN1*	22q11.23	0.6510	3.26 × 10⁻⁹	− 0.0575	0.6437	− 0.2398	0.0525	NM_012295 (CABIN1)
SNS-314	Aurora kinase	*TPM3*	1q21.3	0.6507	3.34 × 10⁻⁹	0.1638	0.1854	0.0760	0.5441	NM_152263 (TPM3)
ENMD-2076	Aurora kinase	*FOXN3*	14q31.3	− 0.6500	3.52 × 10⁻⁹	0.0638	0.6081	− 0.0538	0.6677	NM_001085471 (FOXN3)
Depsipeptide	HDAC	*FYN*	6q21	− 0.6490	3.78 × 10⁻⁹	− 0.1180	0.3415	− 0.0357	0.7762	NM_002037 (FYN)
XL-888	HSP-90	*ETV6, RNU6-19P*	12p13.2	− 0.6474	4.25 × 10⁻⁹	0.2387	0.0518	− 0.2837	0.0210	NM_001987 (ETV6)
Depsipeptide	HDAC	*MTERFD3*	12q23.3	− 0.6468	4.43 × 10⁻⁹	0.1686	0.1725	− 0.3133	0.0104	NM_001033050 (MTERFD3)
ARQ-197	c-Met	*TRIM2*	4q31.3	0.6498	4.73 × 10⁻⁹	− 0.0801	0.5228	− 0.1558	0.2117	NM_015271 (TRIM2)
TAK-901	Aurora kinase	*TREX1*	3p21.31	− 0.6457	4.81 × 10⁻⁹
Flavopiridol	CDK	*ATP13A3*	3q29	− 0.6434	5.68 × 10⁻⁹	0.1702	0.1685	− 0.4160	0.0005	NM_024524 (ATP13A3)
YK-4-279	ERG	*TRIM2*	4q31.3	0.6426	6.00 × 10⁻⁹	− 0.1094	0.3782	− 0.1558	0.2117	NM_015271 (TRIM2 )
R-547	CDK	*GIGYF2*	2q37.1	0.6424	6.09 × 10⁻⁹	− 0.1255	0.3114	− 0.1350	0.2798	NM_001103147 (GIGYF2)
R-547	CDK	*SP2*	17q21.32	0.6407	6.88 × 10⁻⁹	0.2484	0.0427	0.1529	0.2203	NM_003110 (SP2)
ZIP-301		*TRIM2*	4q31.3	0.6406	6.93 × 10⁻⁹	− 0.0669	0.5905	− 0.1558	0.2117	NM_015271 (TRIM2)
TAK-960 analog	PLK-1	*FGF13*	Xq26.3	0.6396	7.42 × 10⁻⁹	− 0.0133	0.9151	0.3407	0.0051	NM_004114 (FGF13)
Digoxin		*SLC16A6, ARSG*	17q24.2	0.6389	7.83 × 10⁻⁹	− 0.1918	0.1199	− 0.3055	0.0126	NM_014960 (ARSG)
SC-1	Ras-GAP	*WT1*	11p13	− 0.6377	8.50 × 10⁻⁹	− 0.3245	0.0074	0.5277	5.28 × 10^-6	NM_024424 (WT1)
Depsipeptide	HDAC	*AHSG*	3q27.3	− 0.6374	8.66 × 10⁻⁹	− 0.0101	0.9356	0.0429	0.7323	NM_001622 (AHSG)
ONX-0912	Proteasome	*HRNBP3*	17q25.3	− 0.6368	9.06 × 10⁻⁹
GSK-461364	PLK-1	*NRP1*	10p11.22	0.6367	9.09 × 10⁻⁹	0.2571	0.0357	0.3968	0.0010	NM_003873 (NRP1)
SB-590885	BRAF	*LOH12CR1*	12p13.2	− 0.6364	9.31 × 10⁻⁹	− 0.1878	0.1280	− 0.0711	0.5705	NM_058169 (LOH12CR1)
Flavopiridol	CDK	*CYP19A1*	15q21.2	0.6360	9.54 × 10⁻⁹	0.1601	0.1955	0.1494	0.2313	NM_031226 (CYP19A1)

Shown are the strongest correlations with drug response, for genes or combined gene regions with at least one probe satisfying p_O < 10⁻⁸ for Spearman correlation between methylation beta-values and log(IC50). Among multiple transcripts matching the same gene, the best matching transcript was identified by finding all Affymetrix transcripts with matching gene names and by selecting the most significant transcript from Spearman correlation between log₂ of transcript expression and methylation of each probe within the gene/gene region that had been associated with log(IC50) of that agent with p_O < 5 × 10⁻⁷. We also provide the NCBI or Ensembl ID of the transcript with a matching gene name that had the most significant Pearson correlation between log2 of transcript expression with log(IC50) of the agent. For those gene regions where probes with p_O < 5 × 10⁻⁷ were assigned to multiple genes in the Infinium MethylationEPIC BeadChip manifest annotation [29] according to the UCSC genome annotation, the output summary for multiple genes was combined, as shown in the Gene Regions column for the regions combining ETV6 and RNU6-19P output and SLC16A6 and ARSG output. An expanded list of genes and combined genome regions containing multiple genes, each with at least one methylation probe satisfying p_O < 9.42 × 10⁻⁸, is provided in Supplementary Table 4. Correlation results of log₂ of expression of the most strongly correlated transcript with probe methylation and with log(IC50) are provided for those genes that had matching transcript data in the Affymetrix GeneChip®Human Exon 1.0 ST Array.
Cluster ID transcript cluster ID for the Affymetrix GeneChip®Human Exon 1.0 ST Array, ρ Spearman correlation coefficient, r Pearson correlation coefficient, CDK cyclin-dependent kinase, HDAC histone deacetylase, LPAAT-β lysophosphatidic acid acyltransferase-β, PLK-1 polo-like kinase 1, SERM selective estrogen receptor modulator

Back to article page

ISSN: 1868-7083

Contact us

Submission enquiries: avalyn.villar@springernature.com
General enquiries: info@biomedcentral.com

Clinical Epigenetics

Contact us