Genes associated with genotype-specific DNA methylation in squamous cell carcinoma as drug target candidates Ryoichi Kinoshita 1 , Mitsuo Iwadate 2 , Hideaki Umeyama 2 and Y-H. Taguchi 1 1 Department of Physics 2 Department of Biological Science Chuo University JSBi Poster #24
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Genes associated with genotype-specific DNA methylation in squamous cell carcinoma as drug target candidates
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Genes associated with genotype-specific DNA methylation in squamous cell
carcinoma as drug target candidates
Ryoichi Kinoshita1, Mitsuo Iwadate2,
Hideaki Umeyama2 and Y-H. Taguchi1
1Department of Physics2Department of Biological Science
Chuo UniversityJSBi Poster
#24
1. Background
Gene (protein coding) → Mutation → Cancer
→ does not explain all cancer related gene anomaly
→ anomaly in unmutated (protein coding) gene expression may also be important
e.g. cancer ↔ aberrant promoter methylation
Cancer Drug → efficiency is always < 100%
→ Need of tailor-made medicine
→ possibly because of genomic divergence
genomic divergence ↔ SNPs ?
Purpose of this study:SNP ↔ DNA methlylation → gene anomaly → Drug discovery
2 Materials
Genotype DNA methylation
microarray measurement Nsp:262339 probes (SNPs)
blood30 samples
adjacentnormaltissue
30 samples
tumor30 samples
microarray measurement Sty:238379 probes (SNPs)
GEO:GSE20123
Taken from 30 patients
assumed to be unmutated
mutatedin between
names of Restriction enzyme → SNP arrays
blood normaltissue
tumor bloodnormaltissue
tumor
Sty1300
SNPs
Nsp68
SNPs
Sty181
SNPs
Sty250
SNPs
Nsp300
SNPs
Sty2300
SNPs
Sty1300
SNPs
Nsp300
SNPs
Sty2300
SNPs
Intersection between genotype and DNA methylation
Selection by PCA
Genotype DNA methylation
These SNPs are …, abundant and aberrantly methylated in cancer
3. Methods
Selection by PCAP
C2
PC1
Gen
otyp
eD
NA
met
hyl
atio
n
2D embeddings of SNPs PC1 PC2
☓
Can
c er△
adjac ent n
ormal tis su
e◯
blood
☓
Can
c er△
adjac ent n
ormal tis su
e◯
blood
Comparison of commonly selcted SNPs between genotype and methylation
hypom
ethylated
abundant in ca
ncer
These SNPs are …, abundant and aberrantly methylated in cancer
Nsp68
SNPs
Nsp59
SNPs
Sty181
SNPs
Sty122
SNPs
Sty250
SNPs
Sty237
SNPs
Screened by pairwise t test (blood, normal tissue, tumor)
155Genes
Genes associated with SNPs
Screened by t test and detection of associated genes
155Genes
86Genes
3DStructures
3D structure Prediction by FAMS & phyre2
Screened by cancer association (by gendoo server)
Screened by cancer association and prediction of protein 3D structure
7-Hydroxystaurosporine binding to ALK(Top ranked drug candidate)
ALK
7-Hydroxystaurosporine
Conclusion
We have successfully constructed virtual screening pipe line for drug discovery from genotype specific DNA methylation information.
This pipeline is expected to be applied to other diseases than cancers
JSBi Poster#24
This study was accepted for the publication in BMC Systems Biology in a supplementary issue as a proceedings of APBC2014 (17th-19th Jan. 2014, Shanghai)