Identification of novel prostate cancer drivers using RegNetDriver: a framework for integration of genetic and epigenetic alterations with tissue-specific regulatory network

Priyanka Dhingra; Alexander Martinez-Fundichely; Adeline Berger; Franklin W Huang; Andre Neil Forbes; Eric Minwei Liu; Deli Liu; Andrea Sboner; Pablo Tamayo; David S Rickman; Mark A Rubin; Ekta Khurana

doi:10.1186/s13059-017-1266-3

Identification of novel prostate cancer drivers using RegNetDriver: a framework for integration of genetic and epigenetic alterations with tissue-specific regulatory network

Genome Biol. 2017 Jul 27;18(1):141. doi: 10.1186/s13059-017-1266-3.

Authors

Priyanka Dhingra^{1

2}, Alexander Martinez-Fundichely^{1

2}, Adeline Berger³, Franklin W Huang^{4

5

6}, Andre Neil Forbes^{1

2}, Eric Minwei Liu^{1

2}, Deli Liu^{1

7}, Andrea Sboner^{2

3

8}, Pablo Tamayo^{6

9

10}, David S Rickman^{11

12

13}, Mark A Rubin^{3

8

14}, Ekta Khurana^{15

16

17

18}

Affiliations

¹ Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York, 10065, USA.
² Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York, 10021, USA.
³ Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York, 10065, USA.
⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA.
⁵ Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, MA, 02115, USA.
⁶ Cancer Program, The Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA, 02142, USA.
⁷ Department of Urology, Weill Cornell Medical College, New York, New York, 10065, USA.
⁸ Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, New York, NY, 10065, USA.
⁹ Department of Medicine, University of California San Diego, La Jolla, California, USA.
¹⁰ Moores Cancer Center, University of California San Diego, La Jolla, California, USA.
¹¹ Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York, 10065, USA. dsr2005@med.cornell.edu.
¹² Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, New York, NY, 10065, USA. dsr2005@med.cornell.edu.
¹³ Meyer Cancer Center, Weill Cornell Medical College, New York, New York, 10065, USA. dsr2005@med.cornell.edu.
¹⁴ Meyer Cancer Center, Weill Cornell Medical College, New York, New York, 10065, USA.
¹⁵ Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York, 10065, USA. ekk2003@med.cornell.edu.
¹⁶ Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York, 10021, USA. ekk2003@med.cornell.edu.
¹⁷ Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, New York, NY, 10065, USA. ekk2003@med.cornell.edu.
¹⁸ Meyer Cancer Center, Weill Cornell Medical College, New York, New York, 10065, USA. ekk2003@med.cornell.edu.

Abstract

We report a novel computational method, RegNetDriver, to identify tumorigenic drivers using the combined effects of coding and non-coding single nucleotide variants, structural variants, and DNA methylation changes in the DNase I hypersensitivity based regulatory network. Integration of multi-omics data from 521 prostate tumor samples indicated a stronger regulatory impact of structural variants, as they affect more transcription factor hubs in the tissue-specific network. Moreover, crosstalk between transcription factor hub expression modulated by structural variants and methylation levels likely leads to the differential expression of target genes. We report known prostate tumor regulatory drivers and nominate novel transcription factors (ERF, CREB3L1, and POU2F2), which are supported by functional validation.

Keywords: Cancer drivers; DNA methylation; Prostate cancer; Single nucleotide variants; Structural variants; Tissue-specific regulatory network.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Algorithms*
Binding Sites
Carcinogenesis / genetics*
Carcinogenesis / metabolism
Carcinogenesis / pathology
Chromosome Mapping
Cyclic AMP Response Element-Binding Protein / genetics*
Cyclic AMP Response Element-Binding Protein / metabolism
DNA Methylation
Deoxyribonuclease I
Epigenesis, Genetic
Gene Expression Regulation, Neoplastic*
Gene Regulatory Networks
Humans
Male
Nerve Tissue Proteins / genetics*
Nerve Tissue Proteins / metabolism
Octamer Transcription Factor-2 / genetics*
Octamer Transcription Factor-2 / metabolism
Organ Specificity
Polymorphism, Single Nucleotide
Promoter Regions, Genetic
Prostatic Neoplasms / genetics*
Prostatic Neoplasms / metabolism
Prostatic Neoplasms / pathology
Protein Binding
Protein Interaction Mapping
Repressor Proteins / genetics*
Repressor Proteins / metabolism

Substances

CREB3L1 protein, human
Cyclic AMP Response Element-Binding Protein
ERF protein, human
Nerve Tissue Proteins
Octamer Transcription Factor-2
POU2F2 protein, human
Repressor Proteins
Deoxyribonuclease I

Abstract

Publication types

MeSH terms

Substances

Grants and funding