title: HES5 silencing is an early and recurrent change in prostate tumourigenesis.
abstract: Prostate cancer is the most common cancer in men, resulting in over 10 000 deaths/year in the UK. Sequencing and copy number analysis of primary tumours has revealed heterogeneity within tumours and an absence of recurrent founder mutations, consistent with non-genetic disease initiating events. Using methylation profiling in a series of multi-focal prostate tumours, we identify promoter methylation of the transcription factor HES5 as an early event in prostate tumourigenesis. We confirm that this epigenetic alteration occurs in 86-97% of cases in two independent prostate cancer cohorts (n=49 and n=39 tumour-normal pairs). Treatment of prostate cancer cells with the demethylating agent 5-aza-2'-deoxycytidine increased HES5 expression and downregulated its transcriptional target HES6, consistent with functional silencing of the HES5 gene in prostate cancer. Finally, we identify and test a transcriptional module involving the AR, ERG, HES1 and HES6 and propose a model for the impact of HES5 silencing on tumourigenesis as a starting point for future functional studies.
authors.affiliation: Cancer Research UK Cambridge InstituteUniversity of Cambridge, Cambridge, CB2 0RE, UKDivision of Genetics and EpidemiologyThe Institute of Cancer Research, Sutton, UKDepartment of Biological Sciences and School of MedicineUniversity of East Anglia, Norwich, UKRoyal Marsden NHS Foundation TrustLondon and Sutton, UKDepartments of PathologyUrologySurgical OncologyAddenbrooke's Hospital, Hills Road, Cambridge, UK charlie.massie@cruk.cam.ac.uk andy.lynch@cruk.cam.ac.uk.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Massie
authors.affiliation: Cancer Research UK Cambridge InstituteUniversity of Cambridge, Cambridge, CB2 0RE, UKDivision of Genetics and EpidemiologyThe Institute of Cancer Research, Sutton, UKDepartment of Biological Sciences and School of MedicineUniversity of East Anglia, Norwich, UKRoyal Marsden NHS Foundation TrustLondon and Sutton, UKDepartments of PathologyUrologySurgical OncologyAddenbrooke's Hospital, Hills Road, Cambridge, UK.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Spiteri
authors.affiliation: Cancer Research UK Cambridge InstituteUniversity of Cambridge, Cambridge, CB2 0RE, UKDivision of Genetics and EpidemiologyThe Institute of Cancer Research, Sutton, UKDepartment of Biological Sciences and School of MedicineUniversity of East Anglia, Norwich, UKRoyal Marsden NHS Foundation TrustLondon and Sutton, UKDepartments of PathologyUrologySurgical OncologyAddenbrooke's Hospital, Hills Road, Cambridge, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Ross-Adams
authors.affiliation: Cancer Research UK Cambridge InstituteUniversity of Cambridge, Cambridge, CB2 0RE, UKDivision of Genetics and EpidemiologyThe Institute of Cancer Research, Sutton, UKDepartment of Biological Sciences and School of MedicineUniversity of East Anglia, Norwich, UKRoyal Marsden NHS Foundation TrustLondon and Sutton, UKDepartments of PathologyUrologySurgical OncologyAddenbrooke's Hospital, Hills Road, Cambridge, UK.
authors.forename: Hayley
authors.initials: H
authors.lastname: Luxton
authors.affiliation: Cancer Research UK Cambridge InstituteUniversity of Cambridge, Cambridge, CB2 0RE, UKDivision of Genetics and EpidemiologyThe Institute of Cancer Research, Sutton, UKDepartment of Biological Sciences and School of MedicineUniversity of East Anglia, Norwich, UKRoyal Marsden NHS Foundation TrustLondon and Sutton, UKDepartments of PathologyUrologySurgical OncologyAddenbrooke's Hospital, Hills Road, Cambridge, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kay
authors.affiliation: Cancer Research UK Cambridge InstituteUniversity of Cambridge, Cambridge, CB2 0RE, UKDivision of Genetics and EpidemiologyThe Institute of Cancer Research, Sutton, UKDepartment of Biological Sciences and School of MedicineUniversity of East Anglia, Norwich, UKRoyal Marsden NHS Foundation TrustLondon and Sutton, UKDepartments of PathologyUrologySurgical OncologyAddenbrooke's Hospital, Hills Road, Cambridge, UK.
authors.forename: Hayley C
authors.initials: HC
authors.lastname: Whitaker
authors.affiliation: Cancer Research UK Cambridge InstituteUniversity of Cambridge, Cambridge, CB2 0RE, UKDivision of Genetics and EpidemiologyThe Institute of Cancer Research, Sutton, UKDepartment of Biological Sciences and School of MedicineUniversity of East Anglia, Norwich, UKRoyal Marsden NHS Foundation TrustLondon and Sutton, UKDepartments of PathologyUrologySurgical OncologyAddenbrooke's Hospital, Hills Road, Cambridge, UK.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Dunning
authors.affiliation: Cancer Research UK Cambridge InstituteUniversity of Cambridge, Cambridge, CB2 0RE, UKDivision of Genetics and EpidemiologyThe Institute of Cancer Research, Sutton, UKDepartment of Biological Sciences and School of MedicineUniversity of East Anglia, Norwich, UKRoyal Marsden NHS Foundation TrustLondon and Sutton, UKDepartments of PathologyUrologySurgical OncologyAddenbrooke's Hospital, Hills Road, Cambridge, UK Cancer Research UK Cambridge InstituteUniversity of Cambridge, Cambridge, CB2 0RE, UKDivision of Genetics and EpidemiologyThe Institute of Cancer Research, Sutton, UKDepartment of Biological Sciences and School of MedicineUniversity of East Anglia, Norwich, UKRoyal Marsden NHS Foundation TrustLondon and Sutton, UKDepartments of PathologyUrologySurgical OncologyAddenbrooke's Hospital, Hills Road, Cambridge, UK Cancer Research UK Cambridge InstituteUniversity of Cambridge, Cambridge, CB2 0RE, UKDivision of Genetics and EpidemiologyThe Institute of Cancer Research, Sutton, UKDepartment of Biological Sciences and School of MedicineUniversity of East Anglia, Norwich, UKRoyal Marsden NHS Foundation TrustLondon and Sutton, UKDepartments of PathologyUrologySurgical OncologyAddenbrooke's Hospital, Hills Road, Cambridge, UK.
authors.forename: Alastair D
authors.initials: AD
authors.lastname: Lamb
authors.affiliation: Cancer Research UK Cambridge InstituteUniversity of Cambridge, Cambridge, CB2 0RE, UKDivision of Genetics and EpidemiologyThe Institute of Cancer Research, Sutton, UKDepartment of Biological Sciences and School of MedicineUniversity of East Anglia, Norwich, UKRoyal Marsden NHS Foundation TrustLondon and Sutton, UKDepartments of PathologyUrologySurgical OncologyAddenbrooke's Hospital, Hills Road, Cambridge, UK.
authors.forename: Antonio
authors.initials: A
authors.lastname: Ramos-Montoya
authors.affiliation: Cancer Research UK Cambridge InstituteUniversity of Cambridge, Cambridge, CB2 0RE, UKDivision of Genetics and EpidemiologyThe Institute of Cancer Research, Sutton, UKDepartment of Biological Sciences and School of MedicineUniversity of East Anglia, Norwich, UKRoyal Marsden NHS Foundation TrustLondon and Sutton, UKDepartments of PathologyUrologySurgical OncologyAddenbrooke's Hospital, Hills Road, Cambridge, UK.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Brewer
authors.affiliation: Cancer Research UK Cambridge InstituteUniversity of Cambridge, Cambridge, CB2 0RE, UKDivision of Genetics and EpidemiologyThe Institute of Cancer Research, Sutton, UKDepartment of Biological Sciences and School of MedicineUniversity of East Anglia, Norwich, UKRoyal Marsden NHS Foundation TrustLondon and Sutton, UKDepartments of PathologyUrologySurgical OncologyAddenbrooke's Hospital, Hills Road, Cambridge, UK Cancer Research UK Cambridge InstituteUniversity of Cambridge, Cambridge, CB2 0RE, UKDivision of Genetics and EpidemiologyThe Institute of Cancer Research, Sutton, UKDepartment of Biological Sciences and School of MedicineUniversity of East Anglia, Norwich, UKRoyal Marsden NHS Foundation TrustLondon and Sutton, UKDepartments of PathologyUrologySurgical OncologyAddenbrooke's Hospital, Hills Road, Cambridge, UK.
authors.forename: Colin S
authors.initials: CS
authors.lastname: Cooper
authors.affiliation: Cancer Research UK Cambridge InstituteUniversity of Cambridge, Cambridge, CB2 0RE, UKDivision of Genetics and EpidemiologyThe Institute of Cancer Research, Sutton, UKDepartment of Biological Sciences and School of MedicineUniversity of East Anglia, Norwich, UKRoyal Marsden NHS Foundation TrustLondon and Sutton, UKDepartments of PathologyUrologySurgical OncologyAddenbrooke's Hospital, Hills Road, Cambridge, UK Cancer Research UK Cambridge InstituteUniversity of Cambridge, Cambridge, CB2 0RE, UKDivision of Genetics and EpidemiologyThe Institute of Cancer Research, Sutton, UKDepartment of Biological Sciences and School of MedicineUniversity of East Anglia, Norwich, UKRoyal Marsden NHS Foundation TrustLondon and Sutton, UKDepartments of PathologyUrologySurgical OncologyAddenbrooke's Hospital, Hills Road, Cambridge, UK.
authors.forename: Rosalind
authors.initials: R
authors.lastname: Eeles
authors.affiliation: Cancer Research UK Cambridge InstituteUniversity of Cambridge, Cambridge, CB2 0RE, UKDivision of Genetics and EpidemiologyThe Institute of Cancer Research, Sutton, UKDepartment of Biological Sciences and School of MedicineUniversity of East Anglia, Norwich, UKRoyal Marsden NHS Foundation TrustLondon and Sutton, UKDepartments of PathologyUrologySurgical OncologyAddenbrooke's Hospital, Hills Road, Cambridge, UK.
authors.forename: Anne Y
authors.initials: AY
authors.lastname: Warren
authors.affiliation: Cancer Research UK Cambridge InstituteUniversity of Cambridge, Cambridge, CB2 0RE, UKDivision of Genetics and EpidemiologyThe Institute of Cancer Research, Sutton, UKDepartment of Biological Sciences and School of MedicineUniversity of East Anglia, Norwich, UKRoyal Marsden NHS Foundation TrustLondon and Sutton, UKDepartments of PathologyUrologySurgical OncologyAddenbrooke's Hospital, Hills Road, Cambridge, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Tavaré
authors.affiliation: Cancer Research UK Cambridge InstituteUniversity of Cambridge, Cambridge, CB2 0RE, UKDivision of Genetics and EpidemiologyThe Institute of Cancer Research, Sutton, UKDepartment of Biological Sciences and School of MedicineUniversity of East Anglia, Norwich, UKRoyal Marsden NHS Foundation TrustLondon and Sutton, UKDepartments of PathologyUrologySurgical OncologyAddenbrooke's Hospital, Hills Road, Cambridge, UK Cancer Research UK Cambridge InstituteUniversity of Cambridge, Cambridge, CB2 0RE, UKDivision of Genetics and EpidemiologyThe Institute of Cancer Research, Sutton, UKDepartment of Biological Sciences and School of MedicineUniversity of East Anglia, Norwich, UKRoyal Marsden NHS Foundation TrustLondon and Sutton, UKDepartments of PathologyUrologySurgical OncologyAddenbrooke's Hospital, Hills Road, Cambridge, UK Cancer Research UK Cambridge InstituteUniversity of Cambridge, Cambridge, CB2 0RE, UKDivision of Genetics and EpidemiologyThe Institute of Cancer Research, Sutton, UKDepartment of Biological Sciences and School of MedicineUniversity of East Anglia, Norwich, UKRoyal Marsden NHS Foundation TrustLondon and Sutton, UKDepartments of PathologyUrologySurgical OncologyAddenbrooke's Hospital, Hills Road, Cambridge, UK.
authors.forename: David E
authors.initials: DE
authors.lastname: Neal
authors.affiliation: Cancer Research UK Cambridge InstituteUniversity of Cambridge, Cambridge, CB2 0RE, UKDivision of Genetics and EpidemiologyThe Institute of Cancer Research, Sutton, UKDepartment of Biological Sciences and School of MedicineUniversity of East Anglia, Norwich, UKRoyal Marsden NHS Foundation TrustLondon and Sutton, UKDepartments of PathologyUrologySurgical OncologyAddenbrooke's Hospital, Hills Road, Cambridge, UK charlie.massie@cruk.cam.ac.uk andy.lynch@cruk.cam.ac.uk.
authors.forename: Andy G
authors.initials: AG
authors.lastname: Lynch
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics; D000071230:Transcriptional Regulator ERG
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; C072312:ERG protein, human; C077478:HES5 protein, human
keywords: AR; ERG; HES5; HES6; NOTCH; epigenetics; methylation; prostate cancer