Androgen receptor reprogramming demarcates prognostic, context-dependent gene sets in primary and metastatic prostate cancer

The androgen receptor (AR) is a prostate master transcription factor. It binds to genetic enhancers, where it regulates gene activity and plays a fundamental role in prostate pathophysiology. Previous work has demonstrated that AR-DNA binding is systematically and consistently reprogrammed during prostate tumorigenesis and disease progression. We charted these reprogrammed AR sites and identified genes proximal to them. We were able to devise gene lists based on AR status within specific histological contexts: normal prostate epithelium, primary prostate tumor, and metastatic prostate cancer. We evaluated expression of the genes in these gene sets in subjects from two distinct clinical cohorts—men treated with surgery for localized prostate cancer and men with metastatic prostate cancer. Among men with localized prostate cancer, expression of genes proximal to AR sites lost in the transition from normal prostate to prostate tumor was associated with clinical outcome. Among men with metastatic disease, expression of genes proximal to AR sites gained in metastatic tumors was associated with clinical outcome. These results are consistent with the notion that AR is fundamental to both maintaining differentiation in normal prostate tissue and driving de-differentiation in advanced prostate cancer. More broadly, the study demonstrates the power of incorporating context-dependent epigenetic data into genetic analyses.

Qiu, XintaoDana-Farber Cancer Institute (författare)
Alshalalfa, MohammedUCSF Helen Diller Family Comprehensive Cancer Center (författare)
Sjöström, MartinLund University,Lunds universitet,Bröstcancer Proteogenomik,Forskargrupper vid Lunds universitet,Individuell Bröstcancerbehandling,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Bröstcancerbehandling,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Breast cancer Proteogenomics,Lund University Research Groups,Personalized Breast Cancer Treatment,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Breast cancer treatment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,UCSF Helen Diller Family Comprehensive Cancer Center(Swepub:lu)med-msm (författare)
Quigley, DavidUCSF Helen Diller Family Comprehensive Cancer Center (författare)
Bergman, AndriesAntoni Van Leeuwenhoek Hospital (författare)
Long, HenryDana-Farber Cancer Institute (författare)
Feng, FelixUCSF Helen Diller Family Comprehensive Cancer Center (författare)
Freedman, Matthew L.Dana-Farber Cancer Institute (författare)
Zwart, WilbertAntoni Van Leeuwenhoek Hospital,Eindhoven University of Technology (författare)
Pomerantz, Mark M.Dana-Farber Cancer Institute (författare)
Antoni Van Leeuwenhoek HospitalDana-Farber Cancer Institute (creator_code:org_t)

Ingår i:Clinical Epigenetics: Springer Science and Business Media LLC14:11868-70751868-7083

Av författaren/redakt...: Severson, Tesa; Qiu, Xintao; Alshalalfa, Moha ...; Sjöström, Martin; Quigley, David; Bergman, Andries; visa fler...; Long, Henry; Feng, Felix; Freedman, Matthe ...; Zwart, Wilbert; Pomerantz, Mark ...; visa färre...

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