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Expansion of Prostate Cancer Genome-wide Association Studies and Follow-up of Clinically Promising Results

Principal Investigator
Name
Sonja Berndt
Degrees
Ph.D., Pharm.D.
Institution
National Cancer Institute
Position Title
Senior Investigator
Email
About this CDAS Project
Study
PLCO (Learn more about this study)
Project ID
2007-0258
Initial CDAS Request Approval
Apr 23, 2008
Title
Expansion of Prostate Cancer Genome-wide Association Studies and Follow-up of Clinically Promising Results
Summary
The PLCO Etiologic and Early Marker Studies (EEMS) have contributed recently to significant advances in understanding the etiology of prostate cancer, including studies of risks in relation to dietary, biochemical, and genetic factors. PLCO is a key component in the NCI Cancer Genetic Markers of Susceptibility (CGEMS) genome-wide association study (GWAS) of prostate cancer and the Breast and Prostate Cancer Cohort Consortium (BPC3) and these investigations have shown the power of large-scale genomic epidemiologic studies to uncover the genetic determinants of this disease. The advances made in studying prostate cancer overall need now to be extended to investigate risks for the most clinically aggressive forms of this disease, to evaluate associations in high-risk African Americans, and to examine translational implications of the new findings from GWAS. In the past 18 months, at least seven novel genetic variants have been related to risk for prostate cancer; work continues in CGEMS to discover new regions of interest, to fine map high-priority regions and to fill in under-assessed regions, such as the Y chromosome. A verified genetic association has been demonstrated between prostate cancer risk and a gene of important function in the prostate, namely MSMB which encodes PSP94, a key protein in seminal fluid. Moreover, PSP94 and its genetic determinants have potential use in early detection and prognosis of this disease, an important development for translational research. We plan new genome-wide association studies (GWAS) focusing on aggressive prostate cancer (Aim 1) and high-risk African Americans (Aim 2), to be carried out in the BPC3 extension and in the Multi-Ethnic Cohort Study (MEC, also member of BPC3), respectively. In the BPC3 extension new GWAS findings from other investigators and other large-scale analyses will also be carried out (Aim 3). The PLCO, with extensive screening-related data and with currently on-going prostate cancer tissue microarray (TMA) construction, will also provide unique opportunities for translational studies, with primary focus on genetic and protein markers in early detection (Aim 4) and tumor-based (Aim 5) applications, with PSP94 the most prominent current lead.
Aims

1. Conduct a GWAS of aggressive prostate cancer in 1300 white prostate cancer cases and 1300 matched controls in the Breast and Prostate Cancer Cohort Consortium (BPC3, PLCO Stage 1 contribution is n= 437 cases, screening arm; 281 have already been genotyped in CGEMS). Confirm findings from this and other GWAS in an equal number of aggressive cases and controls from these cohorts (PLCO Stage 2 contribution is 300 cases, control arm). 2. Conduct a GWAS of prostate cancer in 1500 African Americans and 1500 controls from the Multiethnic Cohort and the Southern Community Cohort, and confirm findings from this and other GWAS in 3100 cases and 3300 controls in other studies of African Americans (PLCO contribution to replication studies is 284 cases and controls from the PLCO screened or control arm). 3. Continue and expand the BPC3 collaborative database for all prostate cancer to accumulate over 16,000 cases of prostate cancer, with matched controls, for genetic association studies of prostate cancer (PLCO contribution is 2500 cases and 2500 controls). 4. Translate GWAS findings to the clinical setting by evaluating GWAS-identified prostate cancer genetic markers and PSP94 and PSA protein profiles in relation to case-control status and tumor aggressiveness (PLCO CGEMS subjects, 1200 cases and 1200 controls, ). 5. Translate GWAS findings to the clinical setting by evaluating MSMB genetics in relation to PSP94 protein expression in tumors (PLCO TMA under preparation, PLCO contribution >= 300 cases).

Collaborators

Ruth Pfeiffer (NCI, DCEG)
Sonja, Berndt (NCI, DCEG)
Chris Haiman (University of Southern California)
David Hunter (Harvard University)
Janet Standford (FHCRC)
Stephen Chanock (NCI, CGF)
Robert Hoover (NCI, DCEG)
Gerald Andriole (Washington University)

Approved Addenda This project has one or more approved addenda.
  • Exome sequencing to identify variants for aggressive prostate cancer
  • Exome sequencing of African American prostate cancer cases and controls
  • Controls for Exome Sequencing of Aggressive and Non-Aggressive Prostate Cancer Cases
Related Publications
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    Nat. Genet. 2018 Jun PUBMED
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