Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer Genome-Wide Association Study (GWAS) - Primary Scan (Stage 1) - PLCO Screening Trial

The Cancer Genetic Markers of Susceptibility (CGEMS) prostate cancer genome-wide association study (GWAS) included genotyping approximately 550,000 SNPs (Phase 1A with HumanHap300 and Phase 1B HumanHap240, both from Illumina, San Diego, CA) in 1,172 prostate cancer patients and 1,157 controls of European ancestry from the Prostate, Lung, Colon and Ovarian (PLCO, http://www.cancer.gov/prevention/plco/) Cancer Screening Trial. The original analysis published in Nature Genetics [PMID: 17401363] included 2,282 subjects. After improvement and revisions of the original analysis, 2,252 subjects were submitted to dbGaP.

• Study Weblinks:
  • Cancer Genetic Markers of Susceptibility (CGEMS)
  • National Health and Nutrition Examination Survey
• Study Design:
  • Case-Control
• Study Type:
  • Case-Control
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 2252
• Subject Sample Telemetry Report (SSTR)

• BioProject
• PubMed
• BioSample
• MeSH
• PMC

A total of 1,361 subjects with prostate cancer met the eligibility criteria and were considered for the CGEMS project; 737 cancers were aggressive 624 cancers were nonaggressive. Of the eligible cases, all aggressive cases (n=737) were chosen to be cases in the CGEMS prostate cancer study. Of the 624 men found to have non-aggressive tumors, 493 men (70.4%) whose diagnosis was temporally closest to the first screening were included in this study.

Controls were selected by incidence-density sampling. The first step was creation of non-overlapping sets of cases characterized by:

1. Calendar year (FY) of entry into the cohort,
2. Age at entry in five-year intervals (55-59, 60-64, 65-69, 70-74)
3. Number of years under follow-up between enrollment and diagnosis of prostate cancer.

Next, for each case set, we identified eligible men among all 28,251 men in the CGEMS cohort who met each of the following three criteria:

1. Same year of entry into the cohort as the case set;
2. Same five-year age-at-entry interval (55-59, 60-64, 65-69, 70-74) as the case set; and
3. Observed through the year of follow-up in the case set with no prostate cancer diagnosis.

The PLCO Cancer Screening Trial is a large, randomized controlled trial of approximately 155,000 men and women. Participants are randomized to either a screening or control arm. Each year after enrollment, subjects are asked to notify the study of any cancers diagnosed in the past year using the Annual Study Update (ASU).

The trial is designed to test the efficacy of cancer screening to prevent early death from prostate, lung, colorectal and ovarian cancer. The collection of questionnaire data and biospecimens (e.g., repeated blood samples and in some instances, buccal cell samples) allows investigation of early markers for cancer as well as etiology of common cancers.

PLCO enrollment began in 1993 and ended in 2001. Recruitment included men and women, aged 55 to 74 with no reported history of prostate, lung, colon and ovarian cancer, although prior diagnoses of other cancers were acceptable.

The CGEMS cohort consisted of men enrolled in the screening arm of the PLCO Trial who:

1. were White and non-Hispanics;
2. had no prior history of prostate of cancer before randomization;
3. had at least one PLCO prostate cancer screen (PSA) before October 1, 2003;
4. had completed a Baseline Questionnaire about risk factors for cancer;
5. had signed informed consent;
6. had provided a blood sample with
1. at least 11 µg DNA
2. at least 1 vial of buffy coat, or
3. at least 7 vials of whole blood was available; and
7. for controls, had returned at least one Annual Study Update (ASU).

Based on these criteria, 28,521 men were included in the CGEMS sub-cohort.

CGEMS distinguishes between non-aggressive and aggressive cases of prostate cancer at the time of diagnosis. The two subtypes are defined as follows:

1. Non-aggressive: cases with a Gleason Score < 7 and Stage < III.
2. Aggressive: cases with a Gleason Sore ≥ 7 or Stage ≥ III.

Study enrollment began on October 1, 1993. Consequently, study years in the PLCO Trial are counted according to the Federal fiscal year, Oct 1 to the next September 30.

All men diagnosed with prostate cancer between enrollment and the end of FY2001 were considered for inclusion in CGEMS. Because of our interest in the clinically more significant, but less common aggressive form of prostate cancer, we increased the fraction of aggressive cases in the CGEMS case series by extending eligibility for cases diagnosed with aggressive prostate cancer through the end of FY2003.

• Primary Phenotype: Prostatic Neoplasms

• Lead Principal Investigator
  • Stephen J. Chanock. Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute and Core Genotyping Facility, Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute (NCI), National Institutes of Health, Department (NIH), Department of Health and Human Services (DHHS), Bethesda, MD, USA.
• Co-Principal Investigators
  • Meredith Yeager. SAIC-Frederick, National Cancer Institute (NCI)-Frederick Cancer Research and Development Center, Frederick, MD, USA and Core Genotyping Facility, DCEG, NCI, NIH, DHHS, Bethesda, MD, USA.
  • David J. Hunter. Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Margaret Tucker. DCEG, NCI, NIH, DHHS, Bethesda, MD, USA.
  • Daniela S. Gerhard. Office of Cancer Genomics, NCI, NIH, DHHS, Bethesda, MD, USA.
  • Joseph F. Fraumeni. DCEG, NCI, NIH, DHHS, Bethesda, MD, USA.
  • Robert Hoover. DCEG, NCI, NIH, DHHS, Bethesda, MD, USA.
  • Gilles Thomas. DCEG, NCI, NIH, DHHS, Bethesda, MD, USA.
• Institutes
  • SAIC-Frederick, National Cancer Institute (NCI)-Frederick Cancer Research and Development Center, Frederick, MD, USA.
  • DCEG, NCI, US NIH, DHHS, Bethesda, MD, USA.
  • Laboratory of Translational Genomics, DCEG, NCI, NIH, DHHS, Bethesda, MD, USA.
  • Bioinformed Consulting Services, Gaithersburg, MD, USA.
  • Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
  • Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
  • Department of Mathematics and Statistics, Lancaster University, Lancaster, UK.
  • Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, GA, USA.
  • Department of Health Promotion and Chronic Disease Prevention, National Public Health Institute, Helsinki, Finland.
  • Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
  • Centre de Recherche pour les Pathologies Prostatiques (CeRePP), Hopital Tenon, Assistance Publique-Hopitaux de Paris, Paris, France.
  • Division of Urologic Surgery, Washington University School of Medicine, St. Louis, MO, USA.
  • Division of Hematology and Oncology, Columbia University, New York, NY, USA.
  • Office of Cancer Genomics, NCI, NIH, DHHS, Bethesda, MD, USA.