Management and Integration Across Sites

1
Breast Prostate Cancer Cohort Consortium (BPC3)
Overview Study Design, Goals, and Achievements
Michael Thun
BPC3
2
Rationale for Consortia
Genetic research on inherited cancer
susceptibility constrained by

• - Problem of false negatives false positives
  from underpowered single studies (especially for
  gene-gene gene-environment
  interactions)
• - Previously no mechanism for planned
  replication of findings
• - Inadequate standardization of genetic methods
  in association studies
• - Insufficient communication across relevant
  disciplines

3
Rationale for BPC3

• Breast prostate cancer most common cancers in
  men and women respectively.
• Steroid hormone and IGF pathways relevant to
  both sites
• Strong evidence for unexplained component of
  inherited genetic susceptibility to breast and
  prostate cancer
• Limited reproducibility of published findings

4
Specific Aims of BPC3

• Comprehensively survey variation in candidate
  genes in steroid hormone and IGF metabolism
  pathways
• Assess associations of SNPs and haplotypes with
  breast and prostate cancer
• Assess associations with plasma steroid hormone
  levels and IGF levels
• Examine effect modification by steroid hormone
  levels
• Assess effect modification by established breast
  and prostate cancer risk factors
• 6. Establish a network of epidemiologists, human
  geneticists and statisticians for collaborative
  studies

5
Candidate Genes of Interest Steroidogenic
Pathway
Testis/Ovary
Prostate/Breast
LHCGR FSHR Steroidogenesis Cholesterol
STAR CYP11A1 CYP17 HSD3
HSD17B ?4 A-dione, T,E1, E2
Steroid Receptors ESR1, ESR2, AR
SRD5A2 ?4 A, T DHT
E1,E2 Inactivation
Metabolism HSD3A HSD3B
CYP1A1 CYP1B1
CYP3A4 COMT
Hypothalmus GNRH Pituitary GNRHR CGA LHB FSHB
LH FSH
T E1 E2 SHBG
CYP19
Four HSD3 genes and four HSD17B genes
6
Candidate Genes of Interest Growth Hormone and
Insulin-like Growth Factor Pathways
IGF
Growth Factor
GH1 GHR GHRH GHRHR SST - somatostatin
SSTR1-SSRT5 (somatostatin receptors) POU1F1
pituitary specific transciption
factor
7
Number of Cases from Each Cohort in Proof of
Principle Study
8
Organizational Structure BPC3
Harvard cohorts
ACS cohort
EPIC cohort
Multiethnic cohort
PLCO cohort
ATBC cohort
Laboratories for Gene sequencing, SNP
Identification Haplotypes Genotyping
IARC
Harvard
Cambridge
USC
U. Hawaii
GENOTYPING Working group
Data Pooling Centers
STEERING COMMITTEE
Secretariat
PUBLICATIONS Working group
POPULATION GENETICS Working group
STATISTICS Working Group
9
Flow of Genetic Information
Gene Sequencing SNP Identification Selection of
htSNPs
Genotyping
DNA from Cohorts
IARC
Harvard
Cambridge
USC
Hawaii
NCI
Assay Validation Quality Control Group Purchasing
Data Pooling Centers
Writing teams
10
Flow of Information on Environmental Factors
Harvard cohorts
ACS cohort
EPIC cohort
Multiethnic cohort
PLCO cohort
ATBC cohort
Inventory Covariate Data Standardize
Coding Conduct Initial Analyses
Data Pooling Centers
Writing teams
11
Timeline- Breast Prostate Study
Oct 2000 Study Concept Endorsed by NCI
Jul-Dec 2002 Reviews by NIH NCI Executive
Committee Advisory Board
Jan 2005 18 Month Progress Review
May 2007 Funding Ends
Apr 2003 Grant Funded
Feb 02 Grant Submitted
12
Progress to date

• Established a mechanism to
• Perform detailed comprehensive
  characterization of candidate genes
• Conduct highly standardized genetic analyses in
  large-scale prospective association studies
• Systematically evaluate pathways
• Validate promising findings from other approaches
  (such as whole gene amplification)

13
Other Progress

• David Altshuler will describe the progress of
  BPC3 in characterizing the candidate genes and
  making this information immediately available on
  the Web.
• David Hunter will describe the progress of BPC3
  in conducting highly standardized
  cost-effective genotyping and then integrating
  this with prospectively collected data on risk
  factors from the cohorts. He will describe some
  early results and discuss possible future
  directions of the consortium.

14
(No Transcript)
15
Interim Goals Comparing Minimum 18-month
Performance Criteria to Actual Accomplishments (1)

• Performance Criteria
• Organizational Needs
• Hold Monthly Conference Calls and Semi-Annual
  Meetings
• Establish Subcommittees
• Determine Work Scope and Data Sharing Methods
• Identify Data Availability Calculate Power
• Prepare a Quality Control Plan
• Genetic Plans
• Resequencing
• Develop Haplotype and Haplotype Tags
• Share Data Across Genotyping Centers
• Identify Specific Case-Control Groups
• Genotype

16
Interim Goals Comparing Minimum 18-month
Performance Criteria to Actual Accomplishments (2)

• Performance Criteria
• Data Congruency
• Identify Common Questionnaire Elements
• Determine Methods for Parallel Analyses
• Develop Plans to Share Pooled Data Internally
• Extra Credit
• Draft Methods Paper Describing Consortium
• Have Results from Parallel Analyses for First
  Genes Typed
• Complete Pooled Analyses for First Genes Typed
• Preliminary Manuscript for Multivariate Analyses
  of Gene-Environment Interactions for Prostate
  Cancer
• Preliminary Manuscript for Multivariate
  Analyses of Gene-Environment Interactions for
  Breast Cancer