# Presentation: 199039

## 			Overview

**	****	****	****Overview**
**Study Design, Goals, and Achievements**

**Michael Thun**
**   **

***BPC3***

**Breast & Prostate Cancer Cohort Consortium (BPC3)**

## Rationale for Consortia

- 	- 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

- Genetic research on inherited cancer susceptibility constrained by:

## 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** **
**	**
**	**

## 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**

## Candidate Genes of Interest – Steroidogenic Pathway

- _Hypothalmus_
**GNRH**
- _Pituitary_
**GNRHR**
**CGA**
**LHB**
**FSHB**

**LHCGR**
**FSHR**
_**Steroidogenesis:**_
**Cholesterol**
**       ****STAR**
**       ****CYP11A1**
**       ****CYP17**
**       ****HSD3***
**       ****HSD17B***
*********4 A-dione, T,******E1, E2***

**Testis/Ovary**

***LH***
***FSH***

**Steroid Receptors**
**ESR1, ESR2, AR**
-            **SRD5A2**
*********4 A, T*****                *****DHT***
**           **
**            **
** *****E1,E2***
**       ****Inactivation &**
**         **_**Metabolism:**_
**            ****HSD3A**
**            ****HSD3B**_** **_
-            **CYP1A1**
**            ****CYP1B1**
**            ****CYP3A4 **
**            ****COMT**

***T***
***E1***
***E2***
**SHBG**

**Prostate/Breast**

**CYP19**

- *Four HSD3 genes and four HSD17B genes

## IGF

- Growth Factor

** ****GH1**
** ****GHR**
** ****GHRH**
** ****GHRHR**
** ****SST**  - somatostatin
** ****SSTR1-SSRT5**
-    (somatostatin receptors)
** ****POU1F1** – pituitary specific
-                   transciption factor

## Number of Cases from Each Cohort in “Proof of Principle” Study

**Number of Cases from Each Cohort in “Proof of Principle” Study**

| Cohort | Breast (N) | Prostate (N) |
| --- | --- | --- |
| CPS-II (ACS) | 500 | 1200 |
| ATBC (NCI) | - | 1060 |
| EPIC (IARC) | 1720 |   950 |
| Harvard Cohorts | 1660 | 2410 |
| MEC (Hawaii/USC) | 1620 | 2320 |
| PLCO (NCI) | - | 1310 |
| Total | 5500 | 9260 |

## Organizational Structure BPC3

**Organizational Structure BPC3**

- STEERING COMMITTEE

- GENOTYPING
- Working group

- POPULATION GENETICS
-  Working group

- Data Pooling Centers

- PUBLICATIONS Working group

- Harvard
- cohorts

- ACS
- cohort

- EPIC
- cohort

- Multiethnic
- cohort

- PLCO
- cohort

- ATBC
- cohort

- Laboratories for:
-     Gene sequencing,     SNP Identification & Haplotypes
-    Genotyping

**STATISTICS **
**Working Group**

- Secretariat

**Harvard**

**IARC**

**   ****Cambridge**

**USC**

**U. Hawaii**

## Flow of Genetic Information 

- Data Pooling Centers

- Gene Sequencing
- SNP Identification
- Selection of htSNPs

- Assay Validation
- Quality Control
- Group Purchasing

- DNA   from Cohorts

- Writing teams

**Harvard**

- Genotyping

**IARC**

**Cambridge**

**USC**

**Hawaii**

**NCI**

## Flow of Information on “Environmental” Factors

**Harvard **
**cohorts**

**ACS **
**cohort**

**EPIC**
**cohort**

**Multiethnic**
**cohort**

**PLCO **
**cohort**

**ATBC **
**cohort**

**Data Pooling Centers**

**Inventory Covariate Data**
**Standardize Coding**
**Conduct Initial Analyses**

**Writing teams**

## Timeline- Breast & Prostate Study

**Oct 2000**
**Study Concept Endorsed by NCI**

**May 2007**
**Funding**
** ****Ends**

**Jan 2005**
**18 Month**
**Progress**
**Review**

**Apr 2003**
**Grant**
**Funded**

**Feb 02**
**Grant**
**Submitted**

**Jul-Dec 2002**
**Reviews by NIH & NCI Executive Committee & Advisory Board**

## 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)

## 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.

## Slide 14

## 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

## 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