# Presentation: 574020

## Status Report: The Cancer Genome Atlas Pilot Project

**National Cancer Advisory Board Meeting**
- February 6, 2007
- Anna D. Barker, Ph.D.
- Deputy Director, National Cancer Institute

## TCGA:  An NCI-NHGRI Collaboration in Medical Genomics 

**The Cancer Genome Atlas (TCGA)**** **is a three-year pilot project of the National Cancer Institute and the National Human Genome Research Institute to increase our comprehensive understanding of the** **_**genetic basis of cancer.**__** **_** **

**It is anticipated that TCGA’s integrated database of molecular and clinical information will provide scientists unprecedented opportunities to discover and develop a new generation of targeted diagnostics, therapies, and preventives for cancer. **** **

## Achievements:
Human Genome Project
Gene families and pathways
Robust genomic analysis technologies
Sanger experience - sequenced known genes (e.g., kinases are druggable)
Number of early indications that somatic mutations are important potential targets

- Human Genome Project
- Gene families and pathways
- Robust genomic analysis technologies
- Sanger experience - sequenced known genes (e.g., kinases are druggable)
- Number of early indications that somatic mutations are important potential targets

**Overall Impact:**
- Known human sequence
- Kinases, phosphatases, transcription factors, hormone responsiveness
- Copy number changes, expression profiling, potentially epigenomic technologies
- Survey of known genes that are abnormal *prior to sequencing - BRAF*
*BCR-ABL, EGFR1, ERBB2*

**Enabling Rationale for TCGA**

## TCGA Development Milestones

**TCGA Development Milestones**

**2003**

**2005**

**2004**

***September 2003:****  *NCAB Ad hoc Committee formed

***April 2004:**** *NCI-NHGRI Workshop

***January 2005:**** *Project RFI issued

***September 2004:****  *Presentation to EC

***November 2004:***  Presentation to BSA

***July 2005:****  *Meeting for community input

***November 2005:***
- Presentation to  the BSA - Approval
- NCI Issuance of Human Cancer Biospecimen RFI

***February 2005:****  *
- Ad hoc Committee Report to NCAB
- NCI-NHGRI Working Group formed

***September2005:***
- NCAB Review
- EC Review

***December 2005:***
- NHGRI Issuance of Sequencing Centers RFA
- Public Launch of Pilot Project

## TCGA Development Milestones

**TCGA Development Milestones**

**Fiscal Year 2006**

**2006**

***March 2006:***
- NCI Issuance of Cancer Genome Characterization Centers RFA

***September 2006:****  *
- Selection of tumor types
- NCI Funding of Biospecimen Core Resource

***May 2006:***
- Data Release Workshop

***July / August 2006:****  *
- Site visits to Biorepositories

***February 2006:***
- NCI Issuance of Biospecimen Core Resource RFP

***October / November 2006:****  *
- Funding of Data Coordinating Center
- NCI Funding of Cancer Genome Characterization Centers
- NHGRI Funding of Genome Sequencing Centers

***December 2006: ***
- First TCGA Steering Committee Meeting – all PIs

## TCGA Development Milestones

**TCGA Development Milestones**

**Fiscal Year 2006**

**2007**

***March 2007:***
- Biospecimen Core Resource distributes GBM, lung, and ovarian tumor biomolecules to GSCs and CGCCs

***May 2007:***
- First set of TCGA data is deposited into public databases managed by DCC

***January / February 2007:***
- TCGA Dry Run

***March / April 2007:***
- GSCs and CGCCs perform sequencing and characterization of tumor biomolecules

## TCGA: How it Works

## TCGA Biospecimen Core Resource (BCR) Functions

**Central to the Success of TCGA Pilot, the BCR is:**
- Verifying all biologic and clinical data and performing the pathologic QC of qualified tumors from selected existing collections
- Performing central processing of specimens to provide uniform biomolecules and distributing to both genome characterization and sequencing centers
- Tracking and quality assuring all specimen-related operations (consent, acquisition, transport, processing, QC, distribution)
- Providing “standard” samples for technology platform comparisons
- Developing (with the Office of Biorepositories and Biospecimen Research) and monitor the SOPs for prospective specimen collection
- Serving as a member of TCGA’s Steering Committee

## Technology platforms for high-throughput genome characterization: 
Expression profiling
Copy number changes
DNA methylation (epigenomics)
Improve existing technologies:
Epigenomics to meet required throughput rate
Copy number detection and expression profiling for characterizing small amount of biological samples
Real-time data release into public database

- Expression profiling
- Copy number changes
- DNA methylation (epigenomics)
**Improve existing technologies:**
- Epigenomics to meet required throughput rate
- Copy number detection and expression profiling for characterizing small amount of biological samples
**Real-time data release into public database**

**Cancer Genome ****Characterization Centers (CGCCs)**

## High-throughput Genome Sequencing Centers (NHGRI): 
Sequence large number of targets from three tumor types
Develop and integrate sequencing technologies

- Sequence large number of targets from three tumor types
- Develop and integrate sequencing technologies

**Genome Sequencing Centers**

## Platform for data collection and management
Track data produced by components of TCGA
Ensure that data meets quality standards set for TCGA
Make TCGA data publicly accessible through databases supported by NCI’s Cancer Biomedical Informatics GridTM (caBIGTM) and the National Library of Medicine’s National Center for Biotechnology Information
Scientists will have access to TCGA data to generate new insights into causes and potential targets for interventions
Access to all TCGA data will be provided in a manner that meets the highest standards for protection and respect of the research participants

- Track data produced by components of TCGA
- Ensure that data meets quality standards set for TCGA
- Make TCGA data publicly accessible through databases supported by NCI’s Cancer Biomedical Informatics GridTM (caBIGTM) and the National Library of Medicine’s National Center for Biotechnology Information
- Scientists will have access to TCGA data to generate new insights into causes and potential targets for interventions
- Access to all TCGA data will be provided in a manner that meets the highest standards for protection and respect of the research participants

**Data Coordinating Center**

## TCGA Components

## TCGA Components

**TCGA Components**

## TCGA Components

## TCGA Components

## TCGA Components

**TCGA Components**

## TCGA Components – Procurement Process Completed in 2006

**A patient donates tumor tissue for study.**

**Genome Sequencing Centers**

**Cancer Genome Characterization Centers**

**Data Management, Bioinformatics, and Computational Analysis**

**Human Cancer****Biospecimen Core Resource**

**Scientists analyze****the data produced by TCGA, and develop a web-based information database.**

**Scientists use information in the database to speed research advances.**

**Research results are translated into new products to help patients.**

**Scientists study genetic material in the tumor tissue.**

**To find the genetic signatures for cancer, scientists study genetic material in many patients’ tissues.  **

**Technology****Development**

**4**

**TCGA Components – ****Procurement Process Completed in 2006**

## Tumors Selected for Study in the Pilot Project

**Tumors Selected for Study in the Pilot Project**

**These three cancers collectively account for more than 210,000 cancer cases each year ****in the United States.**

**Brain (glioblastoma)**
**Lung**
**Ovarian**

## Glioblastoma is Ideal for TCGA Study 

**A "homogenous" tumor – or about as good as it gets**
**Single grade (highest grade) of a single histological type of cancer**
**Few other cell types, such as stromal cells or inflammatory cells, that might contribute extraneous, non-tumor DNA to the extracted biomolecules **

## Genetic Defects in Glioblastoma Suggest Therapeutic Interventions

- To date, glioblastomas seem to have the greatest number of genetic changes of all astrocyte-based cancers.
- A recent study systematically sequenced all tyrosine kinase genes in glioblastomas, confirming the presence of mutations in these and other genes involved in proliferationpathways.
- There are many proliferation pathway-targeted drugs in clinical trials, underlining the role of genetic complexity in glioblastoma.

- From Butowski and Chang (2005). Current Topics in Oncology

- * Rand et al. (2005) *Proc. Natl. Acad. Sci. U S A*. 102(40): 14344-14349

## Target Selection

- Identification of known cancer genes
- Integration of all cancer gene data bases
- Selection of a small number of genes (~800-1,000) to begin sequencing in glioblastoma samples
- Meeting with GBM experts to discuss strategy for identification of new genes from TCGA the CGCCs
- Meeting with participants in NCI’s other programs to begin data interrogation processes

## TCGA and Informed Consent 

**Key Issues:**
**How detailed should informed consent be – more information vs. less? ****TCGA’s informed consent is lengthy and detailed**
**Who should have access to data?**
**How do we leverage and capitalize on potential for progress against disease and ensure privacy protection?  ****TCGA will provide two levels of data access – one completely open; the other password controlled**
**Solving the issues of data access vs. patient protection will likely required genetic privacy legislation **

**Notes:**
Return of Study Results:
Unclear what clinically relevant genetic/genomic information may be discovered (we don’t know what we don’t know...)
Develop policies and procedures for the return of results
Participate in identifying a system of care to provide genetic information/counseling to those research participants who have genetic concerns identified and no access to care

Data Release/IP Issues:
ELP group expect to participate in discussions with scientists and policy makers
Public release of sequence data
Release of health information with IRB approved protocols
Assist in the development of policies and procedures to protect participants’ privacy

## TCGA’s Informed Consent Approach 

- Permission for detailed genomic research
- Permission for broad future research use of samples and health information
- Permission to place genomic and health information in widely accessible databases – with limitations
- Risks associated with loss of privacy
- Potential benefits for future cancer patients
- Issues related to withdrawal (data and samples)

**Notes:**
Consent Issues:

Suggested language for model consent is under IRB review (Both NCI and external IRBs)

## Some Success Factors for TCGA   

**Three-Year Time Horizon**
- Completion of genomic analysis of three tumors, hopefully leading to identification of new genes involved in these cancers
- Ability to find and identify specific genomic alterations in genes associated with cancer
- Ability to differentiate tumor subtypes based on genomic alterations
- Establishment of a genomics database that scientists can access – new questions – new research

## TCGA’s Potential Impact

- Identification of somatic changes in cancer genomes that could establish the molecular basis for each cancer – and inform and enable a new era of molecular oncology
- A molecular taxonomy of cancer
- New molecular targets for diagnostics, therapeutics, and preventives
- Improved ability to stratify patients for clinical trials

## For More Information: Joint NCI-NHGRI TCGA Website 

**Updates on ****TCGA website:**
- Information for patients, scientists, clinicians, policymakers, and the public
**Coming Soon:**Sign up at the TCGA website to receive automatic updates and event news

**http://cancergenome.nih.gov**