International Cancer Genome Consortium

CancerA Disease of the Genome

Challenge in Treating Cancer:

Every tumor is different

Every cancer patient is different

Goals of Cancer Genome Research

Identify changes in the genomes of tumors that drive cancer progression

Identify new targets for therapy

Select drugs based on the genomics of the tumor

Systematic studies of cancer genomes

High rate of abnormalities> often 10,000 mutations per cancer

- minority are “driver” mutations- vast majority are “passengers”

Heterogeneity within and across tumor types

Sample quality matters

‘Next Generation’ sequencing instruments are providing new opportunities for comprehensive analyses of cancer genomes

Capacity of new instruments 100,000 to 1,000,000 times that of instruments used for Human Genome Project

Drastic decrease in costs per genome

Applications: DNA, RNA, chromatin (i.e. epigenome)

Sequencing Evolution/Revolution

1990: thousand bases/day

2000: million bases/day

2010: billion bases/day

International Cancer Genomics

Strategy MeetingOctober 1–2, 2007 Toronto (Canada)

22 countries represented120 participants 34 Genome or Cancer Center Directors

24 Representatives from funding agencies

62 Scientists selected to represent ethics, technologies, statistics, informatics, pathology, clinical oncology and cancer biology

Rationale for an International Consortium

• The scope is huge, such that no country can do it all.

• Coordinated cancer genome initiatives will reduce

duplication of effort for common tumors and ensure

complete studies for many less frequent forms of cancer.

• Standardization and uniform quality measures across

studies will enable the merging of datasets, increasing

power to detect additional targets.

• The spectrum of many cancers varies across the world

for many tumor types.

• The ICGC will accelerate the dissemination of genomic

and analytical methods across participating sites, and the

user community.

ICGC Goal

To obtain a comprehensive description of

genomic, transcriptomic and epigenomic

changes in 50 different tumor types and/or

subtypes which are of clinical and societal

importance across the globe.

- 500 tumors per tumor type

> 25,000 cancer genomes!

April 2010: World Map of Comprehensive Cancer Genome Projects

Commitments for > 10,000 tumor genomes!

New RFAs/projects in development

SELECTED FEATURES OF ICGC

(April 2010)

The level of organization is at the specific cancer type or subtype.

A particular cancer may be investigated by an individual research

lab/center or by a collaborative research group, across

jurisdictions.

The key to inclusion of a project in the ICGC is that it should take

a comprehensive, genome-wide approach to the analysis of that

tumor type (or sub-type).

The ICGC is open to many organizations willing mount a

comprehensive analysis of at least one cancer type or subtype,

and that agree to carry out their efforts according to ICGC

policies.

Basic Tenets

Organization

CLL

HCC

GBM

LungNSCLC

BreastHer+

Colon

etc.

Study Design and Statistical Issues

Every cancer genome project should state a clear rationale for its choice of sample size, in terms of the desired sensitivity to detect mutations. The target number is 500 samples per tumor type/subtype.

Fewer than 500 samples will be acceptable for rare and homogeneous tumors; more than 500 samples may be required for tumors that demonstrate considerable heterogeneity

Tumor Types and Subtypes

The ICGC aims to study cancers of all major organ systems

Studies will cover adult and childhood / adolescent cancers

Guidelines have been developed for ICGC participants for the selection of Cancer Genome Projects

Biobanking needs for ICGC and Cancer Research

This is HARD!

Sample collection can easily be rate limiting

Much of sample collection needs to be prospective

Quality assessment is critical

A committee of clinical and pathology experts (with representation from different institutions) is needed to draft and oversee the specific guidelines that will apply for every tumor type or sub-type.

All samples have to be reviewed by two or more reference pathologists.

Patient-matched control samples, representative for the germline genome, are mandatory to discern “somatic” from “inherited” mutations.

Clinical annotation of specimens are critical, ranging from exposures to outcomes

ICGC Consent and Privacy Protection Policies

ICGC membership implies compliance with Core Bioethical Elements for samples used in ICGC Cancer Projects ICGC acknowledges that the informed consent process used by ICGC members will necessarily differ according to local, socio-cultural and legal requirements

To minimize the risk of patient/individual identification, the ICGC has established the policy that datasets be organized into two categories, open and controlled-access.

Data Releases

ICGC Open Access Datasets

ICGC Controlled Access Datasets

Cancer PathologyHistologic type or subtypeHistologic nuclear grade

Patient/PersonGenderAge range

Gene Expression (normalized) DNA methylation Genotype frequencies Computed Copy Number and

Loss of Heterozygosity Newly discovered somatic

variants

Detailed Phenotype and Outcome Data

Patient demographyRisk factorsExaminationSurgery/Drugs/RadiationSample/SlideSpecific histological featuresProtocolAnalyte/Aliquot

Gene Expression (probe-level data)Raw genotype callsGene-sample identifier linksGenome sequence files

Genome Analyses

Mandatory: Genomic DNA analyses of tumors (and matching control DNA) are core elements of the project.

Complementary (Recommended): Additional studies of DNA methylation and RNA expression are recommended on the same samples that are used to find somatic mutations.

Optional: Proteomic analysesMetabolomic analysesImmunohistochemical analyses

Genome Analyses

Whole genome shotgun analyses (long-term goal)

Interim, large-scale, catalogues of somatic mutations– Sequencing of all coding exons and other genomic

regions of particular biological interest for point mutations.

– Analysis of low genome coverage of paired-end reads for rearrangements.

– Genotyping arrays, to detect copy number changes, LOH and breakpoint information.

Analyses of DNA Methylation

Expression Analyses: protein coding genes, non-coding RNAs, notably microRNAs.

ICGC Data Coordination Centre

Mission

• Establish common standards, data models,

reference datasets

• Develop and maintain ICGC web portal for

data dissemination

• Protect sensitive data

• Coordinate data releases

• Provide support and training

ICGC Database Model

Access mechanisms for Controlled Data

Data Access Compliance Office (DACO)

All ICGC members agree not to make claims to possible IP derived from primary data (including somatic mutations) and to not pursue IP protections that would prevent or block access to or use of any element of ICGC data or conclusions drawn directly from those data.

Note: Users of the data (including Consortium members) may elect to perform further research that would add intellectual and resource capital to ICGC data and elect to exercise their IP rights on these downstream discoveries. However, ICGC participants and other data users are expected to implement licensing policies that do not obstruct further research: (http://tinyurl.com/4rslvy).

ICGC Intellectual Property Policy

ICGC Data Release Policies

The members of the International Cancer Genome Consortium (ICGC) are committed to the principle of rapid data release to the scientific community.

The individual research groups in the ICGC are free to publish the results of their own efforts in independent publications at any time.

Data Release, Data Tiers & Publications Working Group

Data users are free to use data that targets specific genes & mutations without any restrictions.

ICGC member projects may, if they choose, impose a publication moratorium period that will only limit other data users from publishing global analyses. All data shall become free of a Publication Moratorium when either the data are published by the ICGC member project or 1 year after the specified quantity of data on which the initial global analyses will be carried out (e.g. genome dataset from 100 tumors per project) have been released via the ICGC portal or other public databases.

In all cases data shall be free of any restriction 2 years after its initial release.

ICGC Data Generation has started

(April 2010)

http://icgc.org

“OPEN” ICGC Data sets in DCCApril 2010

Institute Tumour type # Donor # Samples

OICR, Canada pancreas 2 6• 2 primary• 2 cell line • 2 xenograft

Garvan, Australia

pancreas 4 6• 1 primary• 4 cell line • 1 control

Japan liver 2 2 primary

Sanger skin 1 1 cell line

Sanger lung 1 1 cell line

Sanger breast 24 24• 15 primary• 9 cell line

Institute Tumour type # Donor # Samples

TCGA, USA GBM 380 687 - multiple use of same sample

• 317 control• 378 primary

ovarian 386 764 - multiple use of same sample

• 386 control• 379 primary

Hopkins, USA GBM 105 • 37 primary• 68 xenograft

pancreas 114 • 97 xenograft• 17 cell line

breast 48 • 36 xenograft• 12 cell line

colorectal 37 • 30 xenograft• 7 cell line

Additional “OPEN” Data sets in DCC, April 2010

Reference cancer genome used by ICGC to compare methods is

available via DCC

COLO-829 malignant melanoma cell line

ICGC Marker Paper

Nature 464, 993-998 (15 April 2010)

The International Cancer Genome Consortium can be the hub of the wheel, but it’s not all of cancer research!

Translating into new interventions, tests, and public health strategies will require biological and clinical studies, changes in health care practices, and

TIME!

2007

2008

2009

2010

Funding/Projects

Data Management

Ethics

Samples

Data Analysis

Data AccessData

An Idea

Discussions

The Launch

A Plan

A Working Consortium

A Consortium sharing ideas and expertise

A Consortium coordinating and collaborating

The Consortium The Work

Pathology

Rare/ChildhoodCancers

3-4 more…

1 project

8 projects

10 projects

3rd Workshop of the International Cancer Genome

Consortium (ICGC)Madrid, Spain – March 2010