International Cancer Genome Consortium Cancer A Disease of the - - PDF document

1

International Cancer Genome Consortium

Cancer

A Disease of the Genome

Challenge in Treating Cancer:

• Every tumor is different
• Every cancer patient is different

2

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
• f 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

3

‘Next Generation’ sequencing instruments are providing new

• pportunities 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

4

International Cancer Genomics Strategy Meeting

October 1–2, 2007 Toronto (Canada)

22 countries represented 120 participants 34 Genome or Cancer Center Directors 24 Representatives from funding agencies 62 Scientists selected to represent ethics, technologies, statistics, informatics, pathology, clinical

• ncology 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.

5

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

6

ICGC Cancer Genome Projects

SELECTED FEATURES OF ICGC

(April 2010)

7

• 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 Lung NSCLC Breast Her+ Colon etc.

8

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
• rgan systems
• Studies will cover adult and childhood /

adolescent cancers

• Guidelines have been developed for ICGC

participants for the selection of Cancer Genome Projects

9

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

• versee 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.

10

Data Releases

ICGC Open Access Datasets ICGC Controlled Access Datasets

• Cancer Pathology

Histologic type or subtype Histologic nuclear grade

• Patient/Person

Gender Age 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 demography Risk factors Examination Surgery/Drugs/Radiation Sample/Slide Specific histological features Protocol Analyte/Aliquot

• Gene Expression (probe-level data)
• Raw genotype calls
• Gene-sample identifier links
• Genome sequence files

Genome Analyses

• Mandatory: Genomic DNA analyses of tumors (and

matching control DNA) are core elements of the project.

• Complementary (Recommended): Additional studies
• f DNA methylation and RNA expression are

recommended on the same samples that are used to find somatic mutations.

• Optional:

Proteomic analyses Metabolomic analyses Immunohistochemical analyses

11

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

12

ICGC Database Model Access mechanisms for Controlled Data

13

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

14

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.

15

ICGC Data Generation has started

(April 2010)

h"p://icgc.org 


16

17

“OPEN” ICGC Data sets in DCC April 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
• varian

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

18

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)

19

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 Access Data 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/Childhood Cancers 3-4 more… 1 project 8 projects 10 projects

20

3rd Workshop of the International Cancer Genome Consortium (ICGC) Madrid, Spain – March 2010