Clonal Architecture of Pre-Malignant and Malignant Tumours (IRAS 61795)

We seek to understand how cancer develops and changes over time by examining the genetic changes that occur in cells that go on to become tumours. To do this we are comparing the DNA in cancer cells, early abnormal cells that may become cancerous, and healthy tissue from the same person. By studying these samples, we hope to identify the genetic changes that drive the development and progression of cancer, and inform research into new diagnostics and treatments.

Our bodies naturally develop small DNA changes during life. Most are harmless, but some may affect important genes and allow cells to grow uncontrollably, leading to cancer. Our research will help us to understand whether or not normal inherited genetic differences can influence how these changes occur, and if they increase a person’s risk of developing cancer.

Rationale

The Cancer Genome Project seeks to understand the genetic changes that occur in cancer. By comparing the DNA from cancer cells with normal DNA, researchers can identify changes that are not inherited but develop during a person’s lifetime. These changes may help identify the genes involved in the development of tumours and provide clues about factors that may have contributed to the cancer, such as previous exposures or problems with the body’s normal DNA repair processes.

Patterns of DNA changes and alterations in chromosomes can provide important information about how cancers develop. When tumour cells die, they release DNA into the bloodstream. Measuring the amount of this tumour DNA may help indicate how much disease is present and allow researchers to monitor genetic changes linked to cancer. Temporary increases in circulating tumour DNA can occur after treatments such as radiotherapy, suggesting that these measurements may also help assess how many tumour cells have been destroyed by treatment.

This work will analyse and compare genetic material from both abnormal and normal samples taken from the same patient during the monitoring of conditions that may develop into cancer. The analysis will look for different types of DNA changes, including changes to individual DNA building blocks, small sections of DNA that have been added or lost, exchanges of genetic material between chromosomes, and increases in the number of copies of particular DNA regions.

Aims

The study aims to:

1. Coordinated generation of comprehensive catalogues of genomic abnormalities (somatic mutations) to include single nucleotide variants, insertions, deletions, copy number changes, translocations and other chromosomal
   rearrangements by sequencing of cancer and matching normal genomes to high levels of coverage.
2. Generate complementary catalogues of transcriptomic and epigenomic data sets from the same tumours.
3. Employ single cell culture studies of cancer cells and cells or clones from nearby normal tissue in order to identify the point at which a mutation occurs during cancer development.
4. Release the data to the research community as rapidly as possible and, where appropriate, with minimal restrictions in order to accelerate research into the causes and control of cancer.

Primary Outcome

The generation of comprehensive catalogues of genomic abnormalities for a range of cancer samples by sequencing to high coverage depth both the cancer and matching normal genomes to facilitate identification of single nucleotide variants, insertions, deletions, copy number changes, translocations and other chromosomal rearrangements in conjunction with the generation of transcriptomic and epigenomic data sets.

Key Secondary outcome(s)

N/a

Study Type

Observational

Case–control

Participant and sample information

Populations involved:

Patients with cancer or premalignant conditions, undergoing routine clinical care and treatment.

Countries of recruitment:

International

Approximate participant or sample numbers (if applicable):

2000

Key inclusion criteria:

Participants have a confirmed diagnosis of a relevant cancer type or are under routine surveillance for a premalignant
condition.

Key exclusion criteria:

Samples which do not yield suffient material to proceed with analyses

Recruitment status:

Non-recruiting: Pre-collected samples only.

Governance and Ethical Approval

Governance and oversight:

Study Sponsor: Wellcome Sanger Institute

All work conducted at the Wellcome Sanger Institute is reviewed and overseen by institutional Research Governance processes, ensuring compliance with ethical, legal, and regulatory requirements.

Ethical approval:

This study has been reviewed by the East of England – Essex NHS Research Ethics Committee. The study received REC approval on 13 June 2011.

IRAS 61795

REC reference: 11/EE/0155

Data and Sample Use

Data sharing:

Anonymised DNA sequence data are stored in the European Genome-Phenome Archive (EGA) and made available to bonafide researchers via managed access, subject to data access agreements. Anonymised samples and cultured cells may also be shared with other legitimate research organisations under appropriate legal agreements.

Information on somatic abnormalities, together with other general features such as cancer pathology (histological type and/or nuclear grade), patient gender, patient age range, gene expression patterns and DNA methylation will be released publicly as it is extremely unlikely that an individual could be identified through them. Nor do they contain other private information concerning or predicting individual phenotype (normal or disease). These data will be released on the COSMIC database run from the Wellcome Sanger Institute. COSMIC, the Catalogue Of Somatic Mutations In Cancer, is the world’s largest and most comprehensive resource for exploring the impact of somatic mutations in human cancer.

IPD sharing statement

Deidentified individual participant-level data (IPD) will not be shared as part of this study.

Completion date

Ongoing

Further information

For enquiries about the scientific aims of this study or potential collaboration, please contact the relevant scientific programme at im3@sanger.ac.uk.

For enquiries relating to research governance, ethics, or regulatory oversight, please contact the Research Governance team at researchgovernance@sanger.ac.uk.