Differential topological accumulation of gastric somatic mutations (IRAS 228343)

Cancer causes more than 1.4 million deaths each year from oesophageal, colorectal and gastric cancers alone, driven by changes that build up in our DNA over time. We will examine tissue, blood and cell samples from people at different stages of cancer development to discover which DNA changes are most important. By sequencing DNA from individual cells, we will track how mutations accumulate and vary with age, location in the digestive system and disease stage. Our findings could improve understanding of how these cancers develop, helping to identify new opportunities for earlier detection, prevention and treatment.

Cancer develops through the accumulation of somatic mutations—DNA changes acquired during life that are not inherited. When these mutations affect cancer-related genes, they can drive the development of cancer. We are studying the genetic changes involved in oesophageal, colorectal and gastric cancers, which together account for more than 1,425,000 deaths worldwide each year. To support this work, we will use pre-collected primary tissue samples, blood samples, isolated DNA and organoids from normal, pre-neoplastic and cancerous gastrointestinal tissues.

Individual clonal cell populations will be isolated from tissue samples and organoids, and their genomic DNA will undergo whole-genome sequencing. The resulting sequence data will be used to identify somatic mutations, including base substitutions, genome rearrangements and copy number signatures, and to characterise mutational burden and mutational signatures across different ages, anatomical sites and stages of tumour progression. This work will improve understanding of the genetic processes underlying gastrointestinal cancer development and progression.

Rationale

Worldwide, there are 1.4 million reported deaths annually from stomach, colorectum and oesophageal cancers. This
represents a significant health problem. We know that DNA in our cells is constantly being altered by factors in the
environment and diets and usually these changes, called somatic mutations, are repaired by cells, but occasionally
this process fails, allowing a cell with altered DNA to divide and eventually generate a cluster of cells carrying the
same somatic mutation. Furthermore, the exposure of our cells to specific chemicals can leave a very distinct pattern
of somatic mutation in DNA called mutational signature. Understanding the pattern of somatic mutations and
mutational signatures in these cancer types, as well as in pre cancerous cells, will allow us to determine the effects of
the environment and other agents on cancer progression and how they might respond to specific therapies.

Aims

The study aims to:

• To analyse differences in mutational burden and signatures in relation to topology, age, risk factors in different stages in pre-neoplastic through to neoplastic progression in different regions of the stomach, colorectum and gastro oesophagus to inform on strategies for cancer prevention, early detection and intervention.

Primary Outcome

Burden and prevalence of somatic mutation and mutational signatures in pre-neoplastic
and neoplastic progression stomach, colorectum and gastro oesophageal samples.

Key Secondary outcome(s)

N/a

Study Type

Observational

Participant and Sample Information

Populations involved:

Individuals donating tissue and blood for colorectal, gastric and gastro-oesophageal junction cancer studies.

Countries of recruitment:

International

Approximate participant or sample numbers (if applicable):

30

Key inclusion criteria:

Patients who consented to participate in the ‘Donation of tissue and blood for study of colorectal, gastric and gastro-oesophageal junction cancers’ study. 

Key exclusion criteria:

Any individual who has not consented to take part in the ‘Donation of tissue and blood for study of colorectal, gastric
and gastro-oesophageal junction cancers’ study.

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 West Midlands – Coverntry NHS Research Ethics Committee. The study received REC approval on 31 July 2017.

IRAS 228343

REC reference: 17/WM/0295

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.

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 mrs@sanger.ac.uk.

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