Genetic Changes in Degenerative Disease (IRAS 260437)

Degenerative joint diseases affect millions of people, yet we still do not fully understand the genetic changes that drive them. We will examine DNA changes that build up in healthy and diseased joint tissues throughout life by analysing existing tissue, blood and cell samples using modern DNA sequencing. By comparing different tissues, diseases and treatments, we can uncover how these genetic changes develop and influence joint health. Our findings could improve understanding of degenerative diseases and help guide future approaches to diagnosis, treatment and patient care.

Somatic mutations accumulate in all human cells throughout life, but their role in connective tissues and degenerative joint disease remains poorly understood. We will analyse pre-collected healthy and diseased joint tissues and associated connective tissues, together with blood samples and derived cell lines, obtained from clinical collaborators, biobanks, commercial suppliers and diagnostic archives in the UK and overseas. Samples may originate from living or deceased healthy and diseased individuals.

Using DNA sequencing, we will characterise the number and patterns of somatic mutations in normal and diseased connective tissues and examine how disease processes and treatments influence their accumulation. By improving understanding of the genetic changes that occur in human joints throughout life and during degenerative disease, this work will provide new insights into disease mechanisms and may inform future diagnosis and treatment of degenerative joint diseases.

Rationale

Our work is starting to find the presence of driver mutations (mutations that can transform normal cells into cancers) in normal (non-diseased) tissues. This unexpected finding has been observed across several different tissue types in our initial studies.

This project will look with greater detail into connective tissues  cross a range of ages to describe the patterns and dynamics of driver mutation acquisition and will help to reveal more information about factors contributing to their acquisition. This study will  provide a unique insight into the fundamental processes that cause somatic mutations and hence advance our understanding of the function of the genome.

In addition, it will provide an unparalleled insight into the mutational processes in normal tissue in both health and disease, and the way in which internal and external factors may influence the competition seen between similar cells in close proximity. It will reveal new findings which may contribute to our understanding of the molecular pathophysiology of diseases and may ultimately have implications for the diagnosis and treatment of patients with degenerative diseases.

Aims

The study aims to:

• understand the genetic changes that take place in human human cells and tissues throughout life and in the context of degenerative, inflammatory, and autoimmune disease.

Primary Outcome

The study will measure the burden and type of somatic mutation and mutational signatures in normal and diseased tissues and blood samples.

Key Secondary outcome(s)

Identify somatic mutations that contribute to the development and progression of degenerative disease.

Study Type

Observational

Participant and Sample Information

Populations involved:

Samples from the Periop Flare study underway at the Hospital for Special Surgery (HSS) in New York

Countries of recruitment:

International

Approximate participant or sample numbers (if applicable):

500

Key inclusion criteria:

• Individuals who consented to donate tissue samples to the Periop Flare study, HSS, New York.

Key exclusion criteria:

• Any individual who has not consented to donate tissue samples to the Periop Flare study, HSS, New York.

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 South West – Central Bristol NHS Research Ethics Committee. The study received REC approval on 8 February 2019.

IRAS 260437

REC reference: 19/SW/0031

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 https://www.sanger.ac.uk/group/martincorena-group/.

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