Somatic Mutations in Individuals with Inherited Cancer Predisposition
Research type
Research Study
Full title
Somatic mutations in normal and abnormal human cells in individuals with inherited cancer predisposition syndrome
IRAS ID
239501
Contact name
Peter Campbell
Contact email
Sponsor organisation
Wellcome Trust Sanger Institute
Duration of Study in the UK
5 years, 0 months, 0 days
Research summary
Summary of Research
All cells of the human body continuously acquire mutations in their DNA. These are known as somatic mutations, and they are not passed onto children. Using modern DNA sequencing technology we can detect somatic mutations present in single cells or small numbers of cells. There are a number of inherited syndromes that are associated with an increase in cancer risk, many of which act through increasing the mutation rate as cells divide.In this study we will use pre-collected tissue biopsy samples from organs and sites across the whole body (taken at definitive surgery for invasive cancer or from biopsies, blood and saliva samples taken during routine care).
It is not possible for us to collect this extensive range of tissue biopsies ourselves. Therefore, for all tissue types we are obtaining samples from donors that have been recruited sensitively through clinics specialising in inherited cancer syndromes in Canada (Sick Kids Hospital, Toronto).
The aim is to sequence the different cells of the human body and identify the somatic mutations. This will provide information on the number and types of somatic mutations, as well as inform on the mutational processes, be that internal or external to the body, that resulted in them. We will search specifically for 'driver' mutations (a mutation within a gene that confers a selective growth advantage and thus promotes cancer development).
Finally we will use the sequence information to develop cell lineage trees (the developmental history of a cell back to the cell type it developed from) of the different cell types in the human body from an individual. This will allow us to gain a deep and meaningful understanding into embryonic development and the changing structures of cells during life.This study will therefore provide insights into the fundamental processes of somatic mutagenesis (the process by which the genetic information is changed resulting in a mutation), in individuals with high inherited cancer risk.
Summary of Results
The Mismatch repair (MMR) pathway is a system that protects the integrity of our genome by repairing DNA damage. This is vital to the normal functioning of cells and in reducing their risk of transforming into cancer. In this study, researchers compared DNA sequences of people born with MMR defects to previously published analysis from MMR-proficient individuals.The study found that MMR typically repairs an average of 1-10 DNA damage events per day in normal epithelial cells in the intestine. The study then goes on to illustrate that once cells begins to show abnormal cell division, which can in turn result in tumour formation, MMR typically repairs tens of thousands of additional DNA damage events over short period of time. This study has shown an increased dependence on MMR’s protective activity as a critical defence mechanism when control of cell division is lost.
A further and unexpected finding of this study, is that some proteins are primarily responsible for repairing a common chemical change in DNA (the deamination of methylated cytosine to thymine), whilst others are primarily concerned with repairing errors made during DNA copying.
The use of human samples from individuals with MMR defects has enriched previous observations made from experimental models systems. It has allowed this study to quantify the day-to-day activity of MMR, to separate the relative contributions of individual components of the MMR pathway to different types of DNA damage and to show when cells are most dependant on MMR’s protective activity.
REC name
North West - Preston Research Ethics Committee
REC reference
17/NW/0713
Date of REC Opinion
30 Nov 2017
REC opinion
Favourable Opinion