The role of common cis-regulatory variation in modifying the penetrance of Lynch Syndrome variants

Precision Medicine Project - The role of common cis-regulatory variation in modifying the penetrance of Lynch Syndrome variants

Supervisor(s): Prof Albert Tenesa & Prof Susan M Farrington
Centre/Institute: Roslin Institute and Insitute of Genetics and Cancer

Background: 

Lynch syndrome is caused by loss of function mutations in the mismatch repair (MMR) mechanism that leads to a substantial increase in the mutation rate during cell division. It is the most common form of hereditary colorectal cancer with carriers having a substantial increased risk of developing colorectal cancer and other extracolonic cancers, mainly endometrial cancer. Because of this increased risk carriers are offered increased surveillance and prophylactic measures. However, there is a huge variation in the risk for different people with MMR mutations, the age at onset varying between the early 20s to the late 70s, and importantly the source of this variation is unknown. One possibility is that common genetic susceptibility variants from genome-wide association studies explain some of this variation, however attempts so far have been unable to show that this is the case (e.g. https://jmg.bmj.com/content/early/2024/08/06/jmg-2023-109791). This proposal aims to test another hypothesis that could explain such variation. The model we propose to test is also valid for many other diseases with known deleterious causal variants such as breast cancer, hypercholesteremia etc. If the causes of this disease variation could be identified and detected, this could lead to better prognostic and stratified screening approaches.Our hypothesis is that interaction between cis-regulatory variation modifies the penetrance of loss of function mutations in MMR genes (and more generally in other genes and diseases). Our model is as follows:

A model that shows our hypothesis is that interaction between cis-regulatory variation modifies the penetrance of loss of function mutations in MMR genes (and more generally in other genes and diseases).

Our hypothesis is that to maintain normal physiological function it is required that a minimum amount of wild type proteins/gene expression is produced in a cell. Our hypothesis therefore can be tested by comparing individuals with the same genotypes at the regulatory variants and the coding variants, but with different phasing (as shown in the figure above). In the top example, the higher production of wild type protein (mediated through gene expression) reduces the penetrance of the mutant genotype, whilst in the bottom example the wild type allele is expressed at such low levels that disease risk is increased. In essence, this epistatic model could explain the differences in age at onset seen in Lynch Syndrome (and other diseases). To focus the research proposal, we will concentrate on MSH6 and PMS2 mutations with moderate penetrance and moderate population frequency, but large variation in penetrance among patients, and these genes also show some level of cellular redundancy with other MMR genes such as MSH3, PMS1, MLH1. Understanding the regulation of MMR gene expression in Lynch Syndrome and how it impacts age of onset and disease spectrum will aid in tailoring screening and treatment regimes.

Aims 

  1. To test whether there is evidence of epistasis between ClinVar variants liked to Lynch Syndrome and cis-regulatory variants identified to be linked to gene expression in normal colon and endometrium tissue in UK Biobank.
  2. To test whether there is evidence of epistasis between ClinVar variants liked to Lynch Syndrome and cis-regulatory variants identified to be linked to gene expression in cancer colon and endometrium tissue in UK Biobank.
  3. To test whether there is evidence of epistasis between ClinVar variants liked to Lynch Syndrome and cis-regulatory variants identified to be linked to gene expression in cancer and normal tissues not linked to Lynch Syndrome in UK Biobank. This will be our negative control.
  4. To validate the results using CRISPR/CAS9 knock-in of the regulatory variant  in colorectal tissue from Lynch Syndrome patients and quantifying expression at transcript and the single cell protein levels using mass spectrometry (https://www.nature.com/articles/s41592-023-01791-5).

Training Outcomes

  1. To test whether there is evidence of epistasis between ClinVar variants liked to Lynch Syndrome and cis-regulatory variants identified to be linked to gene expression in normal colon and endometrium tissue in UK Biobank.
  2. To test whether there is evidence of epistasis between ClinVar variants liked to Lynch Syndrome and cis-regulatory variants identified to be linked to gene expression in cancer colon and endometrium tissue in UK Biobank.
  3. To test whether there is evidence of epistasis between ClinVar variants liked to Lynch Syndrome and cis-regulatory variants identified to be linked to gene expression in cancer and normal tissues not linked to Lynch Syndrome in UK Biobank. This will be our negative control.
  4. To validate the results using CRISPR/CAS9 knock-in of the regulatory variant  in colorectal tissue from Lynch Syndrome patients and quantifying expression at transcript and the single cell protein levels using mass spectrometry (https://www.nature.com/articles/s41592-023-01791-5).

Apply Now

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  • The deadline for 25/26 applications is Monday 13th January 2025
  • Applicants must apply to a specific project. Please ensure you include details of the project on the Recruitment Form below, which you must submit to the research proposal section of your EUCLID application. 
  • Please ensure you upload as many of the requested documents as possible, including a CV, at the time of submitting your EUCLID application.  
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Q&A Sessions

Supervisor(s) of each project will be holding a 30 minute Q&A session in the first two weeks of December. 

If you have any questions regarding this project, you are invited to attend the session on Monday 2nd December at 12pm GMT via Microsoft Teams. Click here to join the session.