We all carry a few million common variations in our genome. Over the last 10 years researchers have discovered that some of these genetic variants can increase the risk of diseases such as cancer. However, the variations normally exist in non-coding or “junk” DNA and do not affect protein structure or function. We think that they control the amount and pattern of protein expression instead. My laboratory is interested in how risk variants can affect the development of colorectal and endometrial cancer. In this project we are investigating how a promoter variant contributes to the silencing of the DNA repair gene MLH1, increasing the risk of certain types of colorectal cancer by two-fold.
We have shown that the variant is involved in increasing DNA methylation in the promoter, which lowers the levels of MLH1 transcription. The variant is important in colorectal cancer, probably due to its interaction with mutations in the BRAF oncogene. In endometrial cancer, where BRAF mutations are rare, the variant has no effect on risk, despite MLH1 silencing being a common event. We have developed cell line and mouse models to further investigate the mechanisms by which this single base pair change increases colorectal cancer development.
Patients with colorectal tumours with MLH1 silencing form a distinct subgroup, both in prognosis and responses to therapies. They usually respond poorly to common chemotherapies but new immune checkpoint blockade therapies have been shown to be highly effective.
A greater understanding of the mechanisms by which this cancer develops will help to guide the clinical treatment of these patients and to identify those individuals who would benefit from early screening for this type of cancer.
17 freelanceria on tarjonnut keskimäärin £170 tähän työhön
I would be willing to do this project as i have been working over 5 years in cancer field data curation which requires reading on various landscape. would be happy to discuss more and get this rolling