Dr Guest - Biomarkers in PSC/biliary duct cancer
An unbiased screen for novel clinical and molecular biomarkers of the progression of primary sclerosing cholangitis to biliary tract cancer
Awarded to University of Edinburgh
Dr Rachel Guest, Department of Surgery, Royal Infirmary of Edinburgh
The total grant awarded is £7,000
Duration of award: 18 July 2016 to 31 August 2019 (extension agreed)
Award details: An unbiased screen for novel clinical and molecular biomarkers of the progression of primary sclerosing cholangitis to biliary tract cancer.
“As a clinician scientist, the PSC Support grant was invaluable in enabling me to continue meaningful research following my PhD after I returned to clinical training. There is a period between PhD and the early career fellowship period which is extremely challenging for clinicians to continue developing as a scientist whilst establishing an independent clinical practice. Without the financial support from this award, I simply would have been unable to gain sufficient data and experience to later successfully apply for the Academy of Medical Sciences and Wellcome Trust Career Development fellowships. In this way, these grants from PSC Support not only help to deliver short term projects, but support the career development of future clinician scientists.” Dr Rachel Guest, April 2023
PSC is a major risk factor for the development of cancer of the bile ducts (cholangiocarcinoma), with a lifetime risk of approximately 20%. Diagnosis of cholangiocarcinoma (CC) can be exceptionally challenging and many patients undergo extensive investigations, including endoscopic or radiological biopsy before diagnosis is made. The genetic and molecular events occurring when cancer develops in the context of PSC are poorly understood and more research is needed to better understand this progression so that cholangiocarcinoma can be detected at an earlier stage.
In the UK liver transplantation has been available for patients with advanced PSC, but to date has not been advocated for those with cholangiocarcinoma due to historically poor survival in patients with cancer who require treatment with immunosuppression following transplant. Although emerging data are beginning to suggest that liver transplantation might offer benefit for a subgroup of selected patients with cholangiocarcinoma following treatment with chemotherapy and radiotherapy, at the time of writing this is not yet approved for clinical use in the UK. Because of the extreme challenges in diagnosis, a small number of patients have undergone liver transplant for advanced PSC and have been found to have cholangiocarcinoma in the explanted liver following pathological examination after transplant. This study used archived tissue from this group of patients to analyse the genetic changes occurring when PSC progresses to bile duct cancer. Tissue was compared between regions of the liver affected by PSC to adjacent tumours, sequencing the DNA to detect ‘mutations’ or changes occurring during the transformation from PSC to cholangiocarcinoma.
Samples were available from 27 patients from 4 liver transplant centres across the UK and ‘whole exome sequencing’ was performed whereby the entire coded sequence of DNA is read; allowing us to perform an unbiased screen of genes that are altered in the PSC-CC transition. We found that advanced PSC is a highly mutated state, with only slightly fewer total number of mutations identified (1347) to those seen in CC (1447). The mutations we observed in CC included known drivers of the disease, including those observed in the ‘intrahepatic’ form of CC found within the liver, for example IDH1, IDH2, ARID1A, ARID1B and ERBB4. A total of 184 mutations were detected in both PSC and CC tissue, suggesting these alterations are likely to be acquired during the transformation of benign PSC into cancer. Mutations in MSH3, a gene known to regulate DNA ‘mismatch repair’ was observed in 20% of patients in both PSC and CC tissue. Of the total 2978 mutations identified, 44 represent ‘targetable’ alterations (changes for which drugs are available for treatment), which can be taken forward for further research. These data have provided us with information about which cellular pathways are subject to mutation in PSC and its transition into cholangiocarcinoma.
Has the Research funded by the above Award generated new knowledge and resources?
Yes - Manuscript in preparation for publication, web publication of sequencing database to follow publication.
Has this research leveraged further funding or partnerships?
Yes - led to Wellcome Trust Clinical Career Development Award
Has this research supported the development of Awardholder or achieved recognition or awards?
Yes - Appointment as a Senior Lecturer and Honorary Consultant Hepatopancreatobiliary Surgeon, University of Edinburgh