Title: Characterisation of somatic mutation analysis in cell free DNA of patients with Non Alcoholic Fatty Liver Disease
Funder: The Academy of Medical Sciences

Abstract: The aim of this research proposal is to utilise next generation sequencing to discover novel biomarkers of disease progression in Non Alcoholic Liver Disease (NAFLD). Specifically, we aim to (1) generate plasma and liver DNA libraries from NAFLD patients, (2) use these libraries to undertake shallow whole genome sequencing to create an genomic map of somatic mutation accumulation in both liver and cell free DNA and (3) discover novel somatic mutations for potential biomarker development. NAFLD represents an urgent, global public health crisis; estimates suggest 25% of the global population are affected. Worryingly, the incidence is increasing alongside the obesity epidemic, one of the key risk factors for this metabolic-related liver disease. Although most people follow a benign disease course, some patients develop an aggressive form of disease called NASH (non-alcoholic steatohepatitis) that can ultimately progress to cirrhosis, liver cancer and transplantation. There are no approved pharmacotherapy for NAFLD, and a key unmet objective to help better manage NAFLD patients is the urgent need to develop robust biomarkers of disease severity. Currently, invasive liver biopsy remains the ‘imperfect’ standard for assessing severity and response to therapy in ongoing drug trials; there are no approved biomarkers that can be used as surrogates of liver histology. The aims of this project not only clearly addresses the key objective of discovery of improved biomarkers of disease severity in NAFLD, but also potentially allow better understanding of the biology of disease progression to ultimately facilitate development of treatments for NAFLD patients

Lay abstract: Fatty liver disease is an urgent, worldwide health problem that is already estimated to affect 25% of the global population. Alarmingly, the number of people living with this condition is rising, alongside increasing global rates of obesity, a key risk factor for this condition. Whilst many patients follow a mild disease course, a significant number of patients develop end stage liver scarring putting them at risk of liver cancer or even requiring a liver transplant. There is no approved treatment for this disease and patients require an invasive procedure called a liver biopsy to determine whether they are at risk of severe disease and complications of this. Interestingly, we now know that gene mutations accumulate as liver disease becomes more severe with time; these mutations have potential to impact on disease progression. Human cells normally have two copies of a gene, but this can change whereby some genes are present multiple times in cells, an effect called Copy Number Alterations (CNAs) which can create harmful, disease-causing mutations . The aim of this study is to discover, use cutting edge DNA sequencing technology, if CNAs are present in the liver of severely diseased patients, and whether they can be detected in the blood of the same patients; we call this a 'liquid biopsy'. Importantly, this could help us determine the likelihood of severe liver disease, without the need for invasive liver biopsy, and improve patient care by offering the exciting prospect of a more personalised healthcare for many of these patients.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL