Title: The molecular pathology of liver cancer: multi-omics dissection of liver cancer in transplant patients
Funder: The Academy of Medical Sciences

Abstract: Hepatocellular carcinoma (HCC) has a rising incidence and poor outcome. Our overall aim is to identify putative clinical, genomic, and/or image features that predict post-transplant recurrence in a unique clinical cohort. AIM 1: Generate whole exome sequencing (WES) libraries of paired HCC/background cirrhotic samples from liver explants. AIM 2: Validate putative biomarkers using multiplexed immunohistochemistry and immunofluorescence, and identify prognostic and predictive image features in liver cancer. HCC usually develops in patients with chronic liver disease (CLD), marked by a cancerisation field effect: patients with CLD can develop synchronous or metachronous primary tumours. Previous genomic studies of HCC have been conducted exclusively in patients undergoing resection, in which the remnant liver retains a high risk of developing new tumours, thus precluding linking genomic features of the original tumour with recurrence risk. This can only be mitigated in patients undergoing transplantation for a solitary HCC. Here, a single lesion is resected together with the cancerised background liver. We have constructed tissue microarrays of tumour and background liver from >150 such patients. Now, we will perform WES and image analyses of the same tissues, and then integrate the genomic, image, and clinical datasets. We hypothesise that using multiparametric analyses we can identify putative clinical, genomic, and/or image prognostic or predictive markers. We will validate putative biomarkers using multiplexed immunohistochemistry and immunofluorescence. Given the increasing importance of genomics in personalised cancer care, this project will enrich our extremely well annotated cohort with molecular data and simultaneously generate tissue resources for future translational research.

Lay abstract: Liver cancer is the second most common cause of cancer death worldwide and its incidence is rapidly increasing in the UK and other developed countries due to alcohol consumption and an epidemic of type 2 diabetes. Liver cancer has many different causes which, in turn, cause a range of molecular (genetic) differences between tumours. Different genetic mutations alter the characteristics of a tumour and can influence how aggressively it behaves. One of the treatments for liver cancer is for a patient to receive a liver transplant. This is a major operation and there is a shortage of organ donors, and therefore difficult decisions must be made about which patients should receive a transplant. In order to optimise decision making, we need to develop a test (or series of tests) which can be applied to tumour samples from clinical studies which are representative of samples found in hospital laboratories. We are requesting funding support to: (i) study the appearances of the tissue and sequence the DNA from patients’ liver tumours and (ii) link these results to their hospital records (blood tests, response to treatment, and cancer recurrence/metastasis). We will then (iii) validate these findings across the cohort of >150 patients. The aim is to identify changes that could be used as a test to predict the behaviour of each tumour. It is only when equipped with a precise understanding of the way a patient’s cancer is likely to behave that doctors will be better able to tailor therapy to each individual.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS