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Understanding the molecular pathogenesis of gastrointestinal tract cancer


Department of Pathology

Applications accepted all year round Funded PhD Project (Students Worldwide)

About the Project

We aim to understand the molecular genetics, epigenetics and genomics of gastric and colorectal cancers, with the goal of their application in molecular classification and genetic diagnosis to facilitate cancer prevention and treatment. We have performed comprehensive molecular profiling and integrative genomic studies on a large series of gastric and colorectal cancers using next-generation sequencing, expression microarray, methylation array and DNA SNP genotyping array. Our studies reveal the complex genomic landscape of gastric cancer and were the first to identify many new gastric cancer driver genes. Examples include frequent mutation of ARID1A, a chromatin remodelling gene, in gastric cancers with MSI or EBV, and hotspot mutation of RHOA in diffuse type gastric cancer. Integrative genomic analysis revealed molecular subtype-specific patterns of genetic and epigenetic perturbations, many of them converging to target the same key cancer driver genes or pathways.

More recently, we have used patient tumour biopsies to establish a living bio-bank of organoid cultures, which are very similar to in vivo tumours. We used the stomach and colon cancer tissue, and nearby normal tissue that was removed during surgery to grow gastric and colon organoids, respectively. These organoids are essentially miniature versions of the stomach or colon, with a proper 3D structure. We have collected a large repertoire of organoids, encompassing different molecular subtypes, key driver gene alterations, stages of disease, as well as normal organoids, and have performed detailed morphological, genomic and transcriptomic analysis of them. Since the organoids are grown from the patients’ cancer tissue and maintains more or less the same morphology, mutations and gene expression patterns, drugs can be tested on the organoids without harm to the patient, while offering a prediction for how the patient might respond to the drug or drug combinations. Currently, we are testing the feasibility of large-scale drug sensitivity screening of organoids as a potential first-line guide for patient treatment. Overall, our organoid bio-bank, with linked genomic data, provides a valuable resource for understanding both cancer biology and anti-cancer drugs that may facilitate the development of precision cancer therapy.

In addition, our team has characterized the genetic basis of early-onset colorectal cancer (CRC) in Hong Kong and was the first to describe a new mechanism of MSH2 inactivation in Lynch Syndrome (a heritable form of CRC), involving large germline deletions in the EPCAM gene which is upstream of MSH2. Our findings have led to the incorporation of EPCAM deletion into the standard genetic diagnosis protocol for Lynch Syndrome worldwide. We now apply our findings to patient care, by providing a charitable genetic diagnosis service, including genetic testing and referral for prophylactic screening for early-onset or familial CRC patients. Our long-term goal is to enable genome-guided patient stratification, prognostication and personalised treatment of colorectal and gastric cancers by utilising genomic technology to identify novel pathways, biomarkers, drug targets and driver genes of carcinogenesis.

Supervisor:

Professor LEUNG Suet Yi is the Head and Chief of Service of the Department of Pathology at Queen Mary Hospital. She is also a Clinical Professor, Chair of Gastrointestinal Cancer Genetics and Genomics, and Director of the Hereditary Gastrointestinal Cancer Genetic Diagnosis Laboratory at the Li Ka Shing Faculty of Medicine at the University of Hong Kong. She has published in numerous high impact journals, such as Cell Stem Cell, Nature Genetics, Gut and PNAS. Her innovative research has received numerous awards, including the Li Ka Shing Faculty of Medicine Faculty Outstanding Research Output Award in 2012, 2015, 2017 and 2019. In 2014, she was also honoured with the Outstanding Women Professionals Award. Professor Leung has consistently secured both public and private funding for her research projects, including over $30 million HKD from the Theme-Based Research Scheme (TBRS), as well as partnerships with the major pharmaceutical companies, Pfizer and Merck, among others.

For recent publications from her team, please visit:
https://www.patho.hku.hk/en/Our-Team/Academic/Head-Of-Department/Professor-LEUNG-Suet-Yi-Item/Professor-LEUNG-Suet-Yi

Faculty information, funding opportunities and application deadlines: https://www.findaphd.com/phds/program/biomedical-research-hku-li-ka-shing-faculty-of-medicine/?i586p4119

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