Suet-Yi Leung

University of Hong Kong


Title:

Gastric Cancer – Linking Pathology, Genomics and Organoid-Based Drug Screening for Precision Oncology


Abstract:


Gastric cancer is characterised by marked histological and molecular heterogeneity linked to different aetiological factors and pathways of cancer development. Our prior comprehensive genomic profiling of gastric cancer revealed pathway-specific genetic and epigenetic perturbations, including extensive genomic wide hypermethylation and ARID1A mutation in EBV-associated gastric cancer; extensive mutation, hypermethylation and demethylation in MSI gastric cancer; extensive demethylation and chromosomal instability with oncogenic amplification in intestinal type gastric cancer; chromosomal stability, hypermethylation and RHOA mutation in diffuse type gastric cancer. Because of these molecular diversity and potential differential mechanisms for aggressive behaviour and therapy resistance, good in vitro models that encompass unique subtypes are necessary for precision medicine development. We hence developed a primary gastric cancer organoid culture (GCO) biobank that includes normal, dysplastic, cancer and lymph node metastases from gastric cancer patients that encompass most known molecular subtypes (including EBV, MSI, intestinal/CIN and diffuse/GS, with CLDN18-ARHGAP6 or CTNND1-ARHGAP26 fusions or RHOA mutations). The organoid cultures capture regional heterogeneity and subclonal architecture, remain closely similar to in vivo tumors by morphology, transcriptome and genomic profiles, that remained stable in long-term culture. Large-scale drug screening revealed sensitivity to new drugs such as Napabucasin, Abemaciclib and ATR inhibitor, the latter associated with ARID1A mutation. Overall, coupling genomics and organoid-based drug screening, linking back to patient pathology and therapeutic response will empower the development of precision cancer therapy.


Bio:

Dr. Suet-Yi Leung is the associate Dean (Research), Li Ka Shing Faculty of Medicine, Professor and Chair of Gastrointestinal Cancer Genetics and Genomics at the University of Hong Kong. Her research interests are focused on the molecular genetics and genomics of gastric and colorectal cancers. She and her research group have performed comprehensive molecular profiling and integrative genomics studies on large series of gastric and colorectal cancers using next-generation sequencing, expression microarray, DNA SNP genotyping array and methylation array.