Genomic and Epigenomic Heterogeneity of Stomach Cancer:
Our research focuses on (epi)genomic strategies to unlock the molecular and clinical diversity of gastric cancer (GC, aka stomach cancer), a leading cause of worldwide cancer mortality with high prevalence in many Asian countries. Understanding how individual gastric tumors vary in their molecular aberrations may allow us to refine therapies for different subgroups of patients.
Over the past 20 years, our research has yielded landmark discoveries on the molecular changes driving GC carcinogenesis, laying the foundations for personalized approaches to detection and therapy. These include one of the earliest transcriptional profiling studies of GC (Tay et al, 2003, Tan et al., 2011) leading to an international industry-sponsored multi-centre clinical trial (Yong et al., 2018), recurrent GC fusion genes (Tao et al., 2011), new tumor suppressor genes such as ARID1A (Zang et al., 2012), somatic copy number alterations identifying novel driver alterations (FGFR2, wild-type KRAS amplifications) and lineage-specific transcription factors (KLF5, GATA) (Deng et al., 2012, Chia et al., 2015) and epigenomic changes in GC (Zouridis et al., 2012). Our group is a member of the Singapore Gastric Cancer Consortium.
More recently, our group has identified higher-order chromatin topologies associated with specific GC molecular subtypes (Okabe et al., 2020), GC enhancers and super-enhancers (Ooi et al., 2016) and charted a comprehensive single-cell atlas of GC (Kumar et al., 2022). We uncovered alternate promoter usage in cancer, underlying tumor immune-editing and responses to immunotherapy pervasive across multiple cancer types (Qamra et al., 2017, Demircioğlu et al., 2019, Sundar et al., 2019). We have systematically analyzed pre-malignant intestinal metaplasia (IM), discovering new IM driver genes and genomic features associated with progression, including a role for microbiome-induced inflammation (Huang et al., 2018; Huang et al., 2023) Our discoveries have defined GC (epi)genomics from pre-cancer to cancer, with impact for our current understanding of tissue-specific carcinogenic mechanisms and enabling translation to personalized medicine and precision prevention.
Asian Molecular Diversity:
In collaboration with Prof Teh Bin Tean and A/Prof Steve Rozen, we have also studied other Asian-endemic cancers such as biliary tract cancers (Ong et al., 2012; Chan-on et al., 2013; Jusukul et al., 2017), breast tumors (Lim et al., 2014; Tan et al., 2015) and urogenital malignancies (Poon et al., 2013; Yao et al., 2017). One of our major discoveries was a mutational signature linked to exposure to aristolochic acid (a compound in certain Traditional Chinese Medicines) in urogenital and liver cancers from Asia that is now categorized as Signature 22 in the global compendium of cancer mutational signatures (https://cancer.sanger.ac.uk/signatures/sbs/sbs22/). Through the National Precision Medicine program, we are assembling PRECISE-SG100K, South East Asia’s most deeply phenotyped longitudinal cohort of 100,000 Singaporeans, comprising Chinese, Indian, and Malay ancestries (Wong et al., 2023).
Our group has also co-led the genomic sequencing of plants of significant cultural and social importance, such as Singapore’s national flower (Lim et al,, 2022) and durian (Teh et al., 2017). The publication of the durian genome drew world-wide media attention from diverse areas such as Nature, CNN, New York Times, BBC News, and Food and Wine magazine.