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STAFF

Professor LEUNG Suet Yi | suetyi@hku.hk

Associate Dean (Research)
Li Ka Shing Faculty of Medicine, HKU

YW Kan Professor in Natural Sciences
Professor, Chair of Gastrointestinal Cancer Genetics and Genomics
MBBS HK; MD; FHKAM (Pathology), FHKCPath; FRCPath (UK); FRCPA

Molecular genetics and genomics of gastrointestinal tract cancer

Clinical Service

Director, Hereditary Gastrointestinal Cancer Genetic Diagnosis Laboratory

Research Description

My research interests are focused on the molecular genetics and genomics of gastric and colorectal cancers. We 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. Our study revealed the complex genomic landscape of gastric cancer and first identified many new gastric cancer driver genes. Examples include frequent mutation of ARID1A, a chromatic remodeling gene, in gastric cancers with MSI or EBV, and hotspot mutation of RHOA in diffuse type gastric cancer. Integative genomics analysis has also identified many novel gastric driver genes altered by DNA copy number changes, DNA hypermethylation or demethylation with corresponding change in gene expression. Our study of gene expression have revealed novel modules reflecting intrinsic properties of tumour and normal cells, tumour-stroma interaction, host immune response and pathways of stem cell regulation. This information have led to the identification of new tumour suppressor genes frequently silenced in gastrointestinal cancers, genes that can modify tumour aggressive behaviour and patient outcome, and genes that contribute to maintenance of stem cell niche.

Our team has extensively characterized the genetic basis for the exceptionally high incidence of early-onset colorectal cancer (CRC) in Hong Kong. We have uncovered the mutation spectrum of germline DNA mismatch repair gene, and revealed a founder mutation that is common in the Southern Chinese population which originated between 22 and 103 generations ago. We have described the first example of heritable germline methylation of MSH2 gene promoter as a cause of hereditary colon cancer, and uncovered a novel mechanism of methylation induction and gene silencing through abrogation of transcriptional termination signal in an upstream neighbouring gene named EPCAM (TACSTD1). These findings have resulted in incorporation of EPCAM deletion into the standard genetic diagnosis protocol for Lynch Syndrome worldwide. Our laboratory is now applying the research findings to patient care, by providing a charitable genetic diagnosis service including genetic testing and referral for prophylactic screening for early-onset or familial colorectal cancer patients and their families. We have also studied in depth the role of the BRAF mutation in colorectal cancers, and discovered an interesting relationship between the BRAF mutation and various pathways of colorectal carcinogenesis.

The long term goal of my laboratory is to utilise genomics technology to identify novel pathways of carcinogenesis and hereditary predisposition for colorectal and gastric cancers, and to identify biomarkers for early detection, patient stratification, prognostication or drug targets.

Research Grant

Awards and Honors

YW Kan Endowed Professorship in Natural Sciences (2012)

Faculty Outstanding Research Output Award, Li Ka Shing Faculty of Medicine,
The University of Hong Kong (2012)

Croucher Senior Medical Research Fellowship (2007)

Outstanding Research Award, The University of Hong Kong (2007)

Research Output Prize, The University of Hong Kong (2007 and 2009)

Outstanding Young Researcher Award, The University of Hong Kong (2001)

Selected Publication List:

Click here for detail publication list

Wang K, Yuen ST, Xu J, Lee SP, Yan HH, Shi ST, Siu HC, Deng S, Chu KM, Law S, Chan KH, Chan AS, Tsui WY, Ho SL, Chan AK, Man JL, Foglizzo V, Ng MK, Chan AS, Ching YP, Cheng GH, Xie T, Fernandez J, Li VS, Clevers H, Rejto PA, Mao M, Leung SY. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat Genet 2014 May 11. doi: 10.1038/ng.2983. [Epub ahead of print]

Wang K, Kan J, Yuen ST, Shi ST, Chu KM, Law S, Chan TL, Kan Z, Chan ASY, Tsui WY, Lee SP, Ho SL, Chan AKW, Cheng GHW, Roberts PC, Reijto PA, Gibson NW, Pocalyko DJ, Mao M, Xu J, Leung SY. Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer. Nat Genet 2011, 43:1219-23.

Ligtenberg MJ, Kuiper RP, Chan TL, Goossens M, Hebeda KM, Voorendt M, Lee TY, Bodmer D, Hoenselaar
E, Hendriks-Cornelissen SJ, Tsui WY, Kong CK, Brunner HG, van Kessel AG, Yuen ST, van Krieken JH, Leung SY, Hoogerbrugge N. Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1. Nat Genet 2009;41(1):112-7.

Kosinski C, Stange DE, Xu C, Chan AS, Ho C, Yuen ST, Mifflin RC, Powell DW, Clevers H, Leung SY, Chen X. Indian hedgehog regulates intestinal stem cell fate through epithelial-mesenchymal interactions during development. Gastroenterology 2010, 139:893-903.

Kosinski C, Li VS, Chan AS, Zhang J, Ho C, Tsui WY, Chan TL, Mifflin RC, Powell DW, Yuen ST, Leung SY, Chen X. Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors. Proc Natl Acad Sci USA 2007, 104:15418–15423.

Chan TL, Yuen ST, Kong CK, Chan YW, Chan AS, Ng WF, Tsui WY, Lo MW, Tam WY, Li VS and Leung SY. Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer. Nat Genet 2006, 38:1178-1183.

Leung SY, Yuen ST, Chu KM, Mathy JA, Li R, Chan AS, Law S, Wong J, Chen X, So S. Expression profiling identifies chemokine (C-C motif) ligand 18 as an independent prognostic indicator in gastric cancer. Gastroenterology 2004, 127:457-469.

Chan TL, Zhao W, Cancer Genome Project, Leung SY and Yuen ST. BRAF and KRAS mutations in colorectal hyperplastic polyps and serrated adenomas. Cancer Res 2003, 63:4878-4881.

Leung SY, Chen X, Chu KM, Yuen ST, Mathy J, Ji J, Chan AS, Li R, Law S, Troyanskaya OG, Tu IP, Wong J, So S, Botstein D, and Brown PO. Phospholipase A2 group IIA expression in gastric adenocarcinoma is associated with prolonged survival and less frequent metastasis. Proc Natl Acad Sci USA 2002, 99:16203-16208.

Yuen ST, Davies H, Chan TL, Ho JW, Bignell GR, Cox C, Stephens P, Edkins S, Tsui WW, Chan AS, Futreal PA, Stratton MR, Wooster R, Leung SY. Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia. Cancer Res 2002, 62:6451-6455.

Leung SY, Yuen ST, Chung LP, Chu KM, Chan ASY and Ho JCI. hMLH1 promoter methylation and lack of hMLH1 expression in sporadic gastric carcinomas with high-frequency microsatellite instability. Cancer Res 1999, 59:159-164.