Laboratory of Cancer Epigenome
|Head of Lab:
||Bin Tean TEH
Poon Song Ling
Cedric Ng Chuan Young
Koh Liang Kai
Swe Swe Myint
Heng Hong Lee
Siew Ee Yan
Max Loh Jia Liang
Giovani Claresta Wijaya
|About the Lab
The Cancer Epigenome research laboratory is focusing on integrated epigenomic and genomic profiling in Asian cancers using enabling technologies such as ChIP-Seq, RNA-seq, Whole-genome and DNA methylation sequencing. The data is then correlated with clinicopathological information including how patients respond to certain drugs. Our research goals are to:
1) understand the molecular mechanism underlying these cancers;
2) to identify novel biomarkers than can help determine the nature and behaviour of the disease as well as predicting patients’ response to certain drugs; and
3) to identify novel therapeutic targets with a focus on chromatin enzymes.
The group has hosted and trained clinician scientists, both locally and abroad, who are interested in pursuing translational research. To date, the laboratory has been instrumental in establishing and nurturing several cancer type-based translational research programs at the National Cancer Centre Singapore including biliary tract cancer, lymphoma, sarcoma, breast disease, urological cancer, and peritoneal cancer. The group always emphasizes on collaboration (both local and international) which is key to scientific breakthroughs. The group is now part of the Singapore team that is leading the International Cancer Genome Consortium (ICGC) project on biliary tract cancer. The group is also an integral part of the Lymphoma TCR (Translational Clinical Research) Program.
Biliary Tract Cancer
Bile Duct Cancer or cholangiocarcinoma (CCA) is an aggressive cancer without effective therapy. It is also endemic in certain parts of South East Asia, particularly in the north east region of Thailand where the disease is considered a long-term outcome of chronic liver fluke-related infestation through local dietary habits. In collaboration with the University of Khon Kaen, the group has been studying this cancer by focusing on its genome (Ong et al., Nature Genetics, 2012). More recently, we also compared the spectrum and frequency of mutations between the liver-fluke and non liver-fluke related CCA and found distinct mutation signature for both groups (Chan-on et al., Nature Genetics, 2013). We are currently working on the whole-genome sequencing of CCA from different parts of the world as part of the ICGC (International Cancer Genome Consortium) project.
Fibroepithelial Tumors of the Breast
Fibroepithelial neoplasms of the breast are a distinct category of breast disease consisting of the very common benign breast fibroadenoma to the relatively rare phyllodes tumors. The latter is further subdivided into benign, borderline, and malignant grades based on their histological features. While FAs affect millions of women worldwide annually, PTs occur at a lower frequency of approximately 1% or less of breast tumors and up to 7% of Asian breast cancers. The diagnosis and classification of PTs often present challenges to pathologists, particularly in the distinction of benign PT from FA. There is currently also no effective therapy for PTs besides surgery. We have recently characterized the genomic landscape of breast fibroepithelial tumors (Lim et al., Nature Genetics, 2014; Tan et al., Nature Genetics, 2015) including the discovery of
1) two commonly mutated genes MED12 and RARA;
2) a series of mutations that appear to contribute to different stages of phyllodes tumors.
These findings may have clinical implications in diagnosis and may provide the foundation for a genomics-based classification of breast fibroepithelial tumors. We are currently working on the mechanistic aspects of some of these mutations to better understand their roles in the tumorigenesis of this very interesting group of tumors. .
In renal cell carcinoma (RCC), our collaboration with the Sanger Institute, UK, has led to the discovery of frequent mutations in chromatin enzymes (Dagliesh et al., Nature, 2010; Valera et al., Nature 2011) and our group is currently working on the mechanistic and functional aspects of these genes in this cancer type. One aspect of investigations involves the profiling of epigenomic modification related to key RCC-related driver mutations. Very recently, through the studies of RCC-related cachexia model, and in collaboration with the Genome Institute of Singapore and medical oncologists at NCCS, one of the molecular mechanisms involved in irreversible wasting of muscle mass in terminally ill patients was identified, which can be alleviated by targeting excessive fatty acid oxidation (Fukawa et al., Nature Medicine, 2016). Separately, we have recently identified the global mutation signature associated with Aristolochic Acid (AA), a chemical found in certain herbal products in urothelial cancer (Poon et al., Science Translational Med, 2013). The signature has been used as a molecular finger print to screen for exposure to this herbal carcinogen in other cancer types such as bladder cancer (Song et al., Genome Medicine, 2015). We are continuing our screening works and are trying to find ways to target therapeutically these AA-associated tumors. For example, one of the most frequently mutated genes in urothelial cancer is UTX and our group is currently studying how the gene contributes to the tumorigenesis of urothelial cancer and how we can therapeutically target this mutation.
1) Fukawa T, Yan-Jiang BC, Min-Wen JC, Jun-Hao ET, Huang D, Qian CN, Ong P, Li Z, Chen S, Mak SY, Lim WJ, Kanayama HO, Mohan RE, Wang RR, Lai JH, Chua C, Ong HS, Tan KK, Ho YS, Tan IB, Teh BT, Shyh-Chang N. Excessive fatty acid oxidation induces muscle atrophy in cancer cachexia. Nature Med 22(6): 666-671, 2016
2) Tan J, Ong CK, Lim WK, Ng CC, Thike AA, Ng LM, Rajasegaran V, Myint SS, Nagarajan S, Thangaraju S, Dey S, Nasir ND, Wijaya GC, Lim JQ, Huang D, Li Z, Wong BH, Chan JY, McPherson JR, Cutcutache I, Poore G, Tay ST, Tan WJ, Putti TC, Ahmad BS, Iau P, Chan CW, Tang AP, Yong WS, Madhukumar P, Ho GH, Tan VK, Wong CY, Hartman M, Ong KW, Tan BK, Rozen SG, Tan P, Tan PH, Teh BT. Genomic landscapes of breast fibroepithelial tumors.
Nature Genet 47(11): 1341-1345, 2015
3) Poon SL, Huang MN, Choo Y, McPherson JR, Yu W, Heng HL, Gan A, Myint SS, Siew EY, Ler LD, Ng LG, Weng WH, Chuang CK, Yuen JS, Pang ST, Tan P, Teh BT, Rozen SG. Mutation signatures implicate aristolochic acid in bladder cancer development.
Genome Med 7(1):38, 2015
4) Lim WK, Ong CK, Tan J, Thike AA, Ng CC, Rajasegaran V, Myint SS, Nagarajan S, Nasir ND, McPherson JR, Cutcutache I, Poore G, Tay ST, Ooi WS, Tan VK, Hartman M, Ong KW, Tan BK, Rozen SG, Tan PH, Tan P, Teh BT. Exome sequencing identifies highly recurrent MED12 somatic mutations in breast fibroadenoma.
Nature Genet 46(8): 877–880, 2014
5) Chan-on W, Nairismägi M-L, Ong CK, Dima S, Pairojkul C, Lim KH, McPherson JR, Lim WK, Cucutache I, Heng HL, Ooi L, Chung A, Chow P, Cheow PC, Lee SY, Huat ITB, Duda D, Nastase A, Myint SS, Wong BH, Gan A, Rajasegaran V, Ng CCY, Jusakul A, Zhang S, Vohra P, Yu W, Huang D, Yongvanit P, Wongkham S, Khuntikeo N, Bhudhisawasdi V, Popescu I, Rozen SG, Tan P, Teh BT. Distinct mutational patters of infection and non-infection-related bile duct cancers revealed by exome sequencing.
Nature Genet 45(12): 1474–1478, 2013
6) Poon SL, Pang ST, McPherson JR, Yu W, Huang KK, Guan P, Weng WH, Siew EY, Liu Y, Heng HL, Chong SC, Gan A, Tay ST, Lim WK, Cutcutache I, Huang D, Ler LD, Nairismägi ML, Lee MH, Chang YH, Yu KJ, Chan-on W, Li BK, Yuan YF, Qiang CN, Ng KF, Wu CF, Hsu CL, Bunte RM, Stratton MR, Futureal PA, Sung WK, Chuang CK, Ong CK, Rozen SG, Tan P, Teh BT. Genome-wide mutational signatures of aristolochic acid and its application as a screening tool.
Sci Transl Med 5(197): 197ra101, 2013
7) Ong CK, Subimerb C, Pairojkul C, Wongkham S, Cutcutache I, Yu W, McPherson J, Allen GE, Ng CCY, Wong BHM, Myint SS, Rajasegaran V, Heng HL, Gan A, Zang ZJ, Wu Y, Wu J, Lee MH, Huang D, Ong P, Chan-on W, Cao Y, Qian CN, Lim KH, Ooi A, Dykema KJ, Furge K, Kukongviriyapan V, Sripa B, Wongkham C, Yongvanit P, Futreal PA, Bhudhisawasdi V, Rozen S, Tan P, Teh BT. Exome sequencing of liver fluke- associated cholangiocarcinoma.
Nature Genet 44(6): 690–693, 2012
8) Koo GC, Tan SY, Tang T, Poon SL, Allen GE, Tan L, Chong SC, Ong WS, Tay K, Tao M, Quek R, Loong S, Yeoh KW, Yap SP, Lee KA, Lim LC, Tan D, Goh C, Cutcutache I, Yu W, Ng CC, Rajasegaran V, Heng HL, Gan A, Ong CK, Rozen S, Tan P, Teh BT, Lim ST. Janus kinase 3-activating mutations identified in natural killer/T-cell lymphoma.
Cancer Discov 2(7): 591-597, 2012
9) Varela I, Tarpey P, Raine K, Huang D, Ong CK, Stephens P, Davies H, Jones D, Lin M-L, Teague J, Bignell G, Butler A, Cho J, Dalgliesh GL, Galappaththige D, Greenman C, Hardy C, Jia M, Latimer C, Lau KW, Marshall J, McLaren S, Menzies A, Mudie L, Stebbings L, Largaespada DA, Wessels LFA, Richard S, Kahnoski RJ, Anema J, Tuveson D, Perez-Mancera P, Mustonen V, Fischer A, Adams DJ, Rust A, Chan-on W, Subimerb C, Dykema K, Furge K, Campbell PJ, Teh BT*, Stratton MR*, Futreal PA*. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma.
Nature 469(7331): 539–542, 2011 *co-corresponding author
10) Dalgliesh GL, Furge K, Greenman C, Chen L, Bignell G, Butler A, Davies H, Edkins S, Hardy C, Latimer C, Teague J, Andrews J, Barthorpe S, Beare D, Buck G, Campbell PJ, Forbes S, Jia M, Jones D, Knott H, Kok CY, Lau KW, Leroy C, Lin ML, McBride DJ, Maddison M, Maquire S, McLay K, Menzies A, Mironenko T, Mulderrig L, Mudie L, O’Meara S, Pleasance E, Rajasingham A, Shepherd R, Smith R, Stebbings L, Stephens P, Tang G, Tarpety PS, Turrell K, Dykema KJ, Khoo SK, Petillo D, Wondergem B, Anema J, Kahnoski RJ, Teh BT*, Stratton MR, Futreal PA. Systemic sequencing of renal cell carcinoma reveals inactivation of histone modifying genes.
Nature 463(7279): 360–363, 2010 *co-corresponding author