by Dr. Daniel G. Tenen & Ms. Meital Hatan
Cancer Science Institute of Singapore, National University of Singapore
Cancer is an ancient disease, first described in humans in the Egyptian Edwin Smith Papyrus dated to the 17th century BCE . Consequently, the research of cancer has been conducted for thousands of years with the earliest theory of cancer articulated by Hippocrates (460–370 BCE), postulating that the disease was caused due to an excess of black bile . Since then, cancer research has come a long way, growing rapidly by the end of the 19th century and the beginning of the 20th, and peaking in popularity and progress in the current century .
Nevertheless, cancer research has always focused on the Western world, neglecting most of the world’s population. It is well known that many cancers endemic to Asia are different from those in the Western countries , however Asian cancer research has not yet reached maturity, leaving the potential risk factors and underlying molecular genetics relatively unexplored.
With this realization, cancer research institutes throughout Asia, including the Cancer Science Institute of Singapore, are now giving their full attention to the types of cancers that are more prevalent in the area and that might have a different genetic/environmental causes, needing different types of prevention, therapeutics, and treatment approaches.
Asian Cancer, an Unmet Clinical Need
The World Health Organization approximates that in 2012, there were 14 million new cancer cases worldwide and 8.2 million cancer-related deaths, with 70% of the world’s cancer deaths occurring in Asia and developing countries. These numbers are expected to rise dramatically over the next two decades and will particularly impact Asia. 
Although the general features of cancers are shared between Asian cancer and non-Asian cancer, it is now clear that the specific features can vastly vary, attributed both to the exposure to different risk factors and different genetic backgrounds. An example is shown with the finding that non-smoking East Asian women feature higher lung cancer incidence rates with different associated mutations than non-Asian non-smoking women . Another example is the fact that clinical outcomes between patients in Asian and non-Asian countries is evidently different and might be attributed to different gene signatures differentially expressed between Asians and non-Asian related to immune function and inflammation . Importantly, as different cancers display tremendous geographic variation (Figure 1), many cancers endemic to Asia are different from those in the Western countries .
Nevertheless, relatively little is known about the underlying molecular genetics of Asian cancers.
Thus, Asian cancers are a key area to which scientific and medical attention should be focused to develop novel therapeutic, diagnostic, and preventive strategies.
Cancer Science Institute of Singapore- Putting the Emphasis on Asian Cancer
The Cancer Science Institute (CSI) of Singapore was established in 2008 as an autonomous Centre of Excellence at the National University of Singapore (NUS), to address the gap in knowledge surrounding Asian cancer. CSI's area of focus lies particularly in gastric, liver, lung, and leukemia cancers, which are prevalent among Asian populations, along with breast cancer that can present specific Asian phenotypes.
CSI conducts basic and translational cancer studies by adopting a multifaceted approach through two strong, multidisciplinary research programs: Cancer Biology & Stem Cell and Experimental Therapeutics. Spanning the spectrum from laboratory-based studies to targeted therapies in humans, facilitating the harnessing of basic science discoveries to create more effective therapeutics, as well as to improve existing cancer treatments.
Through this unique approach of research, CSI has been involved in many outstanding discoveries related to Asian cancers leading to the development of new strategies for cancer prevention, diagnosis, and treatment. Presented below are some of these discoveries.
Recent Discoveries in Upper Gastrointestinal Tract Cancers
Nasopharyngeal carcinoma (NPC), is the most common cancer originating in the nasopharynx, the uppermost region of the pharynx ("throat"). NPC has extremely skewed ethnic and geographic distributions, being very uncommon in the United States but extremely common in Southern China, Hong Kong, and Southeast Asia [9,10]. NPC is poorly understood at the genetic level and is in need of effective therapeutic approaches.
A group of researchers from CSI, led by CSI Senior Principal Investigator H. Phillip Koeffler, have profiled a large number of NPC samples and revealed a distinct mutational signature and nine significantly mutated genes, many of which have not yet been described to be involved in NPC. Importantly, integrated analysis showed enrichment of genetic lesions affecting several important cellular processes and pathways, including chromatin modifications and the machinery of autophagy. Further functional studies suggested the biological relevance of these lesions to the NPC malignant phenotype. Their study provides a molecular basis for a comprehensive understanding of and continuing research into new therapies for NPC .
Gastric cancer (GC), also known as stomach cancer, is a cancer developing from the lining of the stomach. The incidence and mortality due to gastric cancer vary widely according to geographic areas, socio-cultural, and economic entities. It is the 4th most common malignancy in the world, with more than 70% of GC cases occurring in developing countries and half the world’s total cases occurring in East Asia [12-14].
A group of researchers from CSI and other institutes including Senior Principal Investigators Patrick Tan and Bin Tean Teh, surveyed the spectrum of somatic alterations in gastric cancer by profiling 15 gastric adenocarcinomas samples and found frequently mutated genes which were mostly related to cell adhesion and chromatin remodeling. Following these findings, they observed 2 of these genes to have tumor-suppressor activity, which can be key tumorigenic events in a subset of gastric cancers . For this work together with other major findings they were awarded the Singapore President’s Science Award (PSA) 2015.
CSI is also a member of the Singapore Gastric Cancer Consortium (SGCC) which is a translational research group comprising clinicians and scientists working in gastric cancer research. One of the main members is CSI Principal Investigator Yashiaki Ito, who discovered RUNX3, a gene that contributes in multiple ways to strengthen the protective barrier that prevents normal cells from succumbing to malignancy in gastric cancer. His group has identified at least three widely different areas in which RUNX3, may function prominently as a “gatekeeper’’ to prevent the progression of cancer [16,17].
Leukemia as a Model for Studying Cancer
Leukemia is a group of cancers involving white blood cells that include four main types: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML).
Leukemia is an outstanding model to study genetic regulation of differentiation and cancer progression. Researchers who study normal blood development and blood cancer have access to a large numbers of malignant cells, powerful tools to isolate and characterize cellular subpopulations, and a number of cell-line models of different haematopoietic lineages .
The Leukemia Group within CSI comprises investigators working on different aspects of leukemia biology to further identify potential therapeutic strategies in a disease in which treatment advancement has been lagging. Areas of focus include transcription factors involved in myeloid development, stem cell biology, epigenetics, and animal models. The integration of patient materials, suitable model systems, as well as clinical and industry partnership facilitates clinical translation. Of great interest is the strength of CSI in studying a special type of leukemia, Acute Megakaryoblastic Leukemia (AMKL), which is relatively uncommon in other parts of the world, and has its highest prevalence in Singapore and Malaysia.
New Way of Looking at Cancer- the RNA Way
Recently, CSI has formed the new RNA Biology Centre focusing on RNA in the study of cancer. RNA is one of the three major biological macromolecules that are essential for all known forms of life (along with DNA and proteins). Historically, genetic studies have mostly concentrated on DNA, which contains the master instructions for a cell. RNA was suggested to primarily play a role in converting the information stored in DNA into proteins. In recent years it has become clear that RNA does much more than simply play a role in protein synthesis.
RNA, in one form or another, touches upon nearly everything in a cell including the regulation of the activity of genes during development, cellular differentiation, and changing environments. Moreover, there is clear evidence that different forms of RNA are involved in many types of diseases including cancer.
Interesting findings have already arisen from the strong group of investigators in CSI exploring this field, including the identification of a novel RNA originating from a gene locus that is critical in regulating the local DNA methylation profile involved in gene silencing. Collectively, these results suggest strategies for gene-selective demethylation of therapeutic targets in cancer and other human disease . Another interesting finding is related to a machinery called RNA editing, which is defined as post-transcriptional alteration of RNA sequences and is an additional epigenetic control mechanism . Until recently, only a small number of proteins with amino acid substitutions caused by editing were known. In her study, CSI Principal Investigator Polly Chen was able to identify an RNA editing event of a specific transcript that was significantly elevated in tumor specimens, particularly in liver cancer. This over-editing event in tumors is predictive of poor prognosis and is shown to have a protein product that leads to inhibition of tumor-suppressor function, driving liver cancer pathogenesis .
The examples above demonstrate the importance of RNA in the development of cancer, and establishes the great potential encompassing RNA research, leading to the development of new diagnostic tests and therapeutics.
The traditional major focus on western cancer types has become the Achilles heel of cancer research. The CSI is working extensively to close the gap of knowledge and shed some more light on the cancer types that are prevalent in Asia.
CSI has already been able to reveal many important discoveries in the field of Asian cancers, including a number of significantly mutated genes in nasopharyngeal carcinoma, the identification of tumor suppressor genes in gastric cancer, and new findings in AMKL. Currently, the CSI is setting up a new center which will tackle these cancers from a fresh point of view: RNA. The RNA Biology Center’s long-term goal is to develop novel RNA-based biomarkers and therapies for cancer.
About the Authors
- Sudhakar, A., History of Cancer, Ancient and Modern Treatment Methods. J Cancer Sci Ther, 2009. 1(2): p. 1-4.
- Weinstein, I.B. and K. Case, The history of Cancer Research: introducing an AACR Centennial series. Cancer Res, 2008. 68(17): p. 6861-2.
- Wong, J.E.L. Cancer research in Asia: Challenges and opportunities. Clin Cancer Res October 1, 2010 16; PL4-2
- https://www.who.int/mediacentre/factsheets/fs297/en/ (World Cancer Report 2014 (Print), Edited by Bernard Stewart and Christopher P. Wild, IARC Nonserial Publication)
- Lan, Q., et al., Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia. Nat Genet, 2012. 44(12): p. 1330-5.
- Lin, S.J., et al., Signatures of tumour immunity distinguish Asian and non-Asian gastric adenocarcinomas. Gut, 2015. 64(11): p. 1721-31.
- Armstrong, R.W., et al., Nasopharyngeal carcinoma in Malaysian Chinese: salted fish and other dietary exposures. Int J Cancer, 1998. 77(2): p. 228-35.
- Jemal, A., et al., Global cancer statistics. CA Cancer J Clin, 2011. 61(2): p. 69-90.
- Lin, D.C., et al., The genomic landscape of nasopharyngeal carcinoma. Nat Genet, 2014. 46(8): p. 866-71.
- Rahman, R., A.W. Asombang, and J.A. Ibdah, Characteristics of gastric cancer in Asia. World J Gastroenterol, 2014. 20(16): p. 4483-90.
- Yang, L., Incidence and mortality of gastric cancer in China. World J Gastroenterol, 2006. 12(1): p. 17-20.
- Fock, K.M. and T.L. Ang, Epidemiology of Helicobacter pylori infection and gastric cancer in Asia. J Gastroenterol Hepatol, 2010. 25(3): p. 479-86.
- Zang, Z.J., et al., Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. Nat Genet, 2012. 44(5): p. 570-4.
- Li, Q.L., et al., Causal relationship between the loss of RUNX3 expression and gastric cancer. Cell, 2002. 109(1): p. 113-24.
- Ito, Y., S.C. Bae, and L.S. Chuang, The RUNX family: developmental regulators in cancer. Nat Rev Cancer, 2015. 15(2): p. 81-95.
- Tenen, D.G., Disruption of differentiation in human cancer: AML shows the way. Nat Rev Cancer, 2003. 3(2): p. 89-101.
- Di Ruscio, A., et al., DNMT1-interacting RNAs block gene-specific DNA methylation. Nature, 2013. 503(7476): p. 371-6.
- Gommans, W.M., S.P. Mullen, and S. Maas, RNA editing: a driving force for adaptive evolution? Bioessays, 2009. 31(10): p. 1137-45.
- Chen, L., et al., Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma. Nat Med, 2013. 19(2): p. 209-16.
Dr. Daniel G. Tenen
Daniel G. Tenen, MD, is the Director of the Cancer Science Institute of Singapore, National University of Singapore. Distinguished Professor, Department of Medicine, National University of Singapore; Director, Blood Program of the Harvard Stem Cell Institute and Professor of Medicine at Harvard Medical School.
His research efforts have focused on transcription factors, gene regulation, and their role in normal differentiation and cancer. His research contributions have included establishing the role of transcription factors in differentiation of myeloid cells and the role of disruption of these pathways in leukemia and lung cancer. He was born and raised in Los Angeles and received his B.A. from the University of California at Los Angeles in 1967. He subsequently moved to Boston, received his M.D. degree from Harvard Medical School in 1975. He completed training in Internal Medicine at Brigham & Women's Hospital and Medical Oncology at Dana Farber Cancer Institute, and his research training as a postdoctoral fellow in David Livingston's laboratory at Dana Farber Cancer Institute. He established his own independent laboratory at Beth Israel Deaconess Medical School, Harvard Medical School, in 1984, and a second laboratory at the Cancer Science Institute of Singapore in 2008.
Ms. Meital Hatan
Meital Hatan is a Scientific Officer managing the RNA Biology Center of the Cancer Science Institute of Singapore. She was raised in Israel and received her B.Sc. from Ben Gurion University in 2007. In 2010 she received her M.Sc. in Molecular Genetics from the Weizmann Institute of Science, Israel. Subsequently she moved to Boston, MA where she worked as a Project Coordinator as part of the Epigenomics program mainly involved in the Encode project, under the supervision of Dr. Bradley Bernstein. In 2015 in parallel to the establishment of the RNA Biology Center, she started working at the Cancer Science Institute of Singapore, where she helps to manage the center.