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A*STAR's Genome Institute of Singapore Scores Double Headway on Non-Hodgkin Lymphoma (NHL) With the Discovery of Novel DNA Variants That Influence the Risk of Blood Cancer


6/27/2013 8:44:39 AM

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June 27, 2013 -- Scientists at the Genome Institute of Singapore (GIS) recently led in two studies that revealed important genetic insights into the development of non-Hodgkin lymphoma (NHL). NHLs are some of the most common blood cancers and include any kind of lymphoma except Hodgkin’s lymphomas.

A. Study 1: discovered novel inheritable gene variant that increases risk of blood cancer in Asians In the first study, reported in the prestigious scientific journal Nature Genetics, the scientists discovered an inheritable gene variant which increases the risk of non-Hodgkin lymphoma (NHL) in Asians.

In order to identify heritable risk factors influencing susceptibility to NHL, Dr Liu Jianjun, Deputy Director of Research Programmes and Senior Group Leader of Human Genetics at the GIS, led the first Asian genome-wide genetic variation analysis in Singaporean Chinese lymphoma samples. The team then validated the top findings from this analysis with three additional sets of samples from China (comprising two sets from Guangzhou and one from Beijing). In total, 1,428 NHL patients and 6,930 controls of Chinese origin were investigated in this study.

The team identified the DNA variation located in between two genes –B-cell lymphoma protein 6 (BCL6) and lipoma preferred partner (LPP) – that confers a 50 percent increased risk of NHL in individuals that carry this DNA variant as compared to those that do not. This DNA variant is thought to promote the development of NHL by influencing the expression levels of the neighbouring genes.

This study also involved the research teams from the National University Health System/National University of Singapore, National Cancer Centre, Singapore General Hospital, and Tan Tock Seng Hospital in Singapore, and from the Sun Yat-sen University Cancer Center, Guangzhou, China and Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.

B. Study 2: pinpointed culprit for high risk of follicular lymphoma

In a second related study reported in another prestigious scientific journal, American Journal of Human Genetics, GIS scientists made an in-depth investigation on the association of the human leukocyte antigen (HLA) region with follicular lymphoma (FL), a common sub-type of NHL. Previous genetic studies by the GIS scientists as well as others around the world had discovered that multiple genetic variants within the HLA region are independently associated with FL risk.

Scientists have now been able to identify a single amino acid variation encoded by the immune gene HLA-DRB1 as the culprit for these associations.

Every individual inherits and carries any two out of six amino acids of this variation. The particular two amino acids that a person carries will determine if that person has a high, moderate or low risk of contracting FL. The team discovered that individuals carrying two high-risk amino acids had a 4.2 fold higher risk than those with two low-risk amino acids.

These two studies provide novel genetic insights into the development of NHL, and pave the way for further biological investigation that can help to develop more targeted and accurate therapeutic medication.

Dr Liu said, “The novel discovery that the inheritable genetic variation of BCL6-LPP can influence the risk of developing NHL is truly an exciting one. Previous studies have been largely carried out in western populations. The success of our study has demonstrated that the investigation of Asian populations can lead to novel findings. We are now planning further Asian studies to discover additional novel risk variants for NHL by investigating larger numbers of clinical samples”

GIS’ Executive Director Prof Ng Huck Hui added, “Dr Liu and his team have successfully adopted genome-wide association studies to provide crucial biological insights to many diseases such as spine disease (ankylosing spondylitis) and kidney disease (Immunoglobulin A Nephropathy). These latest discoveries are testament to their great work and underscore the importance of collaboration with academic and clinical entities.”

Dr. Stephen J. Chanock, M.D., Chief at the Division of Cancer Epidemiology & Genetics, Laboratory of Translational Genomics, National Cancer Institute said, “JJ Liu and colleagues have conducted a set of informative studies in primarily Asian populations that provide new insights into the underlying genetic susceptibility to two of the major subtypes of non-Hodgkins lymphoma (NHL). Investigation of the HLA region, known to be linked to NHL risk, has revealed a series of important observations on the actual HLA genes, providing a foundation for the next generation of mechanistic studies. In addition, they have identified genetic markers in a region with a plausible candidate gene, BCL6 – the target of extensive research in NHL.”

Research publication:

The research findings described in the press release were published in the advanced online issues of two journals: A. Nature Genetics under the title “Genome-wide association study of B-cell non-Hodgkin’s lymphoma identifies 3q27 as a susceptibility locus in the Chinese population” on 9th June 2013, and

B. American Journal of Human Genetics under the title “Coding Variants at the Hexa-allelic Amino Acid 13 of HLA-DRB1 Explain Independent SNP Associations with Follicular Lymphoma Risk” on 20th June 2013.

Authors for Nature Genetics paper:

Dennis E.K. Tan1,22, Jia Nee Foo1,22, Jin-Xin Bei1,2,22, Jiang Chang3,4,22, Roujun Peng2, Xiaohui Zheng2, Lixuan Wei3,4, Ying Huang3,4, Wei Yen Lim5, Juan Li6, Qian Cui2, Soo Hong Chew7, Richard P. Ebstein8, Ponnudurai Kuperan 9, Soon Thye Lim10, Miriam Tao10, Suat Hoon Tan11, Alvin Wong12, Gee Chuan Wong13, Soo Yong Tan14, Siok Bian Ng15, Yi-Xin Zeng2,16, Chiea Chuen Khor1,5,17,18,19, Dongxin Lin3,4,23, Adeline L.H. Seow5,23, Wei-Hua Jia2,23, Jianjun Liu20,21,1,5,23

1. Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore

2. State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China

3. State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

4. Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

5. Saw Swee Hock School of Public Health, National University Health System, National University of Singapore, Singapore

6. Department of Hematology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

7. Department of Economics, National University of Singapore, Singapore

8. Department of Psychology, National University of Singapore, Singapore

9. Division of Haematology and Laboratory Pathology, Tan Tock Seng Hospital, Singapore

10. Division of Medical Oncology, National Cancer Centre, Singapore

11. Department of Dermatology, National Skin Centre, Singapore

12. Department of Haematology-Oncology, National University Health System, National University of Singapore, Singapore

13. Department of Haematology, Singapore General Hospital, Singapore

14. Department of Pathology, Singapore General Hospital, Singapore

15. Department of Pathology, National University Health System, National University of Singapore, Singapore

16. Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China

17. Singapore Eye Research Institute

18. Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

19. Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

20. School of Biological Sciences, Anhui Medical University, Hefei, Anhui, China

21. Institute of Dermatology and Department of Dermatology, No.1 Hospital, Anhui Medical University, Hefei, Anhui, China

22. These authors contributed equally to this work.

23. These authors jointly directed this work.

Authors for American Journal of Human Genetics paper:

Jia Nee Foo1,17, Karin E. Smedby2,17, Nicholas K. Akers3, Mattias Berglund4, Ishak D. Irwan1, Xiaoming Jia5,6, Yi Li1, Lucia Conde7, Hatef Darabi8, Paige M. Bracci9, Mads Melbye10, Hans-Olov Adami8,11, Bengt Glimelius4, Chiea Chuen Khor1,12,13,14, Henrik Hjalgrim10, Leonid Padyukov15, Keith Humphreys8, Gunilla Enblad4, Christine F. Skibola7,18, Paul I.W. de Bakker5,6,16,18, Jianjun Liu1,14,18

1. Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore 138672, Singapore

2. Department of Medicine, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm SE-171 77, Sweden

3. School of Public Health, Division of Environmental Health Sciences, University of California-Berkeley, Berkeley, CA 94720, USA

4. Department of Radiology, Oncology and Radiation Science, Uppsala University, Uppsala SE-751 85, Sweden

5. Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA

6. Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA

7. School of Public Health, Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA

8. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden

9. University of California, San Francisco, Department of Epidemiology and Biostatistics, San Francisco , CA 94107, USA

10. Department of Epidemiology Research, Statens Serum Institut, Copenhagen DK-2300, Denmark

11. Department. of Epidemiology, Harvard University, Boston, MA 02115, USA

12. Singapore Eye Research Institute, Singapore 168751, Singapore

13. Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore

14. Saw Swee Hock School of Public Health, National University Health Systems, National University of Singapore, Singapore 117597, Singapore

15. Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm SE-171 76, Sweden

16. Department of Medical Genetics and of Epidemiology, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands

17. These authors contributed equally to this work

18. These authors jointly directed this work

Correspondence should be addressed to:

Jianjun Liu, liuj3@gis.a-star.edu.sg, tel (65)6808-8088

Contact

Winnie Lim

Genome Institute of Singapore

Office of Corporate Communications

Tel: (65) 6808 8013

Email: limcp2@gis.a-star.edu.sg

About the Genome Institute of Singapore (GIS)

The Genome Institute of Singapore (GIS) is an institute of the Agency for Science, Technology and Research (A*STAR). It has a global vision that seeks to use genomic sciences to improve public health and public prosperity. Established in 2001 as a centre for genomic discovery, the GIS will pursue the integration of technology, genetics and biology towards the goal of individualized medicine.

The key research areas at the GIS include Systems Biology, Stem Cell & Developmental Biology, Cancer Biology & Pharmacology, Human Genetics, Infectious Diseases, Genomic Technologies, and Computational & Mathematical Biology. The genomics infrastructure at the GIS is utilized to train new scientific talent, to function as a bridge for academic and industrial research, and to explore scientific questions of high impact.

www.gis.a-star.edu.sg

About the Agency for Science, Technology and Research (A*STAR)

The Agency for Science, Technology and Research (A*STAR) is Singapore's lead public sector agency that fosters world-class scientific research and talent to drive economic growth and transform Singapore into a vibrant knowledge-based and innovation driven economy.

In line with its mission-oriented mandate, A*STAR spearheads research and development in fields that are essential to growing Singapore’s manufacturing sector and catalysing new growth industries. A*STAR supports these economic clusters by providing intellectual, human and industrial capital to its partners in industry.

A*STAR oversees 20 biomedical sciences and physical sciences and engineering research entities, located in Biopolis and Fusionopolis as well as their vicinity. These two R&D hubs house a bustling and diverse community of local and international research scientists and engineers from A*STAR’s research entities as well as a growing number of corporate laboratories.

www.a-star.edu.sg

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