This study is the most comprehensive genetic research of the estrogen metabolism pathway involving 7577 participants from Sweden and Finland. It is able to overcome many limitations of previous studies which usually investigated a limited number of single nucleotide polymorphisms (SNPs1) within some candidate genes through single SNP analysis, often in a moderate number of study subjects, leading to inconsistent results across different studies.
Led by GIS Executive Director Prof Edison Liu, GIS Senior Group Leader Dr Liu Jianjun and Prof Per Hall, Medical Director of the Karolinska Institutet, the finding was published in PLoS Genetics on July 1, 2010.
"Previous studies have typically looked at single genes and have produced inconsistent results. Genes work together in complex networks. By using a systematic approach to interrogate the network of genes that affects hormonal exposure and hence risk of breast and endometrial cancers, we found a small group of genes which works together to affect cancer risk,” said first author, Dr Low Yen Ling. “The results of this study has moved us one step closer to understanding the common pathways which are involved in the development of breast cancer and endometrial cancer." Dr Low, who was involved in this research while she was at the GIS, is currently a Clinical Scientist at the Abbott Asia-Pacific Nutrition Research & Development Center.
Similarly, Prof Edison Liu said, “This research raises the possibility of having a test using multiple genetic markers that, when added together, can give an estimate of risk for the most common forms of breast cancer. Previously such genetic risk determination was limited to rare forms of breast cancer. It was the combination of the markers rather than single markers, and our integration of the knowledge of the estrogen metabolism pathways that made the difference.”
Director of the NUS-GIS Centre for Molecular Epidemiology, Prof Chia Kee Seng added, “This study is the result of a very strong collaboration between the Genome Institute of Singapore and the Karolinska Institutet. Swedish and Finnish samples were analysed at GIS and the subsequent joint analyses resulted in a deeper understanding of the complex genetic mechanisms of hormone metabolism and how this leads to breast and endometrial cancer.”
In this study, several hundreds of SNPs were analyzed in a large clinical sample consisting of 7577 participants from Sweden and Finland. The SNPs were analyzed in groups that were categorized according to their potential biochemical functions in the production of estrogen, and the accumulative effect of multiple SNPs within a group on breast cancer development was tested. The scientists found a positive association of breast cancer risk with the DNA variation of the genes involved in the production of estrogen, including the CYP19A1 gene that produce aromatase enzyme.
“Aromatase (coded by CYP19A1) is used to produce estrogen from androgen in postmenopausal women. As estrogen exposure is the most important risk factor for breast cancer, inhibiting aromatase activity and thus lowering estrogen production has been commonly used to treat breast cancer in postmenopausal women,” said Dr Liu Jianjun. “The current study advanced our understanding of aromatase by demonstrating that the modulation of aromatase activity by either DNA variation or pharmacological agents can both influence the development of estrogen-sensitive tumour in postmenopausal women. The convergence of genetic and pharmacological effects of CYP19A1 also suggested that other genes involved in the production of estrogen from androgen can act as potential therapeutic targets for treating breast cancer. In addition, the finding of this study raises the possibility that breast cancer can be prevented by blocking the production of estrogen through the use of an aromatase inhibitor.”
Prof Per Hall added, “The findings published in PLoS Genetics are truly exciting and reassuring. Given the central role of estrogen in the carcinogenesis of breast cancer, researchers have for decades tried to link genetic variation in the estrogen metabolizing pathway to the risk of breast cancer. For the first time, we find compelling evidence that there is a strong link between polymorphisms in genes that metabolize estrogen and risk of both breast and endometrial cancer. The fact that polymorphism in the aromatase gene, CYP191A1, influence the susceptibility to breast cancer, strengthen the utility of the well-established aromatase inhibitors as chemoprophylaxis agents for targeted subgroups of women identified to have an increased risk of breast cancer.”
Research publication: The research findings described in the press release can be found in the July 1, 2010 print issue of PLoS Genetics under the title “Multi-variant Pathway Association Analysis Reveals the Importance of Genetic Determinants of Estrogen Metabolism in Breast and Endometrial Cancer Susceptibility”.
Authors: Yen Ling Low1*, Yuqing Li 1*, Keith Humphreys 2*, Anbupalam Thalamuthu 1, Yi Li 1, Hatef Darabi 2, Sara Wedrén 3, Carine Bonnard 1, Kamila Czene2, Mark MIles4, Tuomas Heikkinen 5, Kristiina Aittomäki6, Carl Blomqvist7,8, Heli Nevanlinna 5, Per Hall 2#, Edison T Liu 9# and Jianjun Liu 1#
1. Human Genetics, Genome Institute of Singapore, Singapore 2. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden 3. Institute for Environmental Medicine, Karolinska Institutet, Stockholm, Sweden 4. Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, UK 5. Departments of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland 6. Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland 7. Oncology, Helsinki University Central Hospital, Helsinki, Finland 8. Department of Oncology, Radiology and Clinical Immunology, Uppsala University Hospital, Uppsala, Sweden 9. Cancer Biology, Genome Institute of Singapore, Singapore
* Equal Contribution
To whom correspondence should be addressed: Jianjun Liu, liuj3@gis.a- star.edu.sg; Edison T Liu, liue@gis.a-star.edu.sg and Per Hall, Per.Hall@ki.se.
About the Genome Institute of Singapore
www.gis.a-star.edu.sg
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.
About the Agency for Science, Technology and Research (A*STAR) www.a-star.edu.sg
The Agency for Science, Technology and Research (A*STAR) is the lead agency for fostering world-class scientific research and talent for a vibrant knowledge-based and innovation-driven Singapore. A*STAR oversees 14 biomedical sciences, and physical sciences and engineering research institutes, and seven consortia & centres, which are located in Biopolis and Fusionopolis, as well as their immediate vicinity.
A*STAR supports Singapore's key economic clusters by providing intellectual, human and industrial capital to its partners in industry. It also supports extramural research in the universities, hospitals, research centres, and with other local and international partners.
For enquiries, please contact the following: Genome Institute of Singapore Winnie Serah Lim Corporate Communications Tel: (65) 6808 8013 (65) 9730 7884 Email: limcp2@gis.a-star.edu.sg
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