Genetic and genomic analysis modeling of germline c-MYC overexpression and cancer susceptibility
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- 作者：Xavier Solé (1)
Pilar Hernández (1)
Miguel López de Heredia (2) (3)
Lluís Armengol (4)
Benjamín Rodríguez-Santiago (5) (6)
Laia Gómez (1)
Christopher A Maxwell (1)
Fernando Aguiló (7)
Enric Condom (8)
Jesús Abril (2)
Luis Pérez-Jurado (5) (6) (9)
Xavier Estivill (4)
Virginia Nunes (10) (2) (3)
Gabriel Capellá (1)
Stephen B Gruber (11)
Víctor Moreno (1)
Miguel Angel Pujana (1) - 刊名：BMC Genomics
- 出版年：2008
- 出版时间：December 2008
- 年：2008
- 卷：9
- 期：1
- 全文大小：1927KB
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Pilar Hernández (1)
Miguel López de Heredia (2) (3)
Lluís Armengol (4)
Benjamín Rodríguez-Santiago (5) (6)
Laia Gómez (1)
Christopher A Maxwell (1)
Fernando Aguiló (7)
Enric Condom (8)
Jesús Abril (2)
Luis Pérez-Jurado (5) (6) (9)
Xavier Estivill (4)
Virginia Nunes (10) (2) (3)
Gabriel Capellá (1)
Stephen B Gruber (11)
Víctor Moreno (1)
Miguel Angel Pujana (1)
1. Bioinformatics and Biostatistics Unit, and Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet, Barcelona, Spain
2. Medical and Molecular Genetics Center, IDIBELL, L'Hospitalet, Barcelona, Spain
3. CIBERER-U730, L'Hospitalet, Barcelona, Spain
4. Genes and Disease Program, Center for Genomic Regulation, Barcelona, Spain
5. Genetics Unit, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
6. CIBERER-U735, Barcelona, Spain
7. Department of Urology, Bellvitge Hospital University, IDIBELL, L'Hospitalet, Barcelona, Spain
8. Department of Pathology, Bellvitge Hospital University, IDIBELL, L'Hospitalet, Barcelona, Spain
9. Program in Molecular Medicine and Genetics, Vall d'Hebron University Hospital, Barcelona, Spain
10. Genetic Unit, Department of Physiology II, University of Barcelona, Barcelona, Spain
11. Departments of Epidemiology, Internal Medicine and Human Genetics, University of Michigan, Ann Arbor, Michigan, USA
文摘
Background Germline genetic variation is associated with the differential expression of many human genes. The phenotypic effects of this type of variation may be important when considering susceptibility to common genetic diseases. Three regions at 8q24 have recently been identified to independently confer risk of prostate cancer. Variation at 8q24 has also recently been associated with risk of breast and colorectal cancer. However, none of the risk variants map at or relatively close to known genes, with c-MYC mapping a few hundred kilobases distally. Results This study identifies cis-regulators of germline c-MYC expression in immortalized lymphocytes of HapMap individuals. Quantitative analysis of c-MYC expression in normal prostate tissues suggests an association between overexpression and variants in Region 1 of prostate cancer risk. Somatic c-MYC overexpression correlates with prostate cancer progression and more aggressive tumor forms, which was also a pathological variable associated with Region 1. Expression profiling analysis and modeling of transcriptional regulatory networks predicts a functional association between MYC and the prostate tumor suppressor KLF6. Analysis of MYC/Myc-driven cell transformation and tumorigenesis substantiates a model in which MYC overexpression promotes transformation by down-regulating KLF6. In this model, a feedback loop through E-cadherin down-regulation causes further transactivation of c-MYC. Conclusion This study proposes that variation at putative 8q24 cis-regulator(s) of transcription can significantly alter germline c-MYC expression levels and, thus, contribute to prostate cancer susceptibility by down-regulating the prostate tumor suppressor KLF6 gene.