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Title: Genetic and genomic analysis modeling of germline c-MYC overexpression and cancer susceptibility
Author: Solé Acha, Xavier
Hernández, Pilar
López de Heredia, Miguel
Armengol, Lluís
Rodríguez Santiago, Benjamín
Gómez, Laia
Maxwell, Christopher A.
Aguiló Lúcia, Fernando
Condom i Mundó, Enric
Abril, Jesús
Pérez Jurado, Luis
Estivill, Xavier, 1955-
Nunes Martínez, Virginia
Capellá, G. (Gabriel)
Gruber, Stephen B.
Moreno Aguado, Víctor
Pujana Genestar, M. Ángel
Keywords: Càncer de pròstata
Patologia cel·lular
Transcripció genètica
Prostate cancer
Cellular pathology
Genetic transcription
Issue Date: 11-Jan-2008
Publisher: BioMed Central
Abstract: 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.
Note: Reproducció del document publicat a:
It is part of: Bmc Genomics, 2008, vol. 9, p. 1-12
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ISSN: 1471-2164
Appears in Collections:Articles publicats en revistes (Ciències Fisiològiques)
Articles publicats en revistes (Ciències Clíniques)
Articles publicats en revistes (Patologia i Terapèutica Experimental)

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