TY - JOUR
T1 - Genetic and genomic analysis modeling of germline c-MYC overexpression and cancer susceptibility
AU - Solé, Xavier
AU - Hernández, Pilar
AU - de Heredia, Miguel López
AU - Armengol, Lluís
AU - Rodríguez-Santiago, Benjamín
AU - Gómez, Laia
AU - Maxwell, Christopher A.
AU - Aguiló, Fernando
AU - Condom, Enric
AU - Abril, Jesús
AU - Pérez-Jurado, Luis
AU - Estivill, Xavier
AU - Nunes, Virginia
AU - Capellá, Gabriel
AU - Gruber, Stephen B.
AU - Moreno, Víctor
AU - Pujana, Miguel Angel
N1 - Funding Information:
The authors are indebted to all those who provided publicly available raw data used in this contribution. We thank Laura González for technical assistance and to three anonymous reviewers for their helpful criticism. Tissue samples were collected through the Tumor Bank of the Bellvitge University Hospital and the Catalan Institute of Oncology, supported by the Tumor Bank Program and the RTICCC C03/10. This work was also supported by the Catalan Institute of Oncology, the "la Caixa" Foundation (BM05-254-00), the ISCIII (FIS-PI06/0545, RCESP-C03/09 and RTICCC-C03/10) and the Spanish Ministry of Education and Science (SAF-2003/5821 and SAF-2005/00166). CAM is supported by a Beatriu de Pinós fellowship from the Agència de Gestió d'Ajuts Universitaris i de Recerca. MAP is a Ramón y Cajal Researcher with the Spanish Ministry of Education and Science.
PY - 2008/1/11
Y1 - 2008/1/11
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/39149134006
U2 - 10.1186/1471-2164-9-12
DO - 10.1186/1471-2164-9-12
M3 - Article
C2 - 18190704
AN - SCOPUS:39149134006
SN - 1471-2164
VL - 9
JO - BMC Genomics
JF - BMC Genomics
M1 - 12
ER -