Genetic and genomic analysis modeling of germline c-MYC overexpression and cancer susceptibility

Xavier Solé, Pilar Hernández, Miguel López de Heredia, Lluís Armengol, Benjamín Rodríguez-Santiago, Laia Gómez, Christopher A. Maxwell, Fernando Aguiló, Enric Condom, Jesús Abril, Luis Pérez-Jurado, Xavier P. Estivill, Virginia Nunes, Gabriel Capellá, Stephen B. Gruber, Víctor Moreno, Miguel Angel Pujana

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article number12
JournalBMC Genomics
Volume9
DOIs
Publication statusPublished - 11 Jan 2008
Externally publishedYes

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Prostatic Neoplasms
Prostate
Neoplasms
HapMap Project
Inborn Genetic Diseases
Gene Regulatory Networks
Cadherins
Tumor Suppressor Genes
Transcriptional Activation
Genes
Colorectal Neoplasms
Carcinogenesis
Down-Regulation
Lymphocytes
Breast Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Solé, X., Hernández, P., de Heredia, M. L., Armengol, L., Rodríguez-Santiago, B., Gómez, L., ... Pujana, M. A. (2008). Genetic and genomic analysis modeling of germline c-MYC overexpression and cancer susceptibility. BMC Genomics, 9, [12]. https://doi.org/10.1186/1471-2164-9-12

Genetic and genomic analysis modeling of germline c-MYC overexpression and cancer susceptibility. / Solé, Xavier; Hernández, Pilar; de Heredia, Miguel López; Armengol, Lluís; Rodríguez-Santiago, Benjamín; Gómez, Laia; Maxwell, Christopher A.; Aguiló, Fernando; Condom, Enric; Abril, Jesús; Pérez-Jurado, Luis; Estivill, Xavier P.; Nunes, Virginia; Capellá, Gabriel; Gruber, Stephen B.; Moreno, Víctor; Pujana, Miguel Angel.

In: BMC Genomics, Vol. 9, 12, 11.01.2008.

Research output: Contribution to journalArticle

Solé, X, Hernández, P, de Heredia, ML, Armengol, L, Rodríguez-Santiago, B, Gómez, L, Maxwell, CA, Aguiló, F, Condom, E, Abril, J, Pérez-Jurado, L, Estivill, XP, Nunes, V, Capellá, G, Gruber, SB, Moreno, V & Pujana, MA 2008, 'Genetic and genomic analysis modeling of germline c-MYC overexpression and cancer susceptibility', BMC Genomics, vol. 9, 12. https://doi.org/10.1186/1471-2164-9-12
Solé X, Hernández P, de Heredia ML, Armengol L, Rodríguez-Santiago B, Gómez L et al. Genetic and genomic analysis modeling of germline c-MYC overexpression and cancer susceptibility. BMC Genomics. 2008 Jan 11;9. 12. https://doi.org/10.1186/1471-2164-9-12
Solé, Xavier ; Hernández, Pilar ; de Heredia, Miguel López ; Armengol, Lluís ; Rodríguez-Santiago, Benjamín ; Gómez, Laia ; Maxwell, Christopher A. ; Aguiló, Fernando ; Condom, Enric ; Abril, Jesús ; Pérez-Jurado, Luis ; Estivill, Xavier P. ; Nunes, Virginia ; Capellá, Gabriel ; Gruber, Stephen B. ; Moreno, Víctor ; Pujana, Miguel Angel. / Genetic and genomic analysis modeling of germline c-MYC overexpression and cancer susceptibility. In: BMC Genomics. 2008 ; Vol. 9.
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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.",
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AU - Gómez, Laia

AU - Maxwell, Christopher A.

AU - Aguiló, Fernando

AU - Condom, Enric

AU - Abril, Jesús

AU - Pérez-Jurado, Luis

AU - Estivill, Xavier P.

AU - Nunes, Virginia

AU - Capellá, Gabriel

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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.

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