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


CONCLUSIONS
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.
Solé
Xavier
X
Bioinformatics and Biostatistics Unit, and Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, L'Hospitalet, Barcelona, Spain. x.sole@iconcologia.net
Hernández
Pilar
P
de Heredia
Miguel López
ML
Armengol
Lluís
L
Rodríguez-Santiago
Benjamín
B
Gómez
Laia
L
Maxwell
Christopher A
CA
Aguiló
Fernando
F
Condom
Enric
E
Abril
Jesús
J
Pérez-Jurado
Luis
L
Estivill
Xavier
X
Nunes
Virginia
V
Capellá
Gabriel
G
Gruber
Stephen B
SB
Moreno
Víctor
V
Pujana
Miguel Angel
MA
D015536:Down-Regulation; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005854:Germ Cells / Q000378:metabolism; D006801:Humans; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012307:Risk Factors
C105465:KLF6 protein, human; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D011518:Proto-Oncogene Proteins