Abstract
BackgroundGermline 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.ResultsThis 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.ConclusionThis 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.
Highlights
Germline genetic variation is associated with the differential expression of many human genes
We examined the proportion of significant SNPs in genomic windows 2- or 4-fold the average size of linkage disequilibrium blocks in CEUs or YRIs, respectively (~42 kb corresponding to ~66 SNPs in CEUs and ~36 kb corresponding to ~61 SNPs in YRIs)
Expression differences in normal prostate tissues Given the possible association of Region 1 variants with germline c-MYC overexpression in immortalized lymphocytes of HapMap individuals, we examined expression differences in normal prostate tissues
Summary
Germline genetic variation is associated with the differential expression of many human genes. Risk of human cancer associated with genetic variation at chromosome 8q24 was first described for prostate cancer in individuals with European ancestry and in African Americans (Risk Region 1) [1,2]. This association was stronger for more aggressive tumor forms [2,3,4] and for earlier age at diagnosis in African Americans [1,5]. Haiman et al.[12] first noted the existence of common risk variants for breast and colorectal cancer at 8q24. These observations suggest that multiple cancer genes may exist at 8q24 or, alternatively, that risk variants converge on a common biological mechanism [7]
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