NMD and microRNA expression profiling of the HPCX1 locus reveal MAGEC1 as a candidate prostate cancer predisposition gene
1 Institute of Biomedical Technology, University of Tampere and Centre for Laboratory Medicine, Tampere University Hospital, Tampere, Finland
2 Bioinformatics, Institute of Biomedical Technology, University of Tampere and Science Center of Pirkanmaa Hospital District, Tampere, Finland
3 School of Health Sciences, University of Tampere, Tampere, Finland
4 Department of Urology and Medical School, Tampere University Hospital and University of Tampere, Tampere, Finland
BMC Cancer 2011, 11:327 doi:10.1186/1471-2407-11-327Published: 2 August 2011
Several predisposition loci for hereditary prostate cancer (HPC) have been suggested, including HPCX1 at Xq27-q28, but due to the complex structure of the region, the susceptibility gene has not yet been identified.
In this study, nonsense-mediated mRNA decay (NMD) inhibition was used for the discovery of truncating mutations. Six prostate cancer (PC) patients and their healthy brothers were selected from a group of HPCX1-linked families. Expression analyses were done using Agilent 44 K oligoarrays, and selected genes were screened for mutations by direct sequencing. In addition, microRNA expression levels in the lymphoblastic cells were analyzed to trace variants that might alter miRNA expression and explain partly an inherited genetic predisposion to PC.
Seventeen genes were selected for resequencing based on the NMD array, but no truncating mutations were found. The most interesting variant was MAGEC1 p.Met1?. An association was seen between the variant and unselected PC (OR = 2.35, 95% CI = 1.10-5.02) and HPC (OR = 3.38, 95% CI = 1.10-10.40). miRNA analysis revealed altogether 29 miRNAs with altered expression between the PC cases and controls. miRNA target analysis revealed that 12 of them also had possible target sites in the MAGEC1 gene. These miRNAs were selected for validation process including four miRNAs located in the X chromosome. The expressions of 14 miRNAs were validated in families that contributed to the significant signal differences in Agilent arrays.
Further functional studies are needed to fully understand the possible contribution of these miRNAs and MAGEC1 start codon variant to PC.