ARLTS1 and prostate cancer risk--analysis of expression and regulation

PLoS One. 2013 Aug 5;8(8):e72040. doi: 10.1371/journal.pone.0072040. Print 2013.

Abstract

Prostate cancer (PCa) is a heterogeneous trait for which several susceptibility loci have been implicated by genome-wide linkage and association studies. The genomic region 13q14 is frequently deleted in tumour tissues of both sporadic and familial PCa patients and is consequently recognised as a possible locus of tumour suppressor gene(s). Deletions of this region have been found in many other cancers. Recently, we showed that homozygous carriers for the T442C variant of the ARLTS1 gene (ADP-ribosylation factor-like tumour suppressor protein 1 or ARL11, located at 13q14) are associated with an increased risk for both unselected and familial PCa. Furthermore, the variant T442C was observed in greater frequency among malignant tissue samples, PCa cell lines and xenografts, supporting its role in PCa tumourigenesis. In this study, 84 PCa cases and 15 controls were analysed for ARLTS1 expression status in blood-derived RNA. A statistically significant (p = 0.0037) decrease of ARLTS1 expression in PCa cases was detected. Regulation of ARLTS1 expression was analysed with eQTL (expression quantitative trait loci) methods. Altogether fourteen significant cis-eQTLs affecting the ARLTS1 expression level were found. In addition, epistatic interactions of ARLTS1 genomic variants with genes involved in immune system processes were predicted with the MDR program. In conclusion, this study further supports the role of ARLTS1 as a tumour suppressor gene and reveals that the expression is regulated through variants localised in regulatory regions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-Ribosylation Factors / genetics*
  • Aged
  • Case-Control Studies
  • Finland / epidemiology
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Prostatic Neoplasms / epidemiology
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Quantitative Trait Loci
  • Risk Factors

Substances

  • ADP-Ribosylation Factors
  • ARL11 protein, human

Grants and funding

This work was supported by the Tampere Graduate Program in Biomedicine and Biotechnology salary and Orion-Farmos Research Foundation grant to S.S. and by the Sigrid Juselius Foundation, the Academy of Finland (251074), the Finnish Cancer Organisations, and the Competitive Research Funding of the Pirkanmaa Hospital District (9N069) grants to J.S. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.