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

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.

Figure 1. Relative ARLTS1 RNA expression from PCa patients and healthy controls.

Relative ARLTS1 RNA expression was determined by RNA sequencing analysis. Columns represent means of individuals; bars represent SD.

Figure 2. Schematic diagram showing the genomic locations of eSNPs gathered by eQTL analysis in PCa patients.

The gene symbols are as follows: CYSLTR2 (cysteinyl leukotriene receptor 2), FNCD3A (fibronectin type III domain containing 3A), MLNR (motilin receptor), CDADC1 (cytidine and dCMP deaminase domain containing 1), CAB39L (calcium binding protein 39-like), SETDB2 (SET domain, bifurcated 2/CLLD8), PHF11 (PHD finger protein 11/NY-REN-34 antigen), RCBTB1 (regulator of chromosome condensation [RCC1] and BTB [POZ] domain containing protein 1/CLLD7), ARLTS1 (/ARL11, ADP-ribosylation factor-like 11), EBPL (emopamil binding protein-like), KPNA3 (karyopherin alpha 3, importin alpha 4), SPRYD7 (SPRY domain containing 7/C13orf1, chromosome open reading frame 1), MIR3613 (microRNA 3613), TRIM13 (tripartite motif containing 13), KCNRG (potassium channel regulator), MIR-15A and MIR16-1 (microRNA genes 15a and 16-1) and DLEU2 (deleted in lymphocytic leukemia 2).

Figure 3. Correlation of the different genotype groups of eSNPs to ARLTS1 RNA expression levels.

A, rs2075610; B, rs7997737; C, rs1543513; D, rs9568232; E, rs9568354; F, rs1886014; G, rs7337547; H, rs7995192; I, rs9562905; J, rs2580189; K, rs2532975; L, rs1262781; M, rs1262774 and N, rs17074618.