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.
Highlights
Prostate cancer (PCa) is a heterogeneous trait, and it is the most common malignancy among men in western countries, including Finland
We previously reported a significant association of ARLTS1 T442C homozygote carriers with PCa [10]
This risk genotype was associated with decreased ARLTS1 expression in the lymphoblastoid cell line samples of PCa patients, and ARLTS1 co-expression signatures from data mining revealed that ARLTS1 expression was strongly associated with immune system processes
Summary
Prostate cancer (PCa) is a heterogeneous trait, and it is the most common malignancy among men in western countries, including Finland It is a multifactorial disease, and definitive risk factors include age, ethnic origin and family history. The same chromosomal area on 13q has been indicated in a multi-centre genome-wide linkage study in families with at least five affected members [6] In another recent study, the immediate adjacent region 13q13 showed a suggestive linkage to PCa, with a HLOD.1.9 [7]. We previously reported a significant association of ARLTS1 T442C (rs3803185) homozygote carriers with PCa [10] This risk genotype was associated with decreased ARLTS1 expression in the lymphoblastoid cell line samples of PCa patients, and ARLTS1 co-expression signatures from data mining revealed that ARLTS1 expression was strongly associated with immune system processes. These processes are of interest because a link between chronic inflammation and PCa progression has been repeatedly proposed, and multiple genes acting in inflammatory pathways have been linked to PCa susceptibility [11,12,13]
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