Contribution of ARLTS1 Cys148Arg (T442C) Variant with Prostate Cancer Risk and ARLTS1 Function in Prostate Cancer Cells

Sanna Siltanen,Outi R Saramäki,Robert L Vessella,Martin Schindler,Tapio Visakorpi,Leena Latonen,Johanna Schleutker,Teuvo L J Tammela,Olli Kallioniemi,John Patrick Mpindi,Tiina Wahlfors

doi:10.1371/journal.pone.0026595

Sanna Siltanen, Outi R Saramäki + Show 9 more

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https://doi.org/10.1371/journal.pone.0026595

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ARLTS1 is a recently characterized tumor suppressor gene at 13q14.3, a region frequently deleted in both sporadic and hereditary prostate cancer (PCa). ARLTS1 variants, especially Cys148Arg (T442C), increase susceptibility to different cancers, including PCa. In this study the role of Cys148Arg substitution was investigated as a risk factor for PCa using both genetic and functional analysis. Cys148Arg genotypes and expression of the ARLTS1 were explored in a large set of familial and unselected PCa cases, clinical tumor samples, xenografts, prostate cancer cell lines and benign prostatic hyperplasia (BPH) samples. The frequency of the variant genotype CC was significantly higher in familial (OR = 1.67, 95% CI = 1.08–2.56, P = 0.019) and unselected patients (OR = 1.52, 95% CI = 1.18–1.97, P = 0.001) and the overall risk was increased (OR = 1.54, 95% CI = 1.20–1.98, P = 0.0007). Additional analysis with clinicopathological data revealed an association with an aggressive disease (OR = 1.28, 95% CI = 1.05-∞, P = 0.02). The CC genotype of the Cys148Arg variant was also contributing to the lowered ARLTS1 expression status in lymphoblastoid cells from familial patients. In addition significantly lowered ARLTS1 expression was observed in clinical tumor samples compared to BPH samples (P = 0.01). The ARLTS1 co-expression signature based on previously published microarray data was generated from 1587 cancer samples confirming the low expression of ARLTS1 in PCa and showed that ARLTS1 expression was strongly associated with immune processes. This study provides strong confirmation of the important role of ARLTS1 Cys148Arg variant as a contributor in PCa predisposition and a potential marker for aggressive disease outcome.

Highlights

ADP-ribosylation factor-like tumor suppressor gene 1 (ARLTS1), known as ADP-ribosylation factor-like protein 11 (ARL11), is a newly characterized gene located at locus 13q14.3
The Cys148Arg (T442C) variant was further genotyped in 48 familial prostate cancer (PCa) patients, 1471 unselected PCa patients, 375 benign prostatic hyperplasia (BPH) patients and 379 controls
The ARLTS1 gene and ARLTS1 polymorphisms have been shown to have a role in the pathogenesis of many cancers

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Introduction

ADP-ribosylation factor-like tumor suppressor gene 1 (ARLTS1), known as ADP-ribosylation factor-like protein 11 (ARL11), is a newly characterized gene located at locus 13q14.3. ARLTS1 belongs to the ADP-ribosylation factor (ARF)-ARF-like (ARL) family of the Ras protein superfamily [1]. ARFs are guanine-nucleotide-binding proteins which are critical components of several different eukaryotic vesicle trafficking pathways. As with other members of the Ras superfamily, ARFs function as molecular switches by cycling between inactive GDP- and active GTP-bound conformations [2]. ARLTS1 has been characterized as an intracellular protein having tissue specific expression in the lung and leucocytes. ARLTS1 variants, such as the nonsense polymorphism Trp149Stop (G446A) and missense polymorphism Cys148Arg (T442C), have been suggested to have a role in different cancers [3,4,5,6]

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