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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.

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