Expression of SLCO transport genes in castration-resistant prostate cancer and impact of genetic variation in SLCO1B3 and SLCO2B1 on prostate cancer outcomes.
Expression of SLCO transport genes in castration-resistant prostate cancer and impact of genetic variation in SLCO1B3 and SLCO2B1 on prostate cancer outcomes.
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DOI：
10.1158/1055-9965.epi-10-1023
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发表时间：
2011-04
期刊：
影响因子：
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通讯作者：
Mostaghel EA
中科院分区：
文献类型：
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作者：
Wright JL;Kwon EM;Ostrander EA;Montgomery RB;Lin DW;Vessella R;Stanford JL;Mostaghel EA
与未经治疗的前列腺癌（PCa）相比，来自去势抵抗性前列腺癌（CRPC）男性的转移瘤具有增加的肿瘤雄激素。这可能反映了OATP/SLCO转运蛋白的类固醇摄取。我们评估了CRPC转移中SLCO基因的表达，并确定PCa结局是否与SLCO 2B 1和SLCO 1B 3的单核苷酸多态性（SNP）相关，这些转运蛋白先前被证明介导雄激素摄取。在未经治疗的PCa和通过快速尸检获得的转移性CRPC肿瘤中分析了编码11个SLCO基因的转录物。在1,309名白人PCa患者的人群队列中对SLCO 2B 1和SLCO 1B 3的SNP进行基因分型。中位生存随访时间为7.0年（0.77-16.4）。采用考克斯比例风险分析评估PCa复发/进展风险和PCa特异性死亡率（PCSM）。与未经治疗的PCa相比，6种SLCO基因在CRPC转移瘤中高度表达，包括SLCO 1B 3（3.6倍，p=0.0517）和SLCO 2B 1（5.5倍，p=0.0034）。携带变异等位基因SLCO 2B 1 SNP rs 12422149（HR 1.99，95% CI 1.11 - 3.55）或SLCO 1B 3 SNP rs 4149117（HR 1.76，95% CI 1.00 - 3.08）的PCSM风险增加。与原发性PCa相比，CRPC转移灶显示SLCO基因表达增加。SLCO 1B 3和SLCO 2B 1的遗传变异与PCSM相关。改变雄激素摄取的SLCO基因的表达和遗传变异可能在PCa结局中起重要作用。OATP/SLCO基因可能是评估前列腺癌特异性死亡风险的潜在生物标志物。这些基因的表达和遗传变异可能使患者分层，以更积极的激素治疗或更早地纳入基于非激素的治疗策略。
Metastases from men with castration resistant prostate cancer (CRPC) harbor increased tumoral androgens vs. untreated prostate cancers (PCa). This may reflect steroid uptake by OATP/SLCO transporters. We evaluated SLCO gene expression in CRPC metastases and determined whether PCa outcomes are associated with single nucleotide polymorphisms (SNPs) in SLCO2B1 and SLCO1B3, transporters previously demonstrated to mediate androgen uptake. Transcripts encoding 11 SLCO genes were analyzed in untreated PCa, and in metastatic CRPC tumors obtained by rapid autopsy. SNPs in SLCO2B1 and SLCO1B3 were genotyped in a population-based cohort of 1,309 Caucasian PCa patients. Median survival follow-up was 7.0 years (0.77–16.4). The risk of PCa recurrence/progression and PCa-specific mortality (PCSM) was estimated with Cox proportional hazards analysis. Six SLCO genes were highly expressed in CRPC metastases vs. untreated PCa, including SLCO1B3 (3.6 fold, p=0.0517) and SLCO2B1 (5.5 fold, p=0.0034). Carriers of the variant alleles SLCO2B1 SNP rs12422149 (HR 1.99, 95% CI 1.11 – 3.55) or SLCO1B3 SNP rs4149117 (HR 1.76, 95% CI 1.00 – 3.08) had an increased risk of PCSM. CRPC metastases demonstrate increased expression of SLCO genes vs. primary PCa. Genetic variants of SLCO1B3 and SLCO2B1 are associated with PCSM. Expression and genetic variation of SLCO genes which alter androgen uptake may be important in PCa outcomes. OATP/SLCO genes may be potential biomarkers for assessing risk of prostate cancer-specific mortality. Expression and genetic variation in these genes may allow stratification of patients to more aggressive hormonal therapy or earlier incorporation of non-hormonal based treatment strategies.