前列腺癌易感基因遗传多态性的研究进展

随着人类基因组研究计划(human genome project,HGP)DNA序列测定和分析研究工作的深入发展,单核苷酸多态性(single nucleotide polymorphism,SNP)作为第三代遗传标记已经广泛应用于人群复杂性疾病易感性机制和个体化治疗方案的设计方面的研究。本文就与前列腺癌相关的遗传易感基因SNP进行了综述,主要阐述了细胞因子、受体以及相关酶类遗传多态性与前列腺癌发生之间的关系并分析其在前列腺癌治疗等方面的作用。     

单核苷酸多态性与前列腺癌的研究进展

前列腺癌是影响西方国家男性健康的常见恶性肿瘤,而单核苷酸多态性(SNPs)作为第3代遗传标记可以影响到前列腺癌的发生、发展及预后。相同SNPs在不同种族间和前列腺癌的关系可能存在差异;本文就与前列腺癌相关的基因进行分类,描述不同SNPs与前列腺癌的关系。SNPs可以预测前列腺癌治疗过程中可能的不良反应,同时也可预测前列腺癌的患病风险,但目前仍存在一定的局限。     

Clinical significance of runt‐related transcription factor 1 polymorphism in prostate cancer

What’s known on the subject? and What does the study add? Although most clinically localized prostate cancer patients who underwent radical prostatectomy have a favorable outcome, molecular markers capable of providing prognostic information are still urgently needed to identify high‐risk patients who might benefit from aggressive treatment. In this study, we found that RUNX1 rs2253319 polymorphism was significantly associated with higher risks of advanced pathological stage, lymph node metastasis, and time to disease recurrence. Our results suggest that a simple and pretreatment analysis of genetic variants might add prognostic value to the currently used indicators for outcome prediction in patients receiving radical prostatectomy.

OBJECTIVE

To investigate the association of RUNX1 rs2253319 with clinicopathological characteristics of prostate cancer (PCa) and disease recurrence after radical prostatectomy (RP).

PATIENTS AND METHODS

Taking advantage of the systematic stage and grade for each tumor in a cohort of 314 patients with localized PCa receiving RP, we evaluated the associations of RUNX1 rs2253319 with age at diagnosis, preoperative prostate‐specific antigen (PSA) level, Gleason score, surgical margin, pathologic stage, status of lymph node metastasis, and PSA recurrence after RP.

RESULTS

The minor allele, T, and the minor homozygote TT genotype of RUNX1 rs2253319 were significantly associated with a 1.49‐ to 2.76‐fold higher risk for advanced pathologic stage and a 3.35‐ to 9.52‐fold higher risk for lymph node metastasis. RUNX1 rs2253319 TT genotype was also associated with poorer PSA‐free survival compared with the major homozygote CC genotype in Kaplan–Meier analysis (log‐rank test, P= 0.038) and multivariate Cox proportional hazards model adjusting for age and PSA concentration (P= 0.045).

CONCLUSION

RUNX1 rs2253319 is associated with adverse clinicopathological features and might be a prognostic factor for the recurrence of PSA in patients with PCa receiving RP.     

Association of prostate cancer risk alleles with unfavourable pathological characteristics in potential candidates for active surveillance

Study Type – Prognosis (cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Men fail active surveillance for a variety of reasons; however, no single reliable biomarker has been found to date which will identify these men from the outset. We know that there are about 35 prostate cancer risk alleles which have been discovered to influence risk of prostate cancer, from large‐scale genome‐wide association studies. Some of these have been associated with aggressive prostate cancer. Nobody has examined the potential for these risk alleles to predict men who might fail active surveillance. This study adds to the growing evidence that single nucleotide polymorphisms may be able to identify men who have aggressive prostate cancers, and that this could be part of a risk algorithm used in active surveillance protocols.

OBJECTIVE

• ? To assess whether the carrier status of 35 risk alleles for prostate cancer (CaP) is associated with having unfavourable pathological features in the radical prostatectomy specimen in men with clinically low risk CaP who fulfil commonly accepted criteria as candidates for active surveillance.

PATIENTS AND METHODS

• ? We studied men of European ancestry with CaP who fulfilled the commonly accepted clinical criteria for active surveillance (T1c, prostate‐specific antigen <10 ng/mL, biopsy Gleason ≤6, three or fewer positive cores, ≤50% tumour involvement/core) but instead underwent early radical prostatectomy.
• ? We genotyped these men for 35 CaP risk alleles. We defined ‘unfavourable’ pathological characteristics to be Gleason ≥7 and/or ≥ pT2b in their radical prostatectomy specimen.

RESULTS

• ? In all, 263 men (median age 60 [46–72] years) fulfilled our selection criteria for active surveillance, and 58 of 263 (22.1%) were found to have ‘unfavourable’ pathological characteristics.
• ? The frequencies of three CaP risk alleles (rs1447295 [8q24], P= 0.004; rs1571801 [9q33.2], P= 0.03; rs11228565 [11q13], P= 0.02) were significantly higher in men with ‘unfavourable’ pathological characteristics.
• ? Two other risk alleles were proportionately more frequent (rs10934853 [3q21], P= 0.06; rs1859962 [17q24], P= 0.07) but did not achieve nominal statistical significance.
• ? Carriers of any one of the significantly over‐represented risk alleles had twice the likelihood of unfavourable tumour features (P= 0.03), and carriers of any two had a sevenfold increased likelihood (P= 0.001).
• ? Receiver–operator curve analysis demonstrated an area under the curve of 0.66, suggesting that the number of single nucleotide polymorphisms carried provided discrimination between men with ‘favourable’ and ‘unfavourable’ tumour features in their prostatectomy specimen.

CONCLUSION

• ? In potential candidates for active surveillance, certain CaP risk alleles are more prevalent in patients with ‘unfavourable’ pathological characteristics in their radical prostatectomy specimen.

     

1667例汉族前列腺癌人群前列腺癌易感性基因多态性验证分析

目的:前列腺癌在工业化国家发病率居男性恶性肿瘤首位,在我国前列腺癌近年发病率不断上升,成为泌尿系统常见恶性肿瘤。本文通过前列腺癌基因多态性分析研究汉族人群前列腺癌易感性危险位点。方法:取1 667例前列腺癌患者与1 525例对照组外周血样双盲利用Sequenom技术进行40个前列腺癌危险位点的SNP分析。结果:40个公认的前列腺癌位点检测结果有16个位点与前列腺癌明显相关(P<0.05);同时发现在不同人种中位于8q24的1、2、5位点与10q11的MSMB编码区及22q13.2编码TTLL1/BIK区域共同决定前列腺癌易感性。结论:汉族前列腺癌人群前列腺癌基因多态性分析结果显示:rs1465618、rs721048、rs12621278、rs7679673、rs12653946、rs339331、rs1512268、rs10086908、rs16901979、rs1447295、rs10993994、rs10896449、rs902774、rs9600079、rs11649743、rs5759167与前列腺癌易感性明显相关。     

CYP1A2基因多态性与前列腺癌的相关性研究

目的:评价CYP1A2基因单核苷酸多态性(SNPs)与前列腺癌分期分级的相关性。方法:对253例良性前列腺增生(BPH)患者与206例去势前列腺癌患者CYP1A2基因中rs2069514-3859(A>G)位点及rs2069525-1707(C>T)位点进行基因测序,并对各基因表型与前列腺癌的分期分级相关性进行统计学分析。结果:BPH及去势前列腺癌患者的两种CYP1A2单核苷酸多态性的发生率无明显差异(P>0.05),其基因多态性与前列腺癌的病理分期均无相关性(P>0.05);但rs2069525-1707(C>T)中含C等位基因型的前列腺癌Gleason评分多在7分以下(P=0.030,OR=4.658,95%CI:1.222～17.754)。结论:CYP1A2基因的SNPs与前列腺癌的病理分级之间可能有一定的相关性,但其发生机制及临床意义有待进一步证实及研究。     

Association of circulating tumor cells with tumor‐related methylated DNA in patients with hormone‐refractory prostate cancer

Objectives: To assess whether circulating tumor cells with tumor‐related methylated DNA can be used to predict survival in patients with hormone‐refractory prostate cancer. Methods: Blood samples from 76 patients with hormone‐refractory prostate cancer were analyzed. Circulating tumor cells were enumerated with the CellSearch System in whole blood. This system was developed using an epithelial cell adhesion molecule antibody‐based immunomagnetic capture and automated staining methodology. Hypermethylation at adenomatosis polyposis coli, glutathione‐S‐transferase‐π, prostaglandin‐endoperoxide synthase 2, multidrug resistance 1 and Ras association domain family 1 isoform A was analyzed using a sensitive SYBR green methylation‐specific polymerase chain reaction. Patient charts were retrospectively examined. Results: Median overall survival time was 19.3 months (range 11–48). Of the 76 patients, 47 (62%) had five or more circulating tumor cells, with a median overall survival of 12.0 months compared with 26.0 months for patients with fewer than five circulating tumor cells (P < 0.001). Circulating tumor cells were detected in 36 of 39 (92%) patients with tumor‐related methylated DNA but only 11 of 37 (30%) patients without methylated DNA (P < 0.001). Thirty‐nine (51%) patients had one or more methylated marker. Their median overall survival time was 12.0 months compared with 48.0 months or more for patients without methylated DNA (P < 0.001). Prostate‐specific antigen‐doubling time, circulating tumor cells and methylated DNA were independent predictors of overall survival time. Conclusions: Hormone refractory prostate cancer patients with circulating tumor cells and/or tumor‐related methylated DNA show a significantly poorer outcome than those without these blood markers.     

Single‐nucleotide polymorphisms within the antioxidant defence system and associations with aggressive prostate cancer

What’s known on the subject? and What does the study add? Prior studies have identified potential interaction effects between antioxidant nutrients and germline gene variants with regards to prostate cancer risk. In particular, the rs4880 gene variant in SOD2 (or MnSOD) has been linked to several cancers, including prostate, and appears to interact with antioxidant status and cancer risk. We identified additional variants in SOD2 and SOD1 that may affect risk of prostate cancer, or interact with selenium status to affect prostate cancer risk.

OBJECTIVE

To study the effects of oxidative stress on prostate cancer development as the exact biological mechanisms behind the relationship remain uncertain. We previously reported a statistically significant interaction between circulating selenium levels, variants in the superoxide dismutase 2 gene (SOD2; rs4880), and risk of developing prostate cancer and presenting with aggressive prostate cancer.

PATIENTS AND METHODS

We genotyped men with localized/regional prostate cancer for 26 loci across eight genes that are central to cellular antioxidant defence: glutathione peroxidase (GPX1, GPX4), peroxisome proliferator‐activated receptor γ coactivator (PPARGC1A, PPARGC1B), SOD1, SOD2, and SOD3, and ‘X‐ray repair complementing defective repair in Chinese hamster cell 1’ (XRCC1). Among 489 men, we examined the relationships between genotypes, circulating selenium levels, and risk of presenting with aggressive prostate cancer at diagnosis, as defined by stage, grade and prostate‐specific antigen (PSA) level (213 aggressive cases).

RESULTS

Two variants in SOD2 were significantly associated with the risk of aggressive prostate cancer (rs17884057, odds ratio 0.83, 95% confidence interval 0.70–0.99; and rs4816407, 1.27, 1.02–1.57); men with A alleles at rs2842958 in SOD2 had lower plasma selenium levels (median 116 vs 121.8 µg/L, P= 0.03); and the association between plasma selenium levels and risk of aggressive prostate cancer was modified by SOD1 (rs10432782) and SOD2 (rs2758330).

CONCLUSION

While this study was cross‐sectional and these associations might be due to chance, further research is warranted on the potential important role of antioxidant defence in prostate cancer.     

Association of single nucleotide polymorphism of vitamin D receptor gene start codon and the suscepbility to prostate cancer in Han nationality in Hubei, China

Aim: To investigate the single nucleotide polymorphism of vitamin D receptor (VDR) gene start codon in the Han nationality in Hubei and its relationship to the susceptibility to prostate cancel (PCa). Methods: The VDR genotypes were determined by poly-merase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 80 patients with PCa and 96 normal male controls from the Han nationality in Hubei, using endonuclease Fok. Direct sequencing was done in part of the PCR products. Results: The frequency distribution of Fok I alleles in this cohort all followed the Hardy-Weinberg equilibrium. The distribution of genotypes and alleles had no significant difference between PCa patients and the controls (P>0.05). Conclusion: There was no significant relationship between Fok I polymorphism of VDR gene start codon and PCa in the Han nationality in Hubei.