Rebbeck T R, Jaffe J M, Walker A H, Wein A J, Malkowicz S B
Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia 19104-6021, USA.
J Natl Cancer Inst. 1998 Aug 19;90(16):1225-9. doi: 10.1093/jnci/90.16.1225.
Pathways involved in androgen metabolism have been implicated in the etiology of prostate cancer. The goal of this study was to evaluate the effect of CYP3A4, a gene associated with the oxidative deactivation of testosterone, on the clinical presentation of prostate cancers.
A polymerase chain reaction-based approach was used to identify sequence variants of the human CYP3A4 gene. To ascertain whether allelic variants of the CYP3A4 gene were associated with tumor stage and grade and age of the patient at diagnosis, we determined CYP3A4 genotypes in 230 Caucasian men with incident prostate cancer.
We identified a novel genetic variant (CYP3A4-V) that has an altered 5' regulatory element, containing an A to G mutation, upstream of the CYP3A4 gene. We then compared clinical characteristics of prostate cancers in men who did and did not carry this variant. The presence of the CYP3A4-V allele was associated with a higher tumor-lymph node-metastasis (TNM) stage and Gleason grade. The association between CYP3A4 genotype and tumor stage was most pronounced in men diagnosed at a relatively old age who reported no family history of prostate cancer. In this group, 46% of men with stage T3/T4 tumors carried CYP3A4-V, whereas only 5% of individuals with stage T1 tumors carried CYP3A4-V (adjusted odds ratio = 9.45; 95% confidence interval = 2.54-35.17; chi2(1) = 12.28; two-sided P<.001).
We determined that a single base change in the 5' flanking region of the CYP3A4 gene was associated with higher clinical stage and grade in men with prostate tumors. Our results suggest that mutations in the CYP3A4 gene may influence prostate carcinogenesis.
雄激素代谢相关通路与前列腺癌的病因有关。本研究的目的是评估与睾酮氧化失活相关的基因CYP3A4对前列腺癌临床表现的影响。
采用基于聚合酶链反应的方法来鉴定人类CYP3A4基因的序列变异。为了确定CYP3A4基因的等位基因变异是否与肿瘤分期、分级以及诊断时患者的年龄相关，我们对230例初发前列腺癌的白人男性进行了CYP3A4基因分型。
我们鉴定出一种新的基因变异（CYP3A4-V），其在CYP3A4基因上游的5'调控元件发生了改变，包含一个从A到G的突变。然后我们比较了携带和不携带该变异的男性前列腺癌的临床特征。CYP3A4-V等位基因的存在与更高的肿瘤-淋巴结-转移（TNM）分期和 Gleason分级相关。CYP3A4基因型与肿瘤分期之间的关联在诊断时年龄相对较大且无前列腺癌家族史的男性中最为明显。在这组患者中，46%的T3/T4期肿瘤男性携带CYP3A4-V，而T1期肿瘤患者中只有5%携带CYP3A4-V（调整后的优势比 = 9.45；95%置信区间 = 2.54 - 35.17；卡方(1) = 12.28；双侧P <.001）。
我们确定CYP3A4基因5'侧翼区域的单个碱基变化与前列腺肿瘤男性的更高临床分期和分级相关。我们的结果表明，CYP3A4基因的突变可能影响前列腺癌的发生。
