Kidd Lacreis R, Jones Dominique Z, Rogers Erica N, Kidd Nayla C, Beache Sydney, Rudd James E, Ragin Camille, Jackson Maria, McFarlane-Anderson Norma, Tulloch-Reid Marshall, Morrison Seian, Brock Guy N, Barve Shirish S, Kimbro Kevin S
Department of Pharmacology & Toxicology, University of Louisville Clinical Translational Research Building, 505 South Hancock Street Room 306, Louisville, KY, 40202, USA.
Hered Cancer Clin Pract. 2012 Nov 20;10(1):16. doi: 10.1186/1897-4287-10-16.
Chemokine and chemokine receptors play an essential role in tumorigenesis. Although chemokine-associated single nucleotide polymorphisms (SNPs) are associated with various cancers, their impact on prostate cancer (PCA) among men of African descent is unknown. Consequently, this study evaluated 43 chemokine-associated SNPs in relation to PCA risk. We hypothesized inheritance of variant chemokine-associated alleles may lead to alterations in PCA susceptibility, presumably due to variations in antitumor immune responses.
Sequence variants were evaluated in germ-line DNA samples from 814 African-American and Jamaican men (279 PCA cases and 535 controls) using Illumina's Goldengate genotyping system.
Inheritance of CCL5 rs2107538 (AA, GA+AA) and rs3817655 (AA, AG, AG+AA) genotypes were linked with a 34-48% reduction in PCA risk. Additionally, the recessive and dominant models for CCR5 rs1799988 and CCR7 rs3136685 were associated with a 1.52-1.73 fold increase in PCA risk. Upon stratification, only CCL5 rs3817655 and CCR7 rs3136685 remained significant for the Jamaican and U.S. subgroups, respectively.
In summary, CCL5 (rs2107538, rs3817655) and CCR5 (rs1799988) sequence variants significantly modified PCA susceptibility among men of African descent, even after adjusting for age and multiple comparisons. Our findings are only suggestive and require further evaluation and validation in relation to prostate cancer risk and ultimately disease progression, biochemical/disease recurrence and mortality in larger high-risk subgroups. Such efforts will help to identify genetic markers capable of explaining disproportionately high prostate cancer incidence, mortality, and morbidity rates among men of African descent.
趋化因子及其受体在肿瘤发生过程中起着至关重要的作用。尽管趋化因子相关单核苷酸多态性（SNP）与多种癌症相关，但其对非洲裔男性前列腺癌（PCA）的影响尚不清楚。因此，本研究评估了43个趋化因子相关SNP与PCA风险的关系。我们推测，趋化因子相关变异等位基因的遗传可能导致PCA易感性改变，这可能是由于抗肿瘤免疫反应的差异所致。
使用Illumina公司的GoldenGate基因分型系统，对814名非裔美国人和牙买加男性（279例PCA患者和535例对照）的生殖系DNA样本中的序列变异进行评估。
CCL5基因rs2107538（AA、GA + AA）和rs3817655（AA、AG、AG + AA）基因型的遗传与PCA风险降低34% - 48%相关。此外，CCR5基因rs1799988和CCR7基因rs3136685的隐性和显性模型与PCA风险增加1.52 - 1.73倍相关。分层分析后，仅CCL5基因rs3817655和CCR7基因rs3136685分别对牙买加和美国亚组仍具有显著性。
总之，即使在调整年龄和多次比较后，CCL5（rs2107538、rs3817655）和CCR5（rs1799988）序列变异仍显著改变了非洲裔男性的PCA易感性。我们的发现仅具有提示性，需要在更大的高危亚组中进一步评估和验证其与前列腺癌风险以及最终疾病进展、生化/疾病复发和死亡率的关系。这些努力将有助于识别能够解释非洲裔男性中前列腺癌发病率、死亡率和发病率过高的遗传标记。
