Johnson Nichola, De Ieso Paolo, Migliorini Gabriele, Orr Nick, Broderick Peter, Catovsky Daniel, Matakidou Athena, Eisen Timothy, Goldsmith Christy, Dudbridge Frank, Peto Julian, Dos-Santos-Silva Isabel, Ashworth Alan, Ross Gillian, Houlston Richard S, Fletcher Olivia
Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK and Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
Alan Walker Cancer Care Centre, Darwin, Australia.
Cancer Res. 2016 Mar 15;76(6):1485-1493. doi: 10.1158/0008-5472.CAN-15-1410.
CYP3A enzymes metabolize endogenous hormones and chemotherapeutic agents used to treat cancer, thereby potentially affecting drug effectiveness. Here, we refined the genetic basis underlying the functional effects of a CYP3A haplotype on urinary estrone glucuronide (E1G) levels and tested for an association between CYP3A genotype and outcome in patients with chronic lymphocytic leukemia (CLL), breast, or lung cancers. The most significantly associated SNP was rs45446698, an SNP that tags the CYP3A71C allele; this SNP was associated with a 54% decrease in urinary E1G levels. Genotyping this SNP in 1,008 breast cancer, 1,128 lung cancer, and 347 CLL patients, we found that rs45446698 was associated with breast cancer mortality (HR, 1.74; P = 0.03), all-cause mortality in lung cancer patients (HR, 1.43; P = 0.009), and CLL progression (HR, 1.62; P = 0.03). We also found borderline evidence of a statistical interaction between the CYP3A71C allele, treatment of patients with a cytotoxic agent that is a CYP3A substrate, and clinical outcome (Pinteraction = 0.06). The CYP3A71C allele, which results in adult expression of the fetal CYP3A7 gene, is likely to be the functional allele influencing levels of circulating endogenous sex hormones and outcome in these various malignancies. Further studies confirming these associations and determining the mechanism by which CYP3A71C influences outcome are required. One possibility is that standard chemotherapy regimens that include CYP3A substrates may not be optimal for the approximately 8% of cancer patients who are CYP3A7*1C carriers.
细胞色素P450 3A（CYP3A）酶可代谢内源性激素和用于治疗癌症的化疗药物，从而可能影响药物疗效。在此，我们完善了CYP3A单倍型对尿雌酮葡萄糖醛酸苷（E1G）水平功能影响的遗传基础，并测试了CYP3A基因型与慢性淋巴细胞白血病（CLL）、乳腺癌或肺癌患者预后之间的关联。最显著相关的单核苷酸多态性（SNP）是rs45446698，该SNP标记了CYP3A71C等位基因；此SNP与尿E1G水平降低54%相关。在1008例乳腺癌、1128例肺癌和347例CLL患者中对该SNP进行基因分型，我们发现rs45446698与乳腺癌死亡率（风险比[HR]，1.74；P = 0.03）、肺癌患者全因死亡率（HR，1.43；P = 0.009）以及CLL进展（HR，1.62；P = 0.03）相关。我们还发现了CYP3A71C等位基因、使用作为CYP3A底物的细胞毒性药物治疗患者与临床结局之间存在统计学交互作用的临界证据（交互作用P值 = 0.06）。导致胎儿CYP3A7基因在成人中表达的CYP3A71C等位基因，可能是影响循环内源性性激素水平及这些不同恶性肿瘤患者预后的功能性等位基因。需要进一步研究来证实这些关联，并确定CYP3A71C影响预后的机制。一种可能性是，对于约8%的CYP3A7*1C携带者癌症患者而言，包含CYP3A底物的标准化疗方案可能并非最佳方案。
