Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Lancet Oncol. 2013 Jan;14(1):81-7. doi: 10.1016/S1470-2045(12)70517-X. Epub 2012 Dec 7.
Germline genetic polymorphisms might affect the risk of recurrence in patients with localised renal-cell carcinoma. We investigated the association between genetic polymorphisms and recurrence of renal-cell carcinoma.
We analysed germline DNA samples extracted from patients with localised renal-cell carcinoma treated at the Dana-Farber/Harvard Cancer Center (Boston, MA, USA). We selected a discovery cohort from a prospective database at the Dana-Farber/Harvard Cancer Center and selected a validation cohort from department records at the Brigham and Women's Hospital (Boston, MA, USA). We validated the findings from the discovery cohort in the validation cohort. We genotyped 70 genes involved in the pathogenesis of renal-cell carcinoma (including the VHL/HIF/VEGF and PI3K/AKT/mTOR pathways, and genes involved in immune regulation and metabolism) for single nucleotide polymorphisms. We assessed the association between genotype and recurrence-free survival, adjusted for baseline characteristics, with the Cox proportional hazards model, the Kaplan-Meier method, and the log-rank test. We used a false discovery rate q value to adjust for multiple comparisons.
We included 554 patients (403 in the discovery cohort and 151 in the validation cohort). We successfully genotyped 290 single nucleotide polymorphisms in the discovery cohort, but excluded five because they did not have a variant group for comparison. The polymorphism rs11762213, which causes a synonymous aminoacid change in MET (144G→A, located in exon 2), was associated with recurrence-free survival. Patients with one or two copies of the minor (risk) allele had an increased risk of recurrence or death (hazard ratio [HR] 1·86, 95% CI 1·17-2·95; p=0·0084) in multivariate analysis. Median recurrence-free survival for carriers of the risk allele was 19 months (95% CI 9-not reached) versus 50 months (95% CI 37-75) for patients without the risk allele. In the validation cohort the HR was 2·45 (95% CI 1·01-5·95; p=0·048).
Patients with localised renal-cell carcinoma and the MET polymorphism rs11762213 might have an increased risk of recurrence after nephrectomy. If these results are further validated in a similar population, they could be incorporated into future prognostic instruments, potentially aiding the design of adjuvant clinical trials of MET inhibitors and management of renal-cell carcinoma.
Conquer Cancer Foundation and American Society of Clinical Oncology (Career Development Award); The Trust Family Research Fund for Kidney Cancer; US National Institutes of Health, National Cancer Institute Kidney Cancer Specialized Program of Research Excellence.
胚系遗传多态性可能会影响局限性肾细胞癌患者的复发风险。我们研究了遗传多态性与肾细胞癌复发之间的关系。
我们分析了在位于美国马萨诸塞州波士顿的 Dana-Farber/Harvard 癌症中心（Dana-Farber/Harvard Cancer Center）接受治疗的局限性肾细胞癌患者的胚系 DNA 样本。我们从 Dana-Farber/Harvard 癌症中心的前瞻性数据库中选择了一个发现队列，并从位于马萨诸塞州波士顿的 Brigham and Women's Hospital 的科室记录中选择了一个验证队列。我们在验证队列中验证了发现队列的结果。我们对 70 个与肾细胞癌发病机制相关的基因（包括 VHL/HIF/VEGF 和 PI3K/AKT/mTOR 途径以及参与免疫调节和代谢的基因）进行了单核苷酸多态性的基因分型。我们使用 Cox 比例风险模型、Kaplan-Meier 方法和对数秩检验，根据基线特征调整基因型与无复发生存期之间的关联，使用错误发现率 q 值进行多重比较调整。
我们纳入了 554 名患者（发现队列中 403 名，验证队列中 151 名）。我们在发现队列中成功对 290 个单核苷酸多态性进行了基因分型，但排除了 5 个因没有可供比较的变异组而无法进行基因分型的多态性。MET（144G→A，位于外显子 2）中的同义氨基酸变化导致的 rs11762213 多态性与无复发生存期相关。在多变量分析中，携带一个或两个次要（风险）等位基因的患者复发或死亡的风险增加（风险比 [HR] 1.86，95%CI 1.17-2.95；p=0.0084）。携带风险等位基因的患者无复发生存期的中位数为 19 个月（95%CI 9-未达到），而不携带风险等位基因的患者为 50 个月（95%CI 37-75）。在验证队列中，HR 为 2.45（95%CI 1.01-5.95；p=0.048）。
局限性肾细胞癌患者的 MET 多态性 rs11762213 可能会增加肾切除术后复发的风险。如果这些结果在类似人群中得到进一步验证，它们可以被纳入未来的预后工具，可能有助于设计 MET 抑制剂的辅助临床试验和肾细胞癌的管理。
美国癌症协会 Conquer Cancer 基金会和美国临床肿瘤学会（职业发展奖）；信托家族肾细胞癌研究基金；美国国立卫生研究院，国家癌症研究所肾癌专项研究卓越计划。
