Werbrouck Emilie, Bastin Julie, Lambrechts Diether, Verbiest Annelies, Van Brussel Thomas, Lerut Evelyne, Machiels Jean-Pascal, Verschaeve Vincent, Richard Vincent, Debruyne Philip R, Decallonne Brigitte, Schöffski Patrick, Bechter Oliver, Wolter Pascal, Beuselinck Benoit
a Department of General Medical Oncology , University Hospitals Leuven, Leuven Cancer Institute and Department of Oncology, KU Leuven , Leuven , Belgium.
b Laboratory for Translational Genetics, Department of Oncology , KU Leuven , Leuven , Belgium.
Acta Clin Belg. 2019 Jun;74(3):180-188. doi: 10.1080/17843286.2018.1477229. Epub 2018 May 23.
Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) cause significant adverse events including thyroid dysfunction, mainly hypothyroidism, in a considerable proportion of patients. In a series of metastatic renal cell carcinoma (mRCC) patients treated with sunitinib, we aimed to study the correlation between hypothyroidism and single nucleotide polymorphisms (SNPs) in genes involved in sunitinib pharmacokinetics and pharmacodynamics.
We included 79 mRCC patients who started sunitinib between November 2005 and March 2016. Serum thyroid function markers were collected at start and during sunitinib therapy. Germ-line DNA genotyping for 16 SNPs in 8 candidate genes was performed. Endpoints were time to increase in thyroid stimulating hormone (TSH) and time to decrease in T4 or free T4 (FT4) on day 1 and day 28 of each sunitinib cycle.
Patients with the ABCG2 rs2231142 CC-genotype had a significantly longer time-to-TSH-increase on day 1 (11 vs. 5 cycles; p = 0.0011), and time-to-T4/FT4-decrease on day 1 (not reached vs. 10 cycles; p = 0.013) and day 28 (28 vs. 7 cycles; p = 0.03) compared to CA-carriers. Patients with the CYP3A5 rs776746 GG-genotype had a significantly longer time-to-TSH-increase at day 1 compared to GA-patients: 11 vs. 5 cycles (p = 0.0071). Significant associations were also found between PDGFRA rs35597368 and rs1800812 and time-to-TSH-increase at day 28.
Polymorphism rs2231142 in the efflux pump ABCG2 is associated with hypothyroidism in mRCC patients treated with sunitinib.
血管内皮生长因子受体酪氨酸激酶抑制剂（VEGFR-TKIs）会导致相当一部分患者出现包括甲状腺功能障碍（主要是甲状腺功能减退）在内的显著不良事件。在一系列接受舒尼替尼治疗的转移性肾细胞癌（mRCC）患者中，我们旨在研究甲状腺功能减退与舒尼替尼药代动力学和药效学相关基因中的单核苷酸多态性（SNP）之间的相关性。
我们纳入了79例在2005年11月至2016年3月期间开始使用舒尼替尼治疗的mRCC患者。在开始使用舒尼替尼治疗时以及治疗期间收集血清甲状腺功能标志物。对8个候选基因中的16个SNP进行种系DNA基因分型。观察终点为每个舒尼替尼周期第1天和第28天时促甲状腺激素（TSH）升高的时间以及T4或游离T4（FT4）降低的时间。
与携带CA基因型的患者相比，具有ABCG2 rs2231142 CC基因型的患者在第1天时TSH升高的时间显著更长（11个周期对5个周期；p = 0.0011），第1天时T4/FT4降低的时间（未达到对10个周期；p = 0.013）以及第28天时T4/FT4降低的时间（28个周期对7个周期；p = 0.03）也显著更长。与携带GA基因型的患者相比，具有CYP3A5 rs776746 GG基因型的患者在第1天时TSH升高的时间显著更长：11个周期对5个周期（p = 0.0071）。在第28天时，还发现血小板衍生生长因子受体A（PDGFRA）rs35597368和rs1800812与TSH升高时间之间存在显著关联。
外排泵ABCG2中的多态性rs2231142与接受舒尼替尼治疗的mRCC患者的甲状腺功能减退有关。
