Milano Gérard
a Centre Antoine-Lacassagne , Nice Cedex , France.
Scand J Clin Lab Invest Suppl. 2016;245:S30-3. doi: 10.1080/00365513.2016.1208438. Epub 2016 Jul 25.
Sequencing of DPYD exome was conducted in a prospective cohort of advanced breast cancer patients receiving capecitabine.
A total of 243 patients were analyzed. Digestive, neurologic and hematotoxicity over cycles 1-2 showed 10.3% G3 and 2.1% G4, including one toxic death. DPYD exome, flanking intronic regions (20 bp), 3'UTR and part of 5'UTR (500 bp) were sequenced on MiSeq Illumina (Integragen, 97% coverage, HWE checked).
In total, 48 SNPs were identified: three in 3'UTR, 19 in coding regions (four synonymous including E412E; 15 missenses including D949V, V732I, R592W, I560S, I543V, S534N, S492L, M406I, D342G, M166V, T65M, C29R), 19 in flanking intronic regions (including *2A) and seven in 5'UTR. In total, 11 SNPs have not been previously described, including three missense variations each heterozygous in three separate patients: R696H, F100L and A26T. The patient with a toxic death carried one D949V allele. The three consensual variants *2A, D949V and I560S were carried by seven patients (heterozygous). Analysis of consensual variants showed that they were associated with G3-4 toxicity (OR = 21.0, sensitivity 16.7%) but not with G4 toxicity. Adding the variants previously associated with DPD deficiency in vitro, i.e. R592W, S492L and D342N/G, increased sensitivity on G3-4 (23.3%, OR = 21.1) and was predictive of G4 toxicity (sensitivity 40%, OR = 19.0). Of note, adding the new F100L variant further improved predictivity of genotyping on G4 toxicity (sensitivity 60%, OR = 42.8).
Present data establish the impact of consensual variants on capecitabine toxicity and reveal the existence of a novel DPYD variant, F100L, associated with G4 toxicity.
对接受卡培他滨治疗的晚期乳腺癌患者前瞻性队列进行了DPYD外显子组测序。
共分析了243例患者。第1 - 2周期的消化、神经和血液毒性显示，3/4级毒性发生率分别为10.3%和2.1%，包括1例毒性死亡。在Illumina MiSeq平台（Integragen公司，覆盖度97%，经哈迪 - 温伯格平衡检验）上对DPYD外显子组、侧翼内含子区域（20bp）、3'UTR和部分5'UTR（500bp）进行测序。
总共鉴定出48个单核苷酸多态性（SNP）：3个在3'UTR，19个在编码区（4个同义突变包括E412E；15个错义突变包括D949V、V732I、R592W、I560S、I543V、S534N、S492L、M406I、D342G、M166V、T65M、C29R），19个在侧翼内含子区域（包括2A），7个在5'UTR。总共11个SNP此前未被描述，包括3个错义变异，分别在3例不同患者中为杂合状态：R696H、F100L和A26T。发生毒性死亡的患者携带一个D949V等位基因。7例患者（杂合）携带3个公认变异2A、D949V和I560S。对公认变异的分析表明，它们与3/4级毒性相关（比值比[OR]=21.0，敏感性16.7%），但与4级毒性无关。加入先前在体外与二氢嘧啶脱氢酶（DPD）缺乏相关的变异，即R592W、S492L和D342N/G，可提高对3/4级毒性的敏感性（23.3%，OR = 21.1），并可预测4级毒性（敏感性40%，OR = 19.0）。值得注意的是，加入新的F100L变异进一步提高了基因分型对4级毒性的预测性（敏感性60%，OR = 42.8）。
目前的数据证实了公认变异对卡培他滨毒性的影响，并揭示了一种与4级毒性相关的新型DPYD变异F100L的存在。
