A genome-wide association study identifies locus at 10q22 associated with clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients in Japanese
A genome-wide association study identifies locus at 10q22 associated with clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients in Japanese
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DOI：
10.1093/hmg/ddr597
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发表时间：
2012-04-01
影响因子：
3.5
通讯作者：
Zembutsu, Hitoshi
中科院分区：
文献类型：
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作者：
Kiyotani, Kazuma;Mushiroda, Taisei;Zembutsu, Hitoshi
虽然已经报道了许多候选基因多态性与接受他莫昔芬辅助治疗的乳腺癌患者的临床结局的关联研究，但决定个体对他莫昔芬反应的遗传因素尚未完全了解。为了确定与他莫昔芬治疗患者临床结局相关的遗传多态性，我们进行了全基因组关联研究（GWAS）。我们研究了462例接受他莫昔芬辅助治疗的日本激素受体阳性浸润性乳腺癌患者。其中，使用Illumina Human 610-Quad BeadChips通过全基因组基因分型分析了240名患者，并使用两组独立的105和117例病例进行复制研究。在GWAS中，我们检测到9个染色体位点（1 p31，1 q41，5 q33，7 p11，10 q22，12 q13，13 q22，18 q12和19 p13）上的15个单核苷酸多态性（SNP）与无复发生存率显著相关，满足全基因组显著性阈值（对数秩P 2.87 10（9）9.41 10（8））。其中，在复制研究中，C10 orf 11基因10 q22上的rs 10509373与无复发生存率显著相关（对数秩P 2.02 10（4）），联合分析表明该SNP与接受他莫昔芬治疗的乳腺癌患者的无复发生存率密切相关（对数秩P 1.26 10（10））。rs 10509373的每个C等位基因的风险比为4.51 [95置信区间（CI），2.727.51; P 6.29 10（9）]。在rs 10509373基因型与先前确定的遗传标记CYP 2D 6和ABCC 2的联合分析中，这三个基因的风险等位基因的数量对345例接受他莫昔芬单药治疗的患者的无复发生存率具有累积效应（对数秩P 2.28 10（12））。总之，我们确定了一个新的基因位点与接受他莫昔芬辅助治疗的日本乳腺癌患者的无复发生存率相关。
Although many association studies of polymorphisms in candidate genes with the clinical outcomes of breast cancer patients receiving adjuvant tamoxifen therapy have been reported, genetic factors determining individual response to tamoxifen are not fully understood. To identify genetic polymorphisms associated with clinical outcomes of patients with tamoxifen treatment, we conducted a genome-wide association study (GWAS). We studied 462 Japanese patients with hormone receptor-positive, invasive breast cancer receiving adjuvant tamoxifen therapy. Of them, 240 patients were analyzed by genome-wide genotyping using the Illumina Human610-Quad BeadChips, and two independent sets of 105 and 117 cases were used for replication studies. In the GWAS, we detected significant associations with recurrence-free survival at 15 single-nucleotide polymorphisms (SNPs) on nine chromosomal loci (1p31, 1q41, 5q33, 7p11, 10q22, 12q13, 13q22, 18q12 and 19p13) that satisfied a genome-wide significant threshold (log-rank P 2.87 10(9)9.41 10(8)). Among them, rs10509373 in C10orf11 gene on 10q22 was significantly associated with recurrence-free survival in the replication study (log-rank P 2.02 10(4)) and a combined analysis indicated a strong association of this SNP with recurrence-free survival in breast cancer patients treated with tamoxifen (log-rank P 1.26 10(10)). Hazard ratio per C allele of rs10509373 was 4.51 [95 confidence interval (CI), 2.727.51; P 6.29 10(9)]. In a combined analysis of rs10509373 genotype with previously identified genetic makers, CYP2D6 and ABCC2, the number of risk alleles of these three genes had cumulative effects on recurrence-free survival among 345 patients receiving tamoxifen monotherapy (log-rank P 2.28 10(12)). In conclusion, we identified a novel locus associated with recurrence-free survival in Japanese breast cancer patients receiving adjuvant tamoxifen therapy.