目的:多达1/4的乳腺癌患者接受手术和放疗后经历了临床上显著的毒性反应。如果在诊断时可以识别出不良反应高风险的患者,他们的治疗可以相应地定制。这项研究旨在鉴定与全乳放疗两年后的毒性相关的常见单核苷酸多态性(SNP)。
方法:对1,640名具有完整SNP的乳腺癌患者进行了全基因组关联研究(GWAS),临床,治疗和毒性数据,招募了18个欧洲和美国中心的前瞻性REQUITE队列研究。在基线时收集毒性数据(CTCAEv4.0),放疗结束,年度随访。总共测试了7,097,340个SNP与毒性终点的残差的关联,根据临床调整,治疗协变量和种群子结构。
结果:分位数-分位数图显示与p<5x10-5水平以上的毒性的关联比偶然预期的多。八个SNP达到了全基因组意义。乳头回缩等级≥2与rs188287402变体相关(p=2.80x10-8),乳腺水肿等级≥2,rs12657177(p=1.12x10-10),rs75912034(p=1.12x10-10),rs145328458(p=1.06x10-9)和rs61966612(p=1.23x10-9),硬化等级≥2,rs77311050(p=2.54x10-8)和rs34063419(p=1.21×10-8),和rs643644的手臂淋巴水肿等级≥1(p=3.54x10-8)。不同终点的遗传力估计范围从25%到39%。我们的研究没有在预先指定的显著性水平上重复先前报道的与乳房辐射毒性相关的SNP。
结论:这种长期乳腺辐射毒性的GWAS为常见SNP与不同毒性终点的显著关联提供了进一步的证据。
Up to a quarter of breast cancer patients treated by surgery and radiotherapy experience clinically significant toxicity. If patients at high risk of adverse effects could be identified at diagnosis, their treatment could be tailored accordingly. This
study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity two years following whole breast radiotherapy.
A genome-wide association
study (GWAS) was performed in 1,640 breast cancer patients with complete SNP, clinical, treatment and toxicity data, recruited across 18 European and US centres into the prospective REQUITE cohort
study. Toxicity data (CTCAE v4.0) were collected at baseline, end of radiotherapy, and annual follow-up. A total of 7,097,340 SNPs were tested for association with the residuals of toxicity endpoints, adjusted for clinical, treatment co-variates and population substructure.
Quantile-quantile plots showed more associations with toxicity above the p < 5 × 10-5 level than expected by chance. Eight SNPs reached genome-wide significance. Nipple retraction grade ≥ 2 was associated with the rs188287402 variant (p = 2.80 × 10-8), breast oedema grade ≥ 2 with rs12657177 (p = 1.12 × 10-10), rs75912034 (p = 1.12 × 10-10), rs145328458 (p = 1.06 × 10-9) and rs61966612 (p = 1.23 × 10-9), induration grade ≥ 2 with rs77311050 (p = 2.54 × 10-8) and rs34063419 (p = 1.21 × 10-8), and arm lymphoedema grade ≥ 1 with rs643644 (p = 3.54 × 10-8). Heritability estimates across significant endpoints ranged from 25% to 39%. Our
study did not replicate previously reported SNPs associated with breast radiation toxicity at the pre-specified significance level.
This GWAS for long-term breast radiation toxicity provides further evidence for significant association of common SNPs with distinct toxicity endpoints.