A 2-Stage Genome-Wide Association Study to Identify Single Nucleotide Polymorphisms Associated with Development of Urinary Symptoms After Radiotherapy for Prostate Cancer
A 2-Stage Genome-Wide Association Study to Identify Single Nucleotide Polymorphisms Associated with Development of Urinary Symptoms After Radiotherapy for Prostate Cancer
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DOI：
10.1016/j.juro.2013.01.096
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发表时间：
2013-07-01
影响因子：
6.6
通讯作者：
Rosenstein, Barry S.
中科院分区：
文献类型：
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作者：
Kerns, Sarah L.;Stone, Nelson N.;Rosenstein, Barry S.
目的：我们确定了单核苷酸多态性与AUA症状评分的变化放疗后前列腺癌。材料和方法：共723例患者接受近距离放射治疗或不接受外照射放射治疗进行了评估，在基线和每年放疗后使用AUA症状评分。进行了2阶段全基因组关联研究，主要终点为4个随访期的AUA症状评分较基线的变化。单核苷酸多态性的相关性采用多变量线性回归进行评估，调整放疗前AUA症状评分严重程度类别和临床变量。结果：染色体9p21.2上含有8个单核苷酸多态性的区域与AUA症状评分变化的相关性最强（放疗后2 - 3年的联合p值为8.8 x 10（-6）-6.5 x 10（-7））。这些单核苷酸多态性形成了一个单倍型块，包括炎症信号基因IFNK。这些单核苷酸多态性与调整临床预测因素（包括吸烟史、高血压、α-受体阻滞剂使用和放疗前AUA症状评分）后的AUA症状评分变化独立相关。另外24个单核苷酸多态性与AUA症状评分的变化有中度显著性相关。这些单核苷酸多态性中的几个与特定AUA症状评分项目的变化更密切相关，包括MYO 3B基因中的rs 13035033，其与应变相关。（β系数0.9，95% CI 0.6-1.2，p = 5.0 x 10（-9））。如果得到验证，这些单核苷酸多态性可以提供对放射治疗后泌尿系统症状的生物学基础的了解，并可能导致开发一种检测方法来识别有风险经历这些影响的患者。
Purpose: We identified single nucleotide polymorphisms associated with change in the AUA Symptom Score after radiotherapy for prostate cancer.Materials and Methods: A total of 723 patients treated with brachytherapy with or without external beam radiation therapy were assessed at baseline and annually after radiotherapy using the AUA Symptom Score. A 2-stage genome-wide association study was performed with the primary end point of change in AUA Symptom Score from baseline at each of 4 followup periods. Single nucleotide polymorphism associations were assessed using multivariable linear regression adjusting for pre-radiotherapy AUA Symptom Score severity category and clinical variables. Fisher's trend method was used to calculate combined p values from the discovery and replication cohorts.Results: A region on chromosome 9p21.2 containing 8 single nucleotide polymorphisms showed the strongest association with change in AUA Symptom Score (combined p values 8.8 x 10(-6) to 6.5 x 10(-7) at 2 to 3 years after radiotherapy). These single nucleotide polymorphisms form a haplotype block that encompasses the inflammation signaling gene IFNK. These single nucleotide polymorphisms were independently associated with change in AUA Symptom Score after adjusting for clinical predictors including smoking history, hypertension, alpha-blocker use and pre-radiotherapy AUA Symptom Score. An additional 24 single nucleotide polymorphisms showed moderate significance for association with change in AUA Symptom Score. Several of these single nucleotide polymorphisms were more strongly associated with change in specific AUA Symptom Score items, including rs13035033 in the MYO3B gene, which was associated with straining (beta coefficient 0.9, 95% CI 0.6-1.2, p = 5.0 x 10(-9)).Conclusions: If validated, these single nucleotide polymorphisms could provide insight into the biology underlying urinary symptoms following radiotherapy and could lead to development of an assay to identify patients at risk for experiencing these effects.