Damaraju Sambasivarao, Murray David, Dufour Jennifer, Carandang Diana, Myrehaug Sten, Fallone Gino, Field Colin, Greiner Russell, Hanson John, Cass Carol E, Parliament Matthew
Cross Cancer Institute, Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
Clin Cancer Res. 2006 Apr 15;12(8):2545-54. doi: 10.1158/1078-0432.CCR-05-2703.
To explore the possible relationship between single nucleotide polymorphisms (SNP) in candidate genes encoding DNA damage recognition/repair/response and steroid metabolism proteins with respect to clinical radiation toxicity in a retrospective cohort of patients previously treated with three-dimensional conformal radiotherapy (3-DCRT) for prostate cancer.
One hundred twenty-four patients with prostate cancer underwent 3-DCRT at our institution between September 1996 and December 2000. Of these, 83 consented for follow-up of blood sampling and SNP analysis. Twenty-eight patients were documented as having experienced grade >/=2 late bladder or rectal toxicity (scoring system of Radiation Therapy Oncology Group) on at least one follow-up visit. We analyzed 49 SNPs in BRCA1, BRCA2, ESR1, XRCC1, XRCC2, XRCC3, NBN, RAD51, RAD52, LIG4, ATM, BCL2, TGFB1, MSH6, ERCC2, XPF, NR3C1, CYP1A1, CYP2C9, CYP2C19, CYP3A5, CYP2D6, CYP11B2, and CYP17A1 genes using the Pyrosequencing technique.
Significant univariate associations with late rectal or bladder toxicity (grade >/=2) were found for XRCC3 (A>G 5' untranslated region NT 4541), LIG4 (T>C Asp(568)Asp), MLH1 (C>T, Val(219)Ile), CYP2D64 (G>A splicing defect), mean rectal and bladder dose, dose to 30% of rectum or bladder, and age <60 years. On Cox multivariate analysis, significant associations with toxicity were found for LIG4 (T>C, Asp(568)Asp), ERCC2 (G>A, Asp(711)Asp), CYP2D64 (G>A, splicing defect), mean bladder dose >60 Gy, and dose to 30% of rectal volume >75 Gy.
In this study, we identified SNPs in LIG4, ERCC2, and CYP2D6 genes as putative markers to predict individuals at risk for complications arising from radiation therapy in prostate cancer.
在一个曾接受前列腺癌三维适形放疗（3-DCRT）的回顾性队列患者中，探讨编码DNA损伤识别/修复/应答及类固醇代谢蛋白的候选基因中的单核苷酸多态性（SNP）与临床放射毒性之间的可能关系。
1996年9月至2000年12月期间，124例前列腺癌患者在我们机构接受了3-DCRT。其中，83例同意进行血样随访及SNP分析。28例患者在至少一次随访中被记录为发生了≥2级晚期膀胱或直肠毒性（放射治疗肿瘤学组评分系统）。我们使用焦磷酸测序技术分析了BRCA1、BRCA2、ESR1、XRCC1、XRCC2、XRCC3、NBN、RAD51、RAD52、LIG4、ATM、BCL2、TGFB1、MSH6、ERCC2、XPF、NR3C1、CYP1A1、CYP2C9、CYP2C19、CYP3A5、CYP2D6、CYP11B2和CYP17A1基因中的49个SNP。
发现XRCC3（A>G 5'非翻译区第4541位核苷酸）、LIG4（T>C，天冬氨酸（568）天冬氨酸）、MLH1（C>T，缬氨酸（219）异亮氨酸）、CYP2D64（G>A剪接缺陷）、直肠和膀胱平均剂量、直肠或膀胱30%体积的剂量以及年龄<60岁与晚期直肠或膀胱毒性（≥2级）存在显著单变量关联。在Cox多变量分析中，发现LIG4（T>C，天冬氨酸（568）天冬氨酸）、ERCC2（G>A，天冬氨酸（711）天冬氨酸）、CYP2D64（G>A，剪接缺陷）、膀胱平均剂量>60 Gy以及直肠体积30%的剂量>75 Gy与毒性存在显著关联。
在本研究中，我们确定LIG4、ERCC2和CYP2D6基因中的SNP为预测前列腺癌放射治疗并发症风险个体的推定标志物。
