Platinum sensitivity-related germline polymorphism discovered via a cell-based approach and analysis of its association with outcome in ovarian cancer patients.
Platinum sensitivity-related germline polymorphism discovered via a cell-based approach and analysis of its association with outcome in ovarian cancer patients.
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DOI：
10.1158/1078-0432.ccr-11-0724
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发表时间：
2011-08-15
期刊：
影响因子：
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通讯作者：
Dolan ME
中科院分区：
文献类型：
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作者：
Huang RS;Johnatty SE;Gamazon ER;Im HK;Ziliak D;Duan S;Zhang W;Kistner EO;Chen P;Beesley J;Mi S;O'Donnell PH;Fraiman YS;Das S;Cox NJ;Lu Y;Macgregor S;Goode EL;Vierkant RA;Fridley BL;Hogdall E;Kjaer SK;Jensen A;Moysich KB;Grasela M;Odunsi K;Brown R;Paul J;Lambrechts D;Despierre E;Vergote I;Gross J;Karlan BY;Defazio A;Chenevix-Trench G;Australian Ovarian Cancer Study Group;Dolan ME
利用基于细胞的方法来识别预测患者化疗前反应不良风险的遗传标记。我们进行了全基因组关联研究（GWAS），以通过其对mRNA表达的影响，使用国际HapMap淋巴母细胞系（LCL）识别与细胞对卡铂敏感性相关的SNP，并在其他LCL中复制它们。测试通过基于细胞的研究的两个阶段的SNP与患者的无进展生存期（PFS）的关联。1期验证基于来自澳大利亚卵巢癌研究（AOCS）的377名接受至少4个周期卡铂和紫杉醇治疗的卵巢癌患者。然后在卵巢癌协会联盟和癌症基因组图谱的1，326名患者的2期验证分析中评估了阳性相关性。在最初的GWAS中，342个SNP与卡铂诱导的细胞毒性相关，其中18个独特的SNP在评估其与基因表达的关联后被保留。一个SNP（rs1649942）在独立的LCL集中重复（p值Bonferroni调整=9×10−3）。发现它与1期AOCS患者的PFS降低显著相关（Pper等位基因=2×10−2），在肿瘤最佳减容的女性亚组中具有更强的影响（Pper等位基因=4×10−3）。rs1649942也与肿瘤最佳减容的女性总体生存率较差相关（Pper等位基因=9×10−3）。然而，该SNP在来自众多队列的患者的2期验证中并不显著。这项研究证明了基于细胞的全基因组方法在识别治疗结果的生殖系预测因子方面的潜力，并强调了在患者中进行广泛验证以评估其临床效果的必要性。
Utilizing cell-based approaches to identify genetic markers predictive of patients’ risk for poor response prior to chemotherapy. We performed genome-wide association studies (GWASs) to identify SNPs associated with cellular sensitivity to carboplatin through their effects on mRNA expression using International HapMap lymphoblastoid cell lines (LCLs) and replicated them in additional LCLs. SNPs passing both stages of the cell-based study were tested for association with progression free survival (PFS) in patients. Phase-1 validation was based on 377 ovarian cancer patients receiving at least 4-cycle of carboplatin and paclitaxel from the Australian Ovarian Cancer Study (AOCS). Positive associations were then assessed in the phase-2 validation analysis of 1,326 patients from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas. In the initial GWAS, 342 SNPs were associated with carboplatin-induced cytotoxicity, of which 18 unique SNPs were retained after assessing their association with gene expression. One SNP (rs1649942) was replicated in an independent LCL set (p-valueBonferroni adjusted=9×10−3). It was found to be significantly associated with decreased PFS in phase-1 AOCS patients (Pper-allele=2×10−2), with a stronger effect in the subset of women with optimally debulked tumours (Pper-allele=4×10−3). rs1649942 was also associated with poorer overall survival in women with optimally debulked tumours (Pper-allele=9×10−3). However, this SNP was not significant in the phase-2 validation with patients from numerous cohorts. This study demonstrates the potential of cell-based, genome-wide approaches to identify germ-line predictors of treatment outcome and highlights the need for extensive validation in patients to assess their clinical effect.