ABCC2 polymorphisms and survival in the Princess Margaret cohort study and the NCIC clinical trials group BR.24 trial of platinum-treated advanced stage non-small cell lung cancer patients.,Cancer Epidemiology

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ABCC2 polymorphisms and survival in the Princess Margaret cohort study and the NCIC clinical trials group BR.24 trial of platinum-treated advanced stage non-small cell lung cancer patients.
Cancer Epidemiology ( IF 2.6 ) Pub Date : 2016-01-24 , DOI: 10.1016/j.canep.2015.12.012
Sinead Cuffe ₁ , Abul Kalam Azad ₂ , Xiaoping Qiu ₂ , Xin Qiu ₃ , Yonathan Brhane ₃ , Qin Kuang ₂ , Sharon Marsh ₄ , Sevtap Savas ₅ , Zhuo Chen ₂ , Dangxiao Cheng ₂ , Natasha B Leighl ₂ , Glenwood Goss ₆ , Scott A Laurie ₆ , Lesley Seymour ₇ , Penelope A Bradbury ₈ , Frances A Shepherd ₂ , Ming Sound Tsao ₉ , Bingshu E Chen ₇ , Wei Xu ₃ , Geoffrey Liu ₂

Affiliation

Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, and Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada; HOPE Directorate, St James's Hospital, Dublin 8, Ireland.
Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, and Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada.
Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, and Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada; Discipline of Genetics, Memorial University of Newfoundland, St. John's, NL, Canada.
Division of Medical Oncology, Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa, ON, Canada.
NCIC Clinical Trials Group, Queens University, Kingston, ON, Canada.
Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, and Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada; NCIC Clinical Trials Group, Queens University, Kingston, ON, Canada.
Department of Pathology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.

Background

The drug transporter ABCC2 is upregulated in non-small cell lung cancer (NSCLC) and implicated in platinum resistance. We evaluated the association between germline polymorphisms in the ABCC2 gene and survival outcomes of platinum-treated advanced NSCLC patients.

Material and methods

Ten candidate and tagging germline polymorphisms in the ABCC2 gene were genotyped in a discovery cohort of 170 platinum-treated stage IV NSCLC patients from the Princess Margaret Cancer Centre. Associations with overall survival were assessed using multivariate Cox proportional hazard models adjusted for prognostic variables. To validate our results, we analyzed the association of the two top polymorphisms in the ABCC2 gene on survival outcomes of 219 stage IIIB-IV NSCLC patients enrolled on the NCIC Clinical Trials Group BR.24 clinical trial.

Results

Only one polymorphism was validated across both cohorts for an association with overall survival: the A allele of the ABCC2 polymorphism, rs8187710 (4544G > A), was associated with adverse overall survival (adjusted hazard ratio [aHR] 2.22; 95% CI: 1.2–4.0; p = 0.009) among our stage IV NSCLC patients. A significant association with overall survival (aHR 1.73; 95% CI: 1.0–2.9; p = 0.036) was observed for the same ABCC2 polymorphism in the BR.24 validation cohort. No other ABCC2 polymorphisms were associated with outcome.

Conclusion

The ABCC2 polymorphism, rs8187710 (4544G > A), is associated with overall survival in platinum-treated advanced NSCLC patients. Additional studies are needed to evaluate the predictive versus prognostic nature of this relationship, and to explore the functional effect of this polymorphism on the pharmacokinetics of platinum drugs.

中文翻译：

公主玛格丽特队列研究和NCIC临床试验小组BR.24试验的铂类药物治疗的晚期非小细胞肺癌患者的ABCC2基因多态性和存活率。

背景

药物转运蛋白ABCC2在非小细胞肺癌（NSCLC）中上调，并与铂耐药相关。我们评估了ABCC2基因的种系多态性与铂治疗晚期NSCLC患者的生存结局之间的关联。

材料与方法

在来自玛格丽特公主癌症中心的170名接受铂金治疗的IV期NSCLC患者的发现队列中，对ABCC2基因中的10个候选和标记种系多态性进行了基因分型。使用针对预后变量进行调整的多变量Cox比例风险模型评估与总体生存率的相关性。为了验证我们的结果，我们分析了ABCC2基因中两个最重要的多态性与NCIC临床试验组BR.24临床试验中招募的219位IIIB-IV期NSCLC患者的生存结局的关系。

结果

在两个队列中仅验证了一个多态性与总体生存率的关联：ABCC2多态性的A等位基因rs8187710（4544G> A）与总体生存率不良相关（调整的危险比[aHR] 2.22； 95％CI：1.2 –4.0；p = 0.009）在我们的IV期NSCLC患者中。在BR.24验证队列中，对于相同的ABCC2多态性，观察到与总体生存率显着相关（aHR 1.73； 95％CI：1.0–2.9；p = 0.036）。没有其他ABCC2多态性与结果相关联。