BRCA1 相互作用因子 SRBC 的表观遗传失活与结直肠癌对奥沙利铂的耐药性。
Epigenetic inactivation of the BRCA1 interactor SRBC and resistance to oxaliplatin in colorectal cancer.
机构信息
Affiliations of authors: Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, Barcelona, Spain (CM, AM-C, FJC, ME); Medical Oncology Service, Catalan Institute of Oncology, Health Sciences Research Institute of the Germans Trias i Pujol Foundation, Barcelona, Spain (AM-C, EM-B, AA); Department of Medical Oncology (CS, RS) and Clinical Informatics Unit (VN-P), Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain; Department of Pathology, Germans Trias i Pujol Foundation, Barcelona, Spain (EM); Department of Hematology and Oncology, Ospedale Niguarda Ca' Granda, Milan, Italy (AS-B, AC, SS); Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain (EE, JT); Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Barcelona, Spain (ME); Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain (ME).
出版信息
J Natl Cancer Inst. 2014 Jan;106(1):djt322. doi: 10.1093/jnci/djt322. Epub 2013 Nov 22.
BACKGROUND
A major problem in cancer chemotherapy is the existence of primary resistance and/or the acquisition of secondary resistance. Many cellular defects contribute to chemoresistance, but epigenetic changes can also be a cause.
METHODS
A DNA methylation microarray was used to identify epigenetic differences in oxaliplatin-sensitive and -resistant colorectal cancer cells. The candidate gene SRBC was validated by single-locus DNA methylation and expression techniques. Transfection and short hairpin experiments were used to assess oxaliplatin sensitivity. Progression-free survival (PFS) and overall survival (OS) in metastasic colorectal cancer patients were explored with Kaplan-Meier and Cox regression analyses. All statistical tests were two-sided.
RESULTS
We found that oxaliplatin resistance in colorectal cancer cells depends on the DNA methylation-associated inactivation of the BRCA1 interactor SRBC gene. SRBC overexpression or depletion gives rise to sensitivity or resistance to oxaliplatin, respectively. SRBC epigenetic inactivation occurred in primary tumors from a discovery cohort of colorectal cancer patients (29.8%; n = 39 of 131), where it predicted shorter PFS (hazard ratio [HR] = 1.83; 95% confidence interval [CI] = 1.15 to 2.92; log-rank P = .01), particularly in oxaliplatin-treated case subjects for which metastasis surgery was not indicated (HR = 1.96; 95% CI = 1.13 to 3.40; log-rank P = .01). In a validation cohort of unresectable colorectal tumors treated with oxaliplatin (n = 58), SRBC hypermethylation was also associated with shorter PFS (HR = 1.90; 95% CI = 1.01 to 3.60; log-rank P = .045).
CONCLUSIONS
These results provide a basis for future clinical studies to validate SRBC hypermethylation as a predictive marker for oxaliplatin resistance in colorectal cancer.
背景
癌症化疗中的一个主要问题是存在原发性耐药和/或获得继发性耐药。许多细胞缺陷导致化疗耐药，但表观遗传变化也可能是一个原因。
方法
使用 DNA 甲基化微阵列来鉴定奥沙利铂敏感和耐药的结直肠癌细胞中的表观遗传差异。通过单基因座 DNA 甲基化和表达技术验证候选基因 SRBC。转染和短发夹实验用于评估奥沙利铂的敏感性。采用 Kaplan-Meier 和 Cox 回归分析探讨转移性结直肠癌患者的无进展生存期（PFS）和总生存期（OS）。所有统计检验均为双侧。
结果
我们发现结直肠癌细胞的奥沙利铂耐药取决于 BRCA1 相互作用物 SRBC 基因的 DNA 甲基化相关失活。SRBC 过表达或耗竭分别导致对奥沙利铂的敏感性或耐药性。在来自结直肠癌患者发现队列的原发性肿瘤中观察到 SRBC 表观遗传失活（29.8%；n=131 例中的 39 例），这预示着较短的 PFS（风险比[HR] = 1.83；95%置信区间[CI] = 1.15 至 2.92；对数秩 P =.01），特别是在未指示转移手术的奥沙利铂治疗病例中（HR = 1.96；95% CI = 1.13 至 3.40；对数秩 P =.01）。在接受奥沙利铂治疗的不可切除结直肠肿瘤验证队列中（n=58），SRBC 高甲基化也与较短的 PFS 相关（HR = 1.90；95% CI = 1.01 至 3.60；对数秩 P =.045）。
结论
这些结果为未来的临床研究提供了依据，以验证 SRBC 高甲基化为结直肠癌奥沙利铂耐药的预测标志物。
Zotero 插件