Epsin Family Member 3 and Ribosome-Related Genes Are Associated with Late Metastasis in Estrogen Receptor-Positive Breast Cancer and Long-Term Survival in Non-Small Cell Lung Cancer Using a Genome-Wide Identification and Validation Strategy
Epsin Family Member 3 and Ribosome-Related Genes Are Associated with Late Metastasis in Estrogen Receptor-Positive Breast Cancer and Long-Term Survival in Non-Small Cell Lung Cancer Using a Genome-Wide Identification and Validation Strategy
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DOI：
10.1371/journal.pone.0167585
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发表时间：
2016-12-07
期刊：
影响因子：
3.7
通讯作者：
Rahnenfuehrer, Joerg
中科院分区：
文献类型：
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作者：
Hellwig, Birte;Madjar, Katrin;Rahnenfuehrer, Joerg
背景在乳腺癌中，预测手术切除肿瘤后转移风险的基因特征主要是早期事件的指示。本研究的目的是确定与转移复发的基因超过3年后surgical.MethodsAffyanderHG U133A和加2.0阵列数据集的信息，无转移，无病或总生存率通过公共资源库访问。使用时间限制的考克斯回归模型来鉴定与手术后前三年期间或之后的转移相关的基因（早期和晚期型基因）。应用具有两个非恶性治疗的发现队列（n = 409）和一个验证队列（n = 169）的顺序验证研究设计，并在他莫昔芬治疗的乳腺癌患者（n = 923）以及非小细胞肺癌患者（n = 169）中进一步评价鉴定的基因。（n = 1779）、结肠癌（n = 893）和卵巢癌（n = 922）。调整临床病理因素和一个既定的增殖相关的签名显着减少了早期型基因的数量为16，而9晚型基因仍然显着。这9个基因在非时间限制模型中也与无转移生存期（MFS）相关，但并非仅在早期，强调其预后影响主要基于手术后3年以上的MFS。在他莫昔芬治疗的乳腺癌队列的荟萃分析中，10个晚期基因中的4个，核糖体相关因子EIF4B、RPL 5、RPL 3和肿瘤血管生成修饰因子EPN 3与晚期MFS显著相关。相比之下，只有一个晚期基因（EPN3）在其他癌症类型的一个以上队列中显示出一致的生存相关性，与两个非小细胞肺癌队列中的预后较差相关。在卵巢癌和结肠癌中没有晚发型基因被验证。ConclusionsRibosome相关基因与晚期转移风险降低相关，无论是未经化疗还是经他莫昔芬治疗的乳腺癌患者。相反，epsin（EPN3）的高表达与晚期转移的风险增加相关。考虑到epsin在肿瘤血管生成中的充分理解的作用和epsin拮抗疗法的持续发展，这具有临床相关性。
BackgroundIn breast cancer, gene signatures that predict the risk of metastasis after surgical tumor resection are mainly indicative of early events. The purpose of this study was to identify genes linked to metastatic recurrence more than three years after surgery.MethodsAffymetrix HG U133A and Plus 2.0 array datasets with information on metastasis-free, disease-free or overall survival were accessed via public repositories. Time restricted Cox regression models were used to identify genes associated with metastasis during or after the first three years post-surgery (early-and late-type genes). A sequential validation study design, with two non-adjuvantly treated discovery cohorts (n = 409) and one validation cohort (n = 169) was applied and identified genes were further evaluated in tamoxifen-treated breast cancer patients (n = 923), as well as in patients with non-small cell lung (n = 1779), colon (n = 893) and ovarian (n = 922) cancer.ResultsTen late-and 243 early-type genes were identified in adjuvantly untreated breast cancer. Adjustment to clinicopathological factors and an established proliferation-related signature markedly reduced the number of early-type genes to 16, whereas nine late-type genes still remained significant. These nine genes were associated with metastasis-free survival (MFS) also in a non-time restricted model, but not in the early period alone, stressing that their prognostic impact was primarily based on MFS more than three years after surgery. Four of the ten late-type genes, the ribosome-related factors EIF4B, RPL5, RPL3, and the tumor angiogenesis modifier EPN3 were significantly associated with MFS in the late period also in a meta-analysis of tamoxifen-treated breast cancer cohorts. In contrast, only one late-type gene (EPN3) showed consistent survival associations in more than one cohort in the other cancer types, being associated with worse outcome in two non-small cell lung cancer cohorts. No late-type gene was validated in ovarian and colon cancer.ConclusionsRibosome-related genes were associated with decreased risk of late metastasis in both adjuvantly untreated and tamoxifen-treated breast cancer patients. In contrast, high expression of epsin (EPN3) was associated with increased risk of late metastasis. This is of clinical relevance considering the well-understood role of epsins in tumor angiogenesis and the ongoing development of epsin antagonizing therapies.