Department of Obstetrics and Gynecology, J. W. Goethe-University, Frankfurt, Germany.
PLoS One. 2011;6(12):e28403. doi: 10.1371/journal.pone.0028403. Epub 2011 Dec 29.
Current prognostic gene signatures for breast cancer mainly reflect proliferation status and have limited value in triple-negative (TNBC) cancers. The identification of prognostic signatures from TNBC cohorts was limited in the past due to small sample sizes.
METHODOLOGY/PRINCIPAL FINDINGS: We assembled all currently publically available TNBC gene expression datasets generated on Affymetrix gene chips. Inter-laboratory variation was minimized by filtering methods for both samples and genes. Supervised analysis was performed to identify prognostic signatures from 394 cases which were subsequently tested on an independent validation cohort (n = 261 cases).
CONCLUSIONS/SIGNIFICANCE: Using two distinct false discovery rate thresholds, 25% and <3.5%, a larger (n = 264 probesets) and a smaller (n = 26 probesets) prognostic gene sets were identified and used as prognostic predictors. Most of these genes were positively associated with poor prognosis and correlated to metagenes for inflammation and angiogenesis. No correlation to other previously published prognostic signatures (recurrence score, genomic grade index, 70-gene signature, wound response signature, 7-gene immune response module, stroma derived prognostic predictor, and a medullary like signature) was observed. In multivariate analyses in the validation cohort the two signatures showed hazard ratios of 4.03 (95% confidence interval [CI] 1.71-9.48; P = 0.001) and 4.08 (95% CI 1.79-9.28; P = 0.001), respectively. The 10-year event-free survival was 70% for the good risk and 20% for the high risk group. The 26-gene signatures had modest predictive value (AUC = 0.588) to predict response to neoadjuvant chemotherapy, however, the combination of a B-cell metagene with the prognostic signatures increased its response predictive value. We identified a 264-gene prognostic signature for TNBC which is unrelated to previously known prognostic signatures.
目前用于乳腺癌的预后基因标记主要反映增殖状态，在三阴性乳腺癌 (TNBC) 中的价值有限。过去，由于样本量小，对 TNBC 队列的预后标记物的鉴定受到限制。
方法/主要发现：我们收集了目前在 Affymetrix 基因芯片上生成的所有公开的 TNBC 基因表达数据集。通过对样本和基因进行过滤方法，最大限度地减少了实验室间的差异。对 394 例病例进行了有监督分析，以确定预后标记物，随后在独立的验证队列（n=261 例）中进行了测试。
结论/意义：使用两个不同的错误发现率阈值（25%和<3.5%），确定了一个更大（n=264 个探针）和一个较小（n=26 个探针）的预后基因集，并将其用作预后预测因子。这些基因大多数与预后不良呈正相关，并与炎症和血管生成的元基因相关。与其他先前发表的预后标记物（复发评分、基因组分级指数、70 基因标记物、伤口反应标记物、7 基因免疫反应模块、基质衍生预后预测因子和类髓样标记物）无相关性。在验证队列的多变量分析中，这两个标记物的危险比分别为 4.03（95%置信区间 [CI] 1.71-9.48；P=0.001）和 4.08（95% CI 1.79-9.28；P=0.001）。低风险组的 10 年无事件生存率为 70%，高风险组为 20%。26 基因标记物对预测新辅助化疗的反应有一定的预测价值（AUC=0.588），但与预后标记物结合的 B 细胞元基因增加了其反应预测价值。我们确定了一个与先前已知的预后标记物无关的用于 TNBC 的 264 基因预后标记物。
