Association between the estrogen receptor α A908G mutation and outcomes in invasive breast cancer
Association between the estrogen receptor α A908G mutation and outcomes in invasive breast cancer
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DOI：
10.1158/1078-0432.ccr-06-2608
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发表时间：
2007-06-01
影响因子：
11.5
通讯作者：
Fuqua, Suzanne A. W.
中科院分区：
文献类型：
--
作者：
Herynk, Matthew H.;Parra, Irma;Fuqua, Suzanne A. W.
目的：雌激素受体α（ERα）无需干预治疗即可预测乳腺癌的自然病程。在这里，我们优化了体细胞突变（Met 的 A908G 转变）的检测，并检查了其与浸润性乳腺癌的临床和生物学特征的关联。实验设计：我们比较了两种检测 A908G ER α 突变的测序方法。然后，我们使用从侵袭性乳腺肿瘤中分离出的基因组 DNA 进行引物延伸测序，以确定该突变是否与 267 个腋窝淋巴结阴性和腋窝淋巴结阳性乳腺肿瘤的临床结果相关。通过 Cox 比例风险回归模型分析突变的存在和临床变量与无复发生存期和总生存期的关联。结果：我们确定染料标记的终止子测序不足以检测 A908G ERa 突变。使用引物延伸测序在侵袭性乳腺肿瘤中以高频率（50%）检测到该突变，并发现该突变与不良结果的临床指标相关，包括较大的肿瘤尺寸和腋窝淋巴结阳性。尽管在单变量分析中该突变与无复发生存相关，但在多变量分析中它并不是结果的独立预测因子。 结论：与我们之前在乳腺导管增生中发现的体细胞 ER α 突变一致，我们现在使用优化测序方法提供证据表明 A908G 突变存在于侵袭性乳腺肿瘤中。我们发现该突变与侵袭性生物肿瘤特征以及不良预后显着相关，但对于未经治疗的患者来说并不是独立的预后标志物。
Purpose: Estrogen receptor alpha (ER alpha) predicts the natural history of breast cancer without intervening therapy. Here, we have optimized the detection of a somatic mutation, an A908G transition of Met, and examined its association with clinical and biological features of invasive breast cancer.Experimental Design: We compared two methods of sequencing to detect the A908G ER alpha mutation. We then used primer extension sequencing with genomic DNA isolated from invasive breast tumors to determine whether the mutation was associated with clinical outcome in 267 axillary node - negative and axillary node - positive breast tumors. The presence of the mutation and clinical variables were analyzed for association with recurrence-free survival and overall survival by Cox proportional hazards regression models.Results: We determined that dye-labeled terminator sequencing was not adequate for detection of the A908G ERa mutation. The mutation was detected at a high frequency (50%) in invasive breast tumors using primer extension sequencing, and was found to be associated with clinical measures of poor outcome, including larger tumor size and axillary lymph node positivity. Although the mutation was associated with recurrence-free survival in univariate analysis, it was not an independent predictor of outcomes in multivariate analysis.Conclusions: Consistent with our previous finding of this somatic ER alpha mutation in breast ductal hyperplasias, we now present evidence that the A908G mutation is present in invasive breast tumors using an optimized sequencing method. We find that the mutation is significantly associated with aggressive biological tumor features, and with an unfavorable prognosis, but was not an independent prognostic marker in untreated patients.