Ploidy and Large-Scale Genomic Instability Consistently Identify Basal-like Breast Carcinomas with BRCA1/2 Inactivation
Ploidy and Large-Scale Genomic Instability Consistently Identify Basal-like Breast Carcinomas with BRCA1/2 Inactivation
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DOI：
10.1158/0008-5472.can-12-1470
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发表时间：
2012-11-01
期刊：
影响因子：
11.2
通讯作者：
Stern, Marc-Henri
中科院分区：
文献类型：
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作者：
Popova, Tatiana;Manie, Elodie;Stern, Marc-Henri
BRCA1 失活是基底样乳腺癌 (BLC) 中的常见事件。然而，BRCA1 可以通过多种机制失活，确定其状态并不是一个小问题。作为替代方法，我们使用单核苷酸多态性阵列对 65 个 BLC 病例进行了分析，以确定 BRCA1 相关基因组不稳定性的特征。大规模状态转换 (LST)（定义为至少 10 Mb 的相邻区域之间的染色体断裂）被发现是这种情况下 BRCA1 状态的可靠指标。 LST 分布中的两个主要倍性特异性截止值足以区分高度重排的 BLC（其中 85% 已证实的 BRCA1 失活病例）与重排程度较低的 BLC（没有证实的 BRCA1 失活病例）。我们定义的基因组特征在第二个独立系列中得到了验证，该系列包含 55 个原发性 BLC 病例和 17 个 BLC 衍生肿瘤细胞系。在 4 个原发性 BLC 病例和 2 个携带 BRCA2 突变的 BLC 细胞系中观察到大量类似于 BRCA1 失活 BLC 的 LST。总体而言，我们定义的基因组特征以 100% 的敏感性和 90% 的特异性（97% 的准确性）预测 BLC 中的 BRCA1/2 失活。该检测可能会缓解选择患者进行基因检测或招募针对癌症 DNA 修复缺陷的新兴疗法临床试验的挑战。癌症研究； 72（21）； 5454-62。 (C)2012 AACR。
BRCA1 inactivation is a frequent event in basal-like breast carcinomas (BLC). However, BRCA1 can be inactivated by multiple mechanisms and determining its status is not a trivial issue. As an alternate approach, we profiled 65 BLC cases using single-nucleotide polymorphism arrays to define a signature of BRCA1-associated genomic instability. Large-scale state transitions (LST), defined as chromosomal break between adjacent regions of at least 10 Mb, were found to be a robust indicator of BRCA1 status in this setting. Two major ploidy-specific cutoffs in LST distributions were sufficient to distinguish highly rearranged BLCs with 85% of proven BRCA1-inactivated cases from less rearranged BLCs devoid of proven BRCA1-inactivated cases. The genomic signature we defined was validated in a second independent series of 55 primary BLC cases and 17 BLC-derived tumor cell lines. High numbers of LSTs resembling BRCA1-inactivated BLC were observed in 4 primary BLC cases and 2 BLC cell lines that harbored BRCA2 mutations. Overall, the genomic signature we defined predicted BRCA1/2 inactivation in BLCs with 100% sensitivity and 90% specificity (97% accuracy). This assay may ease the challenge of selecting patients for genetic testing or recruitment to clinical trials of novel emerging therapies that target DNA repair deficiencies in cancer. Cancer Res; 72(21); 5454-62. (C)2012 AACR.