Bi-allelic alterations in DNA repair genes underpin homologous recombination DNA repair defects in breast cancer.
Bi-allelic alterations in DNA repair genes underpin homologous recombination DNA repair defects in breast cancer.
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DOI：
10.1002/path.4890
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发表时间：
2017-06
期刊：
影响因子：
--
通讯作者：
Powell SN
中科院分区：
文献类型：
--
作者：
Mutter RW;Riaz N;Ng CK;Delsite R;Piscuoglio S;Edelweiss M;Martelotto LG;Sakr RA;King TA;Giri DD;Drobnjak M;Brogi E;Bindra R;Bernheim G;Lim RS;Blecua P;Desrichard A;Higginson D;Towers R;Jiang R;Lee W;Weigelt B;Reis-Filho JS;Powell SN
同源重组（HR） DNA修复缺陷（HRD）乳腺癌已被证明对DNA修复靶向治疗敏感。越来越多的证据表明，缺乏种系BRCA1/BRCA2突变的散发性乳腺癌也可能是HRD。我们开发了一种基于rad51的功能性离体检测来识别HRD原发性乳腺癌。采用综合方法检测甲基化，基因表达和全外显子组测序来确定HRD的病因。功能性HRD乳腺癌表现出缺乏有效HR的基因组特征，包括大规模的状态转变和特定的突变特征。在89%的病例中，导致HR基因双等位基因功能丧失的体细胞和/或种系遗传改变是功能性HRD的基础，并且仅在15个HR熟练样本中观察到。这些发现表明，对HR通路中双等位基因改变进行全面的遗传评估对于提供基于精确医学的方法来选择针对肿瘤特异性DNA修复缺陷的治疗患者的重要性。
Homologous recombination (HR) DNA repair deficient (HRD) breast cancers have been shown to be sensitive to DNA repair targeted therapies. Burgeoning evidence suggests that sporadic breast cancers, lacking germline BRCA1/BRCA2 mutations, may also be HRD. We developed a functional ex-vivo RAD51-based test to identify HRD primary breast cancers. An integrated approach examining methylation, gene expression and whole-exome sequencing was employed to ascertain the etiology of HRD. Functional HRD breast cancers displayed genomic features of lack of competent HR, including large-scale state transitions and specific mutational signatures. Somatic and/or germline genetic alterations resulting in bi-allelic loss-of-function of HR genes underpinned functional HRD in 89% of cases, and were observed in only one of the 15 HR-proficient samples tested. These findings indicate the importance of a comprehensive genetic assessment of bi-allelic alterations in the HR pathway to deliver a precision medicine-based approach to select patients for therapies targeting tumor-specific DNA repair defects.
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影响因子：
28.2
作者：
Birkbak NJ;Wang ZC;Kim JY;Eklund AC;Li Q;Tian R;Bowman-Colin C;Li Y;Greene-Colozzi A;Iglehart JD;Tung N;Ryan PD;Garber JE;Silver DP;Szallasi Z;Richardson AL
通讯作者：
Richardson AL
影响因子：
3.8
作者：
Gutierrez-Enriquez, Sara;Ramon y Cajal, Teresa;Diez, Orland
通讯作者：
Diez, Orland
影响因子：
10.3
作者：
Esteller, M;Silva, JM;Herman, JG
通讯作者：
Herman, JG
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
10.5
作者：
Jiang Q;Paramasivam M;Aressy B;Wu J;Bellani M;Tong W;Seidman MM;Greenberg RA
通讯作者：
Greenberg RA