Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents.
Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents.
复制标题
DOI：
10.1158/2159-8290.cd-11-0206
复制
发表时间：
2012-04
期刊：
影响因子：
28.2
通讯作者：
Richardson AL
中科院分区：
文献类型：
--
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
DNA 修复能力是对某些化疗药物（例如顺铂）敏感性的决定因素之一。具有完整DNA修复的癌细胞可以避免生长过程中基因组损伤的积累，也可以修复铂引起的DNA损伤。我们寻找表明细胞系和肿瘤中 DNA 修复缺陷的基因组特征，并将这些特征与铂敏感性相关联。延伸至端粒的等位基因失衡的亚染色体区域 (NtAI) 的数量可预测三阴性乳腺癌 (TNBC) 患者对顺铂的体外敏感性以及术前顺铂治疗的病理反应。在采用铂类化疗治疗的浆液性卵巢癌中，较高的 NtAI 预示着更好的初始反应。我们发现，在散发性 TNBC 和无 BRCA1 或 BRCA2 突变的浆液性卵巢癌中，BRCA1 表达与 NtAI 之间存在负相关。因此，tAI 的积累是铂敏感性的标志，表明 DNA 修复受损。
DNA repair competency is one determinant of sensitivity to certain chemotherapy drugs, such as cisplatin. Cancer cells with intact DNA repair can avoid the accumulation of genome damage during growth and also can repair platinum-induced DNA damage. We sought genomic signatures indicative of defective DNA repair in cell lines and tumors, and correlated these signatures to platinum sensitivity. The number of sub-chromosomal regions with allelic imbalance extending to the telomere (NtAI) predicted cisplatin sensitivity in-vitro, and pathologic response to preoperative cisplatin treatment in patients with triple-negative breast cancer (TNBC). In serous ovarian cancer treated with platinum-based chemotherapy, higher NtAI forecast better initial response. We found an inverse relationship between BRCA1 expression and NtAI in sporadic TNBC and serous ovarian cancers without BRCA1 or BRCA2 mutation. Thus, accumulation of tAI is a marker of platinum sensitivity and suggests impaired DNA repair.