小柯机器人

美国斯坦福大学医学院Gerald R. Crabtree和Christina Curtis研究团队合作，揭示了染色质调节剂介导乳腺癌患者对蒽环霉素的敏感性。相关论文2019年11月7日在线发表在《自然—医学》上。

由于蒽环霉素部分通过抑制介导DNA可及性的拓扑异构酶II(TOP2)起作用，研究人员推测，介导DNA可及性的染色质调节基因（CRG）可以预测乳腺癌患者对蒽环霉素的响应。通过对患者和细胞系数据的综合分析，研究人员探究了CRGs在蒽环霉素敏感性中的作用。

研究人员通过对十个细胞系数据集中分析，确定了与蒽环霉素反应相关的38个CRG。通过评估表达和治疗间的相互作用，预测1006例早期乳腺癌患者的生存情况，研究人员确定了54个CRG，其表达水平决定了蒽环霉素在整个临床亚组中的功效。这54个CRG中有12个与体外鉴定的CRG重叠。促进DNA可及性的CRG（包括Trithorax复合物成员）高表达与蒽环霉素的敏感性相关，而降低DNA可及性的CRG（例如Polycomb复合蛋白）与蒽环霉素敏感性降低相关。研究人员还发现，KDM4B调节TOP2对染色质的可及性，阐明了TOP2抑制剂敏感性的机制。这些发现表明，CRGs通过改变DNA的可及性来影响蒽环霉素的功效，这对乳腺癌患者的分期和确定治疗方案都很重要。

据悉，蒽环霉素是非常有效的治疗乳腺癌的化疗药物，但也导致很多并发症。

附：英文原文

Title: Chromatin regulators mediate anthracycline sensitivity in breast cancer

Author: Jose A. Seoane, Jacob G. Kirkland, Jennifer L. Caswell-Jin, Gerald R. Crabtree, Christina Curtis

Issue&Volume: 2019-11-07

Abstract: Anthracyclines are a highly effective component of curative breast cancer chemotherapy but are associated with substantial morbidity1,2. Because anthracyclines work in part by inhibiting topoisomerase-II (TOP2) on accessible DNA3,4, we hypothesized that chromatin regulatory genes (CRGs) that mediate DNA accessibility might predict anthracycline response. We studied the role of CRGs in anthracycline sensitivity in breast cancer through integrative analysis of patient and cell line data. We identified a consensus set of 38 CRGs associated with anthracycline response across ten cell line datasets. By evaluating the interaction between expression and treatment in predicting survival in a metacohort of 1006 patients with early-stage breast cancer, we identified 54 CRGs whose expression levels dictate anthracycline benefit across the clinical subgroups; of these CRGs, 12 overlapped with those identified in vitro. CRGs that promote DNA accessibility, including Trithorax complex members, were associated with anthracycline sensitivity when highly expressed, whereas CRGs that reduce accessibility, such as Polycomb complex proteins, were associated with decreased anthracycline sensitivity. We show that KDM4B modulates TOP2 accessibility to chromatin, elucidating a mechanism of TOP2 inhibitor sensitivity. These findings indicate that CRGs mediate anthracycline benefit by altering DNA accessibility, with implications for the stratification of patients with breast cancer and treatment decision making. Epigenetic regulators modulating chromatin accessibility dictate sensitivity to anthracycline-based therapy in early breast cancer and represent potential biomarkers for patient stratification.

DOI: 10.1038/s41591-019-0638-5

Source:https://www.nature.com/articles/s41591-019-0638-5

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
官方网址：https://www.nature.com/nm/
投稿链接：https://mts-nmed.nature.com/cgi-bin/main.plex