四链体DNA结构区域图谱

本期文章：《自然—遗传学》：Online/在线发表

英国剑桥大学Shankar Balasubramanian小组的一项最新研究绘制出乳腺癌G-四链体DNA结构区域图谱。相关论文于2020年8月3日发表于《自然—遗传学》。

研究人员绘制了22个乳腺癌患者来源肿瘤异种移植（PDTX）模型中差异性富集的G-四链体（G4）DNA结构形成区域（G4Rs）。G4Rs与高表达的高度扩增基因启动子以及体细胞单核苷酸变异体相关。G4R图谱的差异揭示了不同PDTX中的七个转录因子程序。G4R的丰度和位置将PDTX分为至少三种G4亚型。大多数PDTX（22个中的14个）中的G4R被发现与一种以上的乳腺癌亚型相关，研究人员也将其称为整合簇（IC）。

这表明PDTX模型中多种乳腺癌状态经常共存，其中大多数表现出侵袭性的三阴性IC10基因活性。高水平G4R PDTX模型的短期培养对靶向G4 DNA的小分子更敏感。因此，G4图谱揭示了PDTX活检中其他与IC相关的肿瘤内异质性，改善了乳腺癌分层，并可能建立新的治疗策略。

据悉，由于肿瘤间和肿瘤内异质性，对抗癌疗法的反应和耐药性会有所不同。

附：英文原文

Title: Landscape of G-quadruplex DNA structural regions in breast cancer

Author: Robert Hnsel-Hertsch, Angela Simeone, Abigail Shea, Winnie W. I. Hui, Katherine G. Zyner, Giovanni Marsico, Oscar M. Rueda, Alejandra Bruna, Alistair Martin, Xiaoyun Zhang, Santosh Adhikari, David Tannahill, Carlos Caldas, Shankar Balasubramanian

Issue&Volume: 2020-08-03

Abstract: Response and resistance to anticancer therapies vary due to intertumor and intratumor heterogeneity1. Here, we map differentially enriched G-quadruplex (G4) DNA structure-forming regions (G4Rs) in 22 breast cancer patient-derived tumor xenograft (PDTX) models. G4Rs are associated with the promoters of highly amplified genes showing high expression, and with somatic single-nucleotide variants. Differences in ΔG4R landscapes reveal seven transcription factor programs across PDTXs. G4R abundance and locations stratify PDTXs into at least three G4-based subtypes. G4Rs in most PDTXs (14 of 22) were found to associate with more than one breast cancer subtype, which we also call an integrative cluster (IC)2. This suggests the frequent coexistence of multiple breast cancer states within a PDTX model, the majority of which display aggressive triple-negative IC10 gene activity. Short-term cultures of PDTX models with increased G4R levels are more sensitive to small molecules targeting G4 DNA. Thus, G4 landscapes reveal additional IC-related intratumor heterogeneity in PDTX biopsies, improving breast cancer stratification and potentially identifying new treatment strategies.

DOI: 10.1038/s41588-020-0672-8

Source: https://www.nature.com/articles/s41588-020-0672-8

期刊信息

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：25.455
官方网址：https://www.nature.com/ng/
投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex