Montes de Oca Rocío, Gurard-Levin Zachary A, Berger Frédérique, Rehman Haniya, Martel Elise, Corpet Armelle, de Koning Leanne, Vassias Isabelle, Wilson Laurence O W, Meseure Didier, Reyal Fabien, Savignoni Alexia, Asselain Bernard, Sastre-Garau Xavier, Almouzni Geneviève
Institut Curie, Centre de Recherche, Paris F-75248, France; CNRS, UMR3664, Paris F-75248, France; Equipe Labellisée Ligue contre le Cancer, UMR3664, Paris F-75248, France; UPMC, UMR3664, Paris F-75248, France; Sorbonne University, PSL*, France.
Sorbonne University, PSL*, France; Institut Curie, U900, Paris F-75248, France; INSERM, U900, Mines Paris-Tech, Paris F-75248, France; Institut Curie, Department of Biostatistics, Paris F-75248, France.
Mol Oncol. 2015 Mar;9(3):657-74. doi: 10.1016/j.molonc.2014.11.002. Epub 2014 Nov 20.
Breast cancer is a heterogeneous disease with different molecular subtypes that have varying responses to therapy. An ongoing challenge in breast cancer research is to distinguish high-risk patients from good prognosis patients. This is particularly difficult in the low-grade, ER-positive luminal A tumors, where robust diagnostic tools to aid clinical treatment decisions are lacking. Recent data implicating chromatin regulators in cancer initiation and progression offers a promising avenue to develop new tools to help guide clinical decisions.
Here we exploit a published transcriptome dataset and an independent validation cohort to correlate the mRNA expression of selected chromatin regulators with respect to the four intrinsic breast cancer molecular subtypes. We then perform univariate and multivariate analyses to compare the prognostic value of a panel of chromatin regulators to Ki67, a currently utilized proliferation marker.
Unsupervised hierarchical clustering revealed a gene cluster containing several histone chaperones and histone variants highly-expressed in the proliferative subtypes (basal-like, HER2-positive, luminal B) but not in the luminal A subtype. Several chromatin regulators, including the histone chaperones CAF-1 (subunits p150 and p60), ASF1b, and HJURP, and the centromeric histone variant CENP-A, associated with local and metastatic relapse and poor patient outcome. Importantly, we find that HJURP can discriminate favorable and unfavorable outcome within the luminal A subtype, outperforming the currently utilized proliferation marker Ki67, as an independent prognostic marker for luminal A patients.
The integration of chromatin regulators as clinical biomarkers, in particular the histone chaperone HJURP, will help guide patient substratification and treatment options for low-risk luminal A breast carcinoma patients.
乳腺癌是一种异质性疾病，具有不同的分子亚型，对治疗的反应各异。乳腺癌研究中一个持续存在的挑战是区分高危患者和预后良好的患者。在低级别、雌激素受体阳性的管腔A型肿瘤中，这尤其困难，因为缺乏有助于临床治疗决策的强大诊断工具。最近有关染色质调节因子参与癌症发生和发展的数据为开发有助于指导临床决策的新工具提供了一条有前景的途径。
在此，我们利用一个已发表的转录组数据集和一个独立的验证队列，将所选染色质调节因子的mRNA表达与四种内在型乳腺癌分子亚型进行关联。然后我们进行单变量和多变量分析，以比较一组染色质调节因子与Ki67（一种目前使用的增殖标志物）的预后价值。
无监督层次聚类揭示了一个基因簇，其中包含几个在增殖性亚型（基底样、HER2阳性、管腔B型）中高表达但在管腔A型中不表达的组蛋白伴侣和组蛋白变体。几种染色质调节因子，包括组蛋白伴侣CAF-1（亚基p150和p60）、ASF1b和HJURP，以及着丝粒组蛋白变体CENP-A，与局部和远处复发及患者预后不良相关。重要的是，我们发现HJURP可以区分管腔A型内的良好和不良预后，作为管腔A型患者的独立预后标志物，其表现优于目前使用的增殖标志物Ki67。
将染色质调节因子整合为临床生物标志物，特别是组蛋白伴侣HJURP，将有助于指导低风险管腔A型乳腺癌患者的分层和治疗选择。
