Alvarez Carolina, Aravena Andrés, Tapia Teresa, Rozenblum Ester, Solís Luisa, Corvalán Alejandro, Camus Mauricio, Alvarez Manuel, Munroe David, Maass Alejandro, Carvallo Pilar
Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.
Mathomics, Center for Mathematical Modeling (UMI 2807 CNRS) and Center for Genome Regulation (Fondap 15090007), University of Chile, Santiago, Chile.
BMC Cancer. 2016 Mar 15;16:219. doi: 10.1186/s12885-016-2261-x.
Array CGH analysis of breast tumors has contributed to the identification of different genomic profiles in these tumors. Loss of DNA repair by BRCA1 functional deficiency in breast cancer has been proposed as a relevant contribution to breast cancer progression for tumors with no germline mutation. Identifying the genomic alterations taking place in BRCA1 not expressing tumors will lead us to a better understanding of the cellular functions affected in this heterogeneous disease. Moreover, specific genomic alterations may contribute to the identification of potential therapeutic targets and offer a more personalized treatment to breast cancer patients.
Forty seven tumors from hereditary breast cancer cases, previously analyzed for BRCA1 expression, and screened for germline BRCA1 and 2 mutations, were analyzed by Array based Comparative Genomic Hybridization (aCGH) using Agilent 4x44K arrays. Overall survival was established for tumors in different clusters using Log-rank (Mantel-Cox) Test. Gene lists obtained from aCGH analysis were analyzed for Gene Ontology enrichment using GOrilla and DAVID tools.
Genomic profiling of the tumors showed specific alterations associated to BRCA1 or 2 mutation status, and BRCA1 expression in the tumors, affecting relevant cellular processes. Similar cellular functions were found affected in BRCA1 not expressing and BRCA1 or 2 mutated tumors. Hierarchical clustering classified hereditary breast tumors in four major, groups according to the type and amount of genomic alterations, showing one group with a significantly poor overall survival (p = 0.0221). Within this cluster, deletion of PLEKHO1, GDF11, DARC, DAG1 and CD63 may be associated to the worse outcome of the patients.
These results support the fact that BRCA1 lack of expression in tumors should be used as a marker for BRCAness and to select these patients for synthetic lethality approaches such as treatment with PARP inhibitors. In addition, the identification of specific alterations in breast tumors associated with poor survival, immune response or with a BRCAness phenotype will allow the use of a more personalized treatment in these patients.
对乳腺肿瘤进行阵列比较基因组杂交（Array CGH）分析有助于识别这些肿瘤中不同的基因组图谱。对于无种系突变的肿瘤，乳腺癌中因BRCA1功能缺陷导致的DNA修复缺失被认为是乳腺癌进展的一个相关因素。识别BRCA1不表达肿瘤中发生的基因组改变将有助于我们更好地理解这种异质性疾病中受影响的细胞功能。此外，特定的基因组改变可能有助于识别潜在的治疗靶点，并为乳腺癌患者提供更个性化的治疗。
对47例遗传性乳腺癌病例的肿瘤进行分析，这些肿瘤先前已检测BRCA1表达，并筛查种系BRCA1和2突变，使用安捷伦4x44K阵列通过基于阵列的比较基因组杂交（aCGH）进行分析。使用对数秩（Mantel-Cox）检验确定不同聚类中肿瘤的总生存期。使用GOrilla和DAVID工具对从aCGH分析获得的基因列表进行基因本体富集分析。
肿瘤的基因组分析显示了与BRCA1或2突变状态以及肿瘤中BRCA1表达相关的特定改变，这些改变影响了相关的细胞过程。在BRCA1不表达和BRCA1或2突变的肿瘤中发现了相似的受影响细胞功能。层次聚类根据基因组改变的类型和数量将遗传性乳腺肿瘤分为四个主要组，其中一组的总生存期明显较差（p = 0.0221）。在这个聚类中，PLEKHO1、GDF11、DARC、DAG1和CD63的缺失可能与患者较差的预后相关。
这些结果支持以下事实，即肿瘤中BRCA1缺乏表达应用作BRCA样性的标志物，并选择这些患者采用合成致死方法，如使用PARP抑制剂进行治疗。此外，识别与生存不良、免疫反应或BRCA样性表型相关的乳腺肿瘤中的特定改变，将有助于对这些患者采用更个性化的治疗。
