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Multi-Omics Analysis Detects Novel Prognostic Subgroups of Breast Cancer
Frontiers in Genetics ( IF 3.7 ) Pub Date : 2020-09-23 , DOI: 10.3389/fgene.2020.574661
Quang-Huy Nguyen , Hung Nguyen , Tin Nguyen , Duc-Hau Le

The unprecedented proliferation of recent large-scale and multi-omics databases of cancers has given us many new insights into genomic and epigenomic deregulation in cancer discovery in general. However, we wonder whether or not there exists a systematic connection between copy number aberrations (CNA) and methylation (MET)? If so, what is the role of this connection in breast cancer (BRCA) tumorigenesis and progression? At the same time, the PAM50 intrinsic subtypes of BRCA have gained the most attention from BRCA experts. However, this classification system manifests its weaknesses including low accuracy as well as a possible lack of association with biological phenotypes, and even further investigations on their clinical utility were still needed. In this study, we performed an integrative analysis of three-omics profiles, CNA, MET, and mRNA expression, in two BRCA patient cohorts (one for discovery and another for validation) – to elucidate those complicated relationships. To this purpose, we first established a set of CNAcor and METcor genes, which had CNA and MET levels significantly correlated (and anti-correlated) with their corresponding expression levels, respectively. Next, to revisit the current classification of BRCA, we performed single and integrated clustering analyses using our clustering method PINSPlus. We then discovered two biologically distinct subgroups that could be an improved and refined classification system for breast cancer patients, which can be validated by a third-party data. Further studies were then performed and realized each-subgroup-specific genes and different interactions between each of the two identified subgroups with the age factor. These findings can show promise as diagnostic and prognostic values in BRCA, and a potential alternative to the PAM50 intrinsic subtypes in the future.



中文翻译:

多组学分析可检测乳腺癌的新预后亚组

最近,大规模的癌症数据库和多组学数据库的空前普及,使我们对癌症发现中的基因组和表观基因组失调有了许多新见解。但是,我们想知道拷贝数像差(CNA)和甲基化(MET)之间是否存在系统的联系?如果是这样,这种联系在乳腺癌(BRCA)肿瘤发生和发展中的作用是什么?同时,BRCA的PAM50内在亚型引起了BRCA专家的最多关注。然而,该分类系统表现出其缺点,包括准确性低以及可能与生物表型缺乏关联,甚至仍需要对其临床实用性进行进一步研究。在这项研究中,我们对三组学概况CNA,MET,和两个BRCA患者队列中的mRNA表达(一个用于发现,另一个用于验证)–阐明了这些复杂的关系。为此,我们首先建立了一套CNAcor和METcor基因,它们的CNA和MET水平分别与它们各自的表达水平显着相关(和抗相关)。接下来,为了重新查看BRCA的当前分类,我们使用聚类方法PINSPlus进行了单个和集成的聚类分析。然后,我们发现了两个生物学上不同的亚组,它们可能是针对乳腺癌患者的改进和完善的分类系统,可以通过第三方数据进行验证。然后进行了进一步的研究,并实现了每个亚组特异性基因以及两个已鉴定亚组之间每个与年龄因子的不同相互作用。

更新日期:2020-10-16
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