Abstract
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.
Highlights
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 (Rappoport and Shamir, 2018)
A total of 3,772 CNAcor genes and 2,118 METcor genes were identified by the R package “geneCor” (See Supplementary Table S1)
Available databases like TCGA, METABRIC, or GEO, which are common in the cancer research community, help better understand tumor heterogeneity, detect biomarker genes, and define hidden molecular mechanisms in multi-omics research (Xia Q. et al, 2019)
Summary
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 (Rappoport and Shamir, 2018). DNA copy number aberration (CNA) or mutations, resulting in genomic alteration, play vital roles in cancer occurrence and progression (Kim et al, 2018); DNA methylation (MET), resulting in epigenetic regulation of the. CNA profiling using CGH and SNP microarrays in prior studies has revealed hot spots of CNA in cancer genomes (Russnes et al, 2010; Huang et al, 2013; Endesfelder et al, 2014), such as, the frequent copy number gains have involved chromosomes 1q, 6q, 8q, 11q, 16q, 17q, 19, and 20q, whereas common deletion of copy number at 6q, 16q, 17p, and 22q in BRCA (Richard et al, 2000). Several oncogenes and tumor suppressor genes such as HER2 ( known as ERBB2), c-Myc, CCND1, and TP53 have been altered by CNA and exerted their key regulatory functions in both progression and prognosis of BRCA (Richard et al, 2000). Previous studies have found several mutated epigenetic genes, partaking in establishing and maintaining epigenetic patterns, such as MLL3 or MLL2 mutations in BRCA (Stephens et al, 2012), or a recurrent epigenetic inactivation of BRCA1 by epigenetic mechanisms in sporadic BRCA (Dobrovic and Simpfendorfer, 1997; Rice et al, 2000)
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