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Genome-wide screen identifies a novel prognostic signature for breast cancer survival.

ABSTRACT: Large genomic datasets in combination with clinical data can be used as an unbiased tool to identify genes important in patient survival and discover potential therapeutic targets. We used a genome-wide screen to identify 587 genes significantly and robustly deregulated across four independent breast cancer (BC) datasets compared to normal breast tissue. Gene expression of 381 genes was significantly associated with relapse-free survival (RFS) in BC patients. We used a gene co-expression network approach to visualize the genetic architecture in normal breast and BCs. In normal breast tissue, co-expression cliques were identified enriched for cell cycle, gene transcription, cell adhesion, cytoskeletal organization and metabolism. In contrast, in BC, only two major co-expression cliques were identified enriched for cell cycle-related processes or blood vessel development, cell adhesion and mammary gland development processes. Interestingly, gene expression levels of 7 genes were found to be negatively correlated with many cell cycle related genes, highlighting these genes as potential tumor suppressors and novel therapeutic targets. A forward-conditional Cox regression analysis was used to identify a 12-gene signature associated with RFS. A prognostic scoring system was created based on the 12-gene signature. This scoring system robustly predicted BC patient RFS in 60 sampling test sets and was further validated in TCGA and METABRIC BC data. Our integrated study identified a 12-gene prognostic signature that could guide adjuvant therapy for BC patients and includes novel potential molecular targets for therapy.

SUBMITTER: Mao XY

PROVIDER: S-EPMC5355157 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Genome-wide screen identifies a novel prognostic signature for breast cancer survival.

Mao Xuan Y XY Lee Matthew J MJ Zhu Jeffrey J Zhu Carissa C Law Sindy M SM Snijders Antoine M AM

Oncotarget 20170201 8

Large genomic datasets in combination with clinical data can be used as an unbiased tool to identify genes important in patient survival and discover potential therapeutic targets. We used a genome-wide screen to identify 587 genes significantly and robustly deregulated across four independent breast cancer (BC) datasets compared to normal breast tissue. Gene expression of 381 genes was significantly associated with relapse-free survival (RFS) in BC patients. We used a gene co-expression network ...[more]

PMID: 28122328

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Project description:PurposeGastric cancer (GC) is a product of multiple genetic abnormalities, including genetic and epigenetic modifications. This study aimed to integrate various biomolecules, such as miRNAs, mRNA, and DNA methylation, into a genome-wide network and develop a nomogram for predicting the overall survival (OS) of GC.Materials and methodsA total of 329 GC cases, as a training cohort with a random of 150 examples included as a validation cohort, were screened from The Cancer Genome Atlas database. A genome-wide network was constructed based on a combination of univariate Cox regression and least absolute shrinkage and selection operator analyses, and a nomogram was established to predict 1-, 3-, and 5-year OS in the training cohort. The nomogram was then assessed in terms of calibration, discrimination, and clinical usefulness in the validation cohort. Afterward, in order to confirm the superiority of the whole gene network model and further reduce the biomarkers for the improvement of clinical usefulness, we also constructed eight other models according to the different combinations of miRNAs, mRNA, and DNA methylation sites and made corresponding comparisons. Finally, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were also performed to describe the function of this genome-wide network.ResultsA multivariate analysis revealed a novel prognostic factor, a genomics score (GS) comprising seven miRNAs, eight mRNA, and 19 DNA methylation sites. In the validation cohort, comparing to patients with low GS, high-GS patients (HR, 12.886; P < 0.001) were significantly associated with increased all-cause mortality. Furthermore, after stratification of the TNM stage (I, II, III, and IV), there were significant differences revealed in the survival rates between the high-GS and low-GS groups as well (P < 0.001). The 1-, 3-, and 5-year C-index of whole genomics-based nomogram were 0.868, 0.895, and 0.928, respectively. The other models have comparable or relatively poor comprehensive performance, while they had fewer biomarkers. Besides that, DAVID 6.8 further revealed multiple molecules and pathways related to the genome-wide network, such as cytomembranes, cell cycle, and adipocytokine signaling.ConclusionWe successfully developed a GS based on genome-wide network, which may represent a novel prognostic factor for GC. A combination of GS and TNM staging provides additional precision in stratifying patients with different OS prognoses, constituting a more comprehensive sub-typing system. This could potentially play an important role in future clinical practice.

Dataset Information

Genome-wide screen identifies a novel prognostic signature for breast cancer survival.

Publications

Genome-wide screen identifies a novel prognostic signature for breast cancer survival.

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