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2017 ; 8
(ä): 56-65
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Signatures derived from increase in SHARPIN gene copy number are associated with
poor prognosis in patients with breast cancer
#MMPMID28879097
Ojo D
; Seliman M
; Tang D
BBA Clin
2017[Dec]; 8
(ä): 56-65
PMID28879097
show ga
We report three signatures produced from SHARPIN gene copy number increase
(GCN-Increase) and their effects on patients with breast cancer (BC). In the
Metabric dataset (n = 2059, cBioPortal), SHARPIN GCN-Increase occurs
preferentially or mutual exclusively with mutations in TP53, PIK3CA, and CDH1.
These genomic alterations constitute a signature (SigMut) that significantly
correlates with reductions in overall survival (OS) in BC patients (n = 1980;
p = 1.081e - 6). Additionally, SHARPIN GCN-Increase is associated with 4220
differentially expressed genes (DEGs). These DEGs are enriched in activation of
the pathways regulating cell cycle progression, RNA transport, ribosome
biosynthesis, DNA replication, and in downregulation of the pathways related to
extracellular matrix. These DEGs are thus likely to facilitate the proliferation
and metastasis of BC cells. Additionally, through forward (FWD) and backward
(BWD) stepwise variate selections among the top 160 downregulated and top 200
upregulated DEGs using the Cox regression model, a 6-gene (SigFWD) and a 50-gene
(SigBWD) signature were derived. Both signatures robustly associate with
decreases in OS in BC patients within the Curtis (n = 1980; p = 6.16e - 11 for
SigFWD; p = 1.06e - 10, for SigBWD) and TCGA cohort (n = 817; p = 4.53e - 4 for
SigFWD and p = 0.00525 for SigBWD). After adjusting for known clinical factors,
SigMut (HR 1.21, p = 0.0297), SigBWD (HR 1.25, p = 0.0263), and likely SigFWD (HR
1.17, p = 0.062) remain independent risk factors of BC deaths. Furthermore, the
proportion of patients positive for these signatures is significantly increased
in ER -, Her2-enriched, basal-like, and claudin-low BCs compared to ER + and
luminal BCs. Collectively, these SHARPIN GCN-Increase-derived signatures may have
clinical applications in management of patients with BC.