Shahad W Kattan1, Yahya H Hobani2, Sameerah Shaheen3, Sara H Mokhtar4, Mohammad H Hussein5, Eman A Toraih5,6, Manal S Fawzy7,8, Hussein Abdelaziz Abdalla9,10. 1. Department of Medical Laboratory, College of Applied Medical Sciences, Taibah University, Yanbu, Saudi Arabia. 2. Department of Medical Laboratory Technology, College of Applied Medical Sciences, Jazan University, Jazan, Kingdom of Saudi Arabia. 3. Anatomy Department and Stem Cell Unit, College of Medicine, King Saud University, Riyadh, Saudi Arabia. 4. Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia. 5. Department of Surgery, Tulane University, School of Medicine, New Orleans, LA, USA. 6. Genetics Unit, Department of Histology and Cell Biology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt. 7. Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt. manal2_khashana@ymail.com. 8. Department of Biochemistry, College of Medicine, Northern Border University, Arar, Saudi Arabia. manal2_khashana@ymail.com. 9. Department of Medical Biochemistry, Faculty of Medicine, Taibah University, Medina, Saudi Arabia. 10. Department of Medical Biochemistry, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
Abstract
BACKGROUND: The expression signature of deregulated long non-coding RNAs (lncRNAs) and related genetic variants is implicated in every stage of tumorigenesis, progression, and recurrence. This study aimed to explore the association of lncRNA cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1) gene expression and the rs2383207A>G intronic variant with breast cancer (BC) risk and prognosis and to verify the molecular role and networks of this lncRNA in BC by bioinformatics gene analysis. METHODS: Serum CDKN2B-AS1 relative expression and rs2383207 genotypes were determined in 214 unrelated women (104 primary BC and 110 controls) using real-time PCR. Sixteen BC studies from The Cancer Genome Atlas (TCGA) including 8925 patients were also retrieved for validation of results. RESULTS: CDKN2B-AS1 serum levels were upregulated in the BC patients relative to controls. A/A genotype carriers were three times more likely to develop BC under homozygous (OR = 3.27, 95% CI 1.20-8.88, P = 0.044) and recessive (OR = 3.17, 95% CI 1.20-8.34, P = 0.013) models. G/G homozygous patients had a higher expression level [median and quartile values were 3.14 (1.52-4.25)] than A/G [1.42 (0.93-2.35)] and A/A [1.62 (1.33-2.51)] cohorts (P = 0.006). The Kaplan-Meier curve also revealed a higher mean survival duration of G/G cohorts (20.6 months) compared to their counterparts (A/A: 15.8 and A/G: 17.2 months) (P < 0.001). Consistently, BC data sets revealed better survival in cohorts with high expression levels (P = 0.003). Principal component analysis (PCA) showed a deviation of patients who had shorter survival towards A/A and A/G genotypes, multiple lesions, advanced stage, lymphovascular invasion, and HER2+ receptor staining. Ingenuity Pathway Analysis (IPA) showed key genes highly enriched in BC with CDKN2B-AS1. CONCLUSIONS: The findings support the putative role of CDKN2B-AS1 as an epigenetic marker in BC and open a new avenue for its potential use as a therapeutic molecular target in this type of cancer.
BACKGROUND: The expression signature of deregulated long non-coding RNAs (lncRNAs) and related genetic variants is implicated in every stage of tumorigenesis, progression, and recurrence. This study aimed to explore the association of lncRNA cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1) gene expression and the rs2383207A>G intronic variant with breast cancer (BC) risk and prognosis and to verify the molecular role and networks of this lncRNA in BC by bioinformatics gene analysis. METHODS: Serum CDKN2B-AS1 relative expression and rs2383207 genotypes were determined in 214 unrelated women (104 primary BC and 110 controls) using real-time PCR. Sixteen BC studies from The Cancer Genome Atlas (TCGA) including 8925 patients were also retrieved for validation of results. RESULTS:CDKN2B-AS1 serum levels were upregulated in the BC patients relative to controls. A/A genotype carriers were three times more likely to develop BC under homozygous (OR = 3.27, 95% CI 1.20-8.88, P = 0.044) and recessive (OR = 3.17, 95% CI 1.20-8.34, P = 0.013) models. G/G homozygous patients had a higher expression level [median and quartile values were 3.14 (1.52-4.25)] than A/G [1.42 (0.93-2.35)] and A/A [1.62 (1.33-2.51)] cohorts (P = 0.006). The Kaplan-Meier curve also revealed a higher mean survival duration of G/G cohorts (20.6 months) compared to their counterparts (A/A: 15.8 and A/G: 17.2 months) (P < 0.001). Consistently, BC data sets revealed better survival in cohorts with high expression levels (P = 0.003). Principal component analysis (PCA) showed a deviation of patients who had shorter survival towards A/A and A/G genotypes, multiple lesions, advanced stage, lymphovascular invasion, and HER2+ receptor staining. Ingenuity Pathway Analysis (IPA) showed key genes highly enriched in BC with CDKN2B-AS1. CONCLUSIONS: The findings support the putative role of CDKN2B-AS1 as an epigenetic marker in BC and open a new avenue for its potential use as a therapeutic molecular target in this type of cancer.
Entities:
Keywords:
Breast cancer; CDKN2B-AS1; Gene expression; Long non-coding RNA; Single nucleotide polymorphism; Survival
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