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CNV Identification: Prostate Cancer (PCa) vs Benign Prostatic Hyperplasia (BPH) Human DNA Samples

ABSTRACT: Copy number variations (CNVs) in the human genome have been linked to various carcinomas including prostate cancer (PCa). This study was conducted to identify CNVs in high grade PCa. We performed a pilot genome-wide CNV analysis in 36 subjects (18 high grade PCa and 18 benign prostatic hyperplasia) using array comparative genomic hybridization (aCGH) technique. Array results were validated using PCR-based copy number counting method. A total of 339 CNV regions were found to be unique to PCa subjects in this cohort (P < 0.05). Data segregation and filtering revealed six putative CNV loci associated with susceptibility to PCa. Of these, four were rare (1q21.3, 15q15, 3q27.2 and 7p12.1) and one was a novel copy number gain (12q23.1), harbouring genes such as the ARNT, THBS1, SLC5A8 and DDC which are crucial in the p53 and cancer pathways. Another CNV was a loss at 8p11.21 which contains the SFRP1 gene from the Wnt signalling pathway, known for its interaction with androgen receptors as reported for urological malignancy. Cross comparison analysis with genes already known to be associated with PCa revealed significant CNVs involved in crucial biological processes that elicit cancer pathogenesis via cytokine production, disease progression through endothelial cell proliferation and xenobiotic metabolism. In conclusion, these findings suggest that the CNV regions identified could provide an insight into the development of high grade PCa.

ORGANISM(S): Homo sapiens

PROVIDER: GSE79402 | GEO | 2018/12/18

REPOSITORIES: GEO

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Project description:Copy number variants (CNVs) reshape gene structure, modulate gene expression, and contribute to significant phenotypic variation. Previous studies have revealed CNV patterns in natural populations of Drosophila melanogaster and suggested that selection and mutational bias shape genomic patterns of CNV. While previous CNV studies focused on heterogeneous strains, here we established a number of second-chromosome substitution lines to uncover CNV characteristics when homozygous. The percentage of genes harboring CNVs is higher than found in previous studies. More CNVs are detected in homozygous than heterozygous substitution strains, suggesting the comparative genomic hybridization arrays underestimate CNV owing to heterozygous masking. We incorporated previous gene expression data collected from some of the same substitution lines to investigate relationships between CNV gene dosage and expression. Most genes present in CNVs show no evidence of increased or diminished transcription, and the fraction of such dosage-insensitive CNVs is greater in heterozygotes. More than 70% of the dosage-sensitive CNVs are recessive with undetectable effects on transcription in heterozygotes. A deficiency of singletons in recessive dosage-sensitive CNVs supports the hypothesis that most CNVs are subject to negative selection. On the other hand, relaxed purifying selection might account for the higher number of protein-protein interactions in dosage insensitive CNVs than in dosage-sensitive CNVs. Dosage-sensitive CNVs that are up-regulated and down-regulated coincide with copy number increases and decreases. Our results help clarify the relation between CNV dosage and gene expression in the D. melanogaster genome. To determine copy number variation, the genomic DNA from five homozygous and two heterozygous second chromosome substitution lines were extracted and compared to another second chromosome substitution line. Gene expression levels can be referred to at Series GSE12191 (Lemos et al. (2008) PMID:18791071).

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CNV Identification: Prostate Cancer (PCa) vs Benign Prostatic Hyperplasia (BPH) Human DNA Samples

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