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DNA Replication Stress Generates Distinctive landscapes of DNA copy number alterations and chromosome scale losses

ABSTRACT: DNA Replication Stress Generates Distinctive landscapes of DNA copy number alterations and chromosome scale losses

PROVIDER: PRJNA713395 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13931500.fastq.gz	Fastqsanger.gz
	SRR13931501.fastq.gz	Fastqsanger.gz
	SRR13931490.fastq.gz	Fastqsanger.gz
	SRR13931491.fastq.gz	Fastqsanger.gz
	SRR13931492.fastq.gz	Fastqsanger.gz

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Project description:Multiple myeloma (MM) remains incurable despite the introduction of novel agents and a relapsing course is observed in the majority of patients. Although the development of genomic technologies has greatly improved our understanding of MM pathogenesis, the mechanisms underlying relapse have been less investigated. In this study, an integrative analysis of DNA copy number, DNA methylation and gene expression was conducted in matched diagnosis and relapse samples from 17 MM patients. Overall, the acquisition of abnormalities at relapse was much more frequent than the lost of lesions present at diagnosis, and DNA losses were significantly more frequent at relapse than in diagnosis samples. Interestingly, copy number abnormalities involving more than 100 Mb of DNA at relapse significantly impact the gene expression of these samples, provoking a particular deregulation of IL-8 pathway. On the contrary, no relevant modifications of gene expression were observed in those samples with less than 100 Mb affected by chromosomal changes. Although different statistical approaches were used to uncover genes whose abnormal expression at relapse was regulated by DNA methylation, only two genes significantly deregulated in relapse samples (SORL1 and GLT1D1) showed a negative methylation-expression correlation. A deeper analysis demonstrated that DNA methylation was involved in regulation of SORL1 expression in MM. Finally, relevant changes in gene expression observed in relapse samples, such us downregulation of CD27 and P2RY8, were not apparently preceded by alterations in corresponding DNA. Taken together, these results showed that genomic heterogeneity, both at the DNA and RNA level, is a hallmark of MM transition from diagnosis to relapse. Please note that an a first step all analyses were carried out independently in each series, being the number of samples of 40 in methylation, 38 in SNP and 34 in expression series. In the next step, association studies were performed only in the overlapping samples, being 34 matching samples between expression and methylation and 32 samples between expression and SNP data.

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DNA Replication Stress Generates Distinctive landscapes of DNA copy number alterations and chromosome scale losses

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