Genomic landscape of DNA repair genes in cancer: Mutation and copy number variation (CNV) frequencies.

281 Background: Cell-free DNA (cfDNA) present in the plasma of advanced cancer patients can reflect tumor related genetic alterations. Recent data suggests copy number variations (CNVs) in AR-associated and DNA repair pathway genes play a potential role in prostate cancer progression. Here, we performed sequencing of cfDNA from 13 mCRPC patients to evaluate its potential in elucidating tumor related genetic variations. The long-term goal of our project is to correlate cfDNA derived genetic alterations with prostate cancer progression and/or therapeutic resistance/responses. Methods: cfDNA was isolated from 13 advanced mCRPC patient plasma samples using the Qiagen circulating nucleic acid kit. 100ng of cfDNA was utilized for library construction; and the libraries were paired-end sequenced on the Illumina HiSeq 2000. The resulting data was analyzed using the GATK best practices bioinformatics pipeline and the visualized using the SNP & Variation Suite v8.x. Results: The bioanalyzer profiles of cfDNA derived from mCRPC patients is highly fragmented with an average fragment size of 306-605bp. Although, several CNVs were found across the genome, we focused analysis on CNVs related to AR associated and DNA repair genes. Our preliminary analysis of cfDNA, despite low sequencing depth, shows full or partial amplifications in AR (13/13), and other genes including FOXA1, NCOR1, NCOR2 and/or PIK3CA (7/13) and NCOR2 (10/13). For DNA repair genes partial/full amplifications were present in BRAC1, BRAC2, ATM, CDK12, MLH1 and/or MSH2 (7/13). Deletions are less reliably detected in the highly fragmented cfDNA. The majority of these CNVs have been reported in the WGS studies from metastatic CRPC tissue derived genomic DNA (cBioPortal). We are currently validating cfDNA genomic alterations by comparing it to germ line DNA derived via qPCR. Conclusions: Our preliminary study indicates that AR and DNA repair related genetic alterations could be found in the cfDNA derived from metastatic CRPC patients. This warrants more detailed examination of these cfDNA genetic alterations for identifying clinically relevant issues in mCRPC patients.

Download Full-text

Transcriptomics & copy number variation of radiotoxicity points to altered mitochondrial and DNA repair mechanisms

10.21203/rs.3.rs-24270/v1 ◽

2020 ◽

Author(s):

Gita A Pathak ◽

Renato Polimanti ◽

Talisa K Silzer ◽

Frank R Wendt ◽

Ranajit Chakraborty ◽

...

Keyword(s):

Gene Expression ◽

Dna Repair ◽

Copy Number Variation ◽

Whole Blood ◽

Copy Number ◽

Radiation Treatment ◽

Snp Array ◽

Prostate Tissue ◽

Repair Mechanisms ◽

Number Variation

Abstract Proctitis is an inflammation of the rectum and may be induced by radiation treatment for cancer. We investigated proctitis as a radiotoxic endpoint in prostate cancer patients who received radiotherapy (n=222). We analyzed the copy number variation and SNP-derived transcriptomic profiles of whole-blood and prostate tissue associated with proctitis. The SNP and copy number data were genotyped on Affymetrix® Genome-wide Human SNP Array 6.0. Following QC measures, the genotypes were used to obtain gene expression by leveraging GTEx, a reference dataset for gene expression association based on genotype and RNA-seq information for prostate (n= 132) and whole-blood tissue (n=369). In prostate tissue, 62 genes were significantly associated with proctitis, and 98 genes in whole-blood tissue. Six genes - CABLES2, ATP6AP1L, IFIT5, ATRIP, TELO2 , and PARD6G were common to both tissues. The copy number analysis identified seven regions associated with proctitis, one of which ( ALG1L2) was also associated with proctitis based on transcriptomic profiles in the whole-blood tissue. The genes identified via transcriptomics and copy number variation association were further investigated for enriched pathways and gene ontology. Some of the enriched processes were DNA repair, mitochondrial apoptosis regulation, cell-to-cell signaling interaction processes for renal and urological system, and organismal injury.

Download Full-text

Decision letter: A network of epigenetic modifiers and DNA repair genes controls tissue-specific copy number alteration preference

10.7554/elife.16519.032 ◽

2016 ◽

Keyword(s):

Dna Repair ◽

Copy Number ◽

Copy Number Alteration ◽

Dna Repair Genes ◽

Tissue Specific ◽

Epigenetic Modifiers ◽

Repair Genes

Download Full-text

Genomic landscape of copy number variation and copy neutral loss of heterozygosity events in equine sarcoids reveals increased instability of the sarcoid genome

Biochimie ◽

10.1016/j.biochi.2017.07.006 ◽

2017 ◽

Vol 140 ◽

pp. 122-132 ◽

Cited By ~ 2

Author(s):

Klaudia Pawlina-Tyszko ◽

Artur Gurgul ◽

Tomasz Szmatoła ◽

Katarzyna Ropka-Molik ◽

Ewelina Semik-Gurgul ◽

...

Keyword(s):

Copy Number Variation ◽

Loss Of Heterozygosity ◽

Copy Number ◽

Neutral Loss ◽

Genomic Landscape ◽

Number Variation

Download Full-text

Genetically-regulated transcriptomics & copy number variation of proctitis points to altered mitochondrial and DNA repair mechanisms in individuals of European ancestry

10.21203/rs.3.rs-24270/v2 ◽

2020 ◽

Author(s):

Gita A Pathak ◽

Renato Polimanti ◽

Talisa K Silzer ◽

Frank R Wendt ◽

Ranajit Chakraborty ◽

...

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

Dna Repair ◽

Copy Number Variation ◽

Whole Blood ◽

Genetic Variants ◽

Copy Number ◽

Prostate Tissue ◽

Number Variation ◽

Regulated Gene Expression

Abstract BACKGROUND: Proctitis is an inflammation of the rectum and may be induced by radiation treatment for cancer. The genetic heritability of developing radiotoxicity and prior role of genetic variants as being associated with side-effects of radiotherapy necessitates further investigation for underlying molecular mechanisms. In this study, we investigated gene expression regulated by genetic variants, and copy number variation in prostate cancer survivors with radiotoxicity.METHODS: We investigated proctitis as a radiotoxic endpoint in prostate cancer patients who received radiotherapy (n=222). We analyzed the copy number variation and genetically regulated gene expression profiles of whole-blood and prostate tissue associated with proctitis. The SNP and copy number data were genotyped on Affymetrix® Genome-wide Human SNP Array 6.0. Following QC measures, the genotypes were used to obtain gene expression by leveraging GTEx, a reference dataset for gene expression association based on genotype and RNA-seq information for prostate (n= 132) and whole-blood tissue (n=369). RESULTS: In prostate tissue, 62 genes were significantly associated with proctitis, and 98 genes in whole-blood tissue. Six genes - CABLES2, ATP6AP1L, IFIT5, ATRIP, TELO2, and PARD6G were common to both tissues. The copy number analysis identified seven regions associated with proctitis, one of which (ALG1L2) was also associated with proctitis based on transcriptomic profiles in the whole-blood tissue. The genes identified via transcriptomics and copy number variation association were further investigated for enriched pathways and gene ontology. Some of the enriched processes were DNA repair, mitochondrial apoptosis regulation, cell-to-cell signaling interaction processes for renal and urological system, and organismal injury.CONCLUSIONS: We report gene expression changes based on genetic polymorphisms. Integrating gene-network information identified these genes to relate to canonical DNA repair genes and processes. This investigation highlights genes involved in DNA repair processes and mitochondrial malfunction possibly via inflammation. Therefore, it is suggested that larger studies will provide more power to infer the extent of underlying genetic contribution for an individual’s susceptibility to developing radiotoxicity.

Download Full-text