Single nucleotide polymorphisms in DNA repair genes as risk factors associated to prostate cancer progression

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.

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EP-1824: Quality of life of prostate cancer patients is influenced by single nucleotide polymorphisms in DNA repair genes

Radiotherapy and Oncology ◽

10.1016/s0167-8140(15)31942-3 ◽

2014 ◽

Vol 111 ◽

pp. S298

Author(s):

L. Henríquez Hernández ◽

A. Riveros-Pérez ◽

A. Valenciano ◽

J.I. Rodríguez-Melcón ◽

M. Lloret ◽

...

Keyword(s):

Quality Of Life ◽

Prostate Cancer ◽

Dna Repair ◽

Single Nucleotide Polymorphisms ◽

Cancer Patients ◽

Dna Repair Genes ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Repair Genes

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Single Nucleotide Polymorphisms in DNA Repair Genes and Prostate Cancer Risk

Methods in Molecular Biology - Cancer Epidemiology ◽

10.1007/978-1-59745-416-2_18 ◽

2009 ◽

pp. 361-385 ◽

Cited By ~ 17

Author(s):

Jong Y. Park ◽

Yifan Huang ◽

Thomas A. Sellers

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Cancer Risk ◽

Single Nucleotide Polymorphisms ◽

Prostate Cancer Risk ◽

Dna Repair Genes ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Repair Genes

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Genetic Variants of DNA Repair Genes as Predictors of Radiation-Induced Subcutaneous Fibrosis in Oropharyngeal Carcinoma

Frontiers in Oncology ◽

10.3389/fonc.2021.652049 ◽

2021 ◽

Vol 11 ◽

Author(s):

Ankita Gupta ◽

Don Mathew ◽

Shabir Ahmad Bhat ◽

Sushmita Ghoshal ◽

Arnab Pal

Keyword(s):

Dna Repair ◽

Genetic Variants ◽

Oropharyngeal Carcinoma ◽

Dna Repair Genes ◽

Nucleotide Polymorphisms ◽

Radical Radiotherapy ◽

Single Nucleotide ◽

Radiation Induced ◽

Repair Genes ◽

Severe Fibrosis

PurposeTo investigate the impact of genetic variants of DNA repair and pro-fibrotic pathway genes on the severity of radiation-induced subcutaneous fibrosis in patients of oropharyngeal carcinoma treated with radical radiotherapy.Materials and MethodsPatients of newly diagnosed squamous cell carcinoma of oropharynx being treated with two-dimensional radical radiotherapy were enrolled in the study. Patients who had undergone surgery or were receiving concurrent chemotherapy were excluded. Patients were followed up at 6 weeks post completion of radiotherapy and every 3 months thereafter for a median of 16 months. Subcutaneous fibrosis was graded according to the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) grading system and the maximum grade was recorded over the length of the patient’s follow-up. Patients with severe fibrosis (≥G3), were compared to patients with minor (≤G2) fibrotic reactions. Eight single nucleotide polymorphisms of 7 DNA repair genes and 2 polymorphisms of a single pro-fibrotic pathway gene were analyzed by Polymerase Chain Reaction and Restriction Fragment Length Polymorphism and were correlated with the severity of subcutaneous fibrosis.Results179 patients were included in the analysis. Subcutaneous fibrosis was seen in 168 (93.9%) patients. 36 (20.1%) patients had severe (grade 3) fibrosis. On multivariate logistic regression analysis, Homozygous CC genotype of XRCC3 (722C>T, rs861539) (p=0.013*, OR 2.350, 95% CI 1.089-5.382), Homozygous AA genotype of ERCC4 Ex8 (1244G>A, rs1800067) (p=0.001**, OR 11.626, 95% CI 2.490-275.901) and Homozygous TT genotype of XRCC5 (1401G>T, rs828907) (p=0.020*, OR 2.188, 95% CI 1.652-7.334) were found to be predictive of severe subcutaneous fibrosis. On haplotype analysis, the cumulative risk of developing severe fibrosis was observed in patients carrying both haplotypes of variant Homozygous AA genotype of ERCC4 Ex8 (1244G>A, rs1800067) and Homozygous TT genotype of XRCC5 (1401 G>T, rs828907) (p=0.010*, OR 26.340, 95% CI 4.014-76.568).ConclusionWe demonstrated significant associations between single nucleotide polymorphisms of DNA repair genes and radiation-induced subcutaneous fibrosis in patients of oropharyngeal carcinoma treated with radiotherapy. We propose to incorporate these genetic markers into predictive models for identifying patients genetically predisposed to the development of radiation-induced fibrosis, thus guiding personalized treatment protocols.

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RAD51 and XRCC3 Polymorphisms Are Associated with Increased Risk of Prostate Cancer

Journal of Oncology ◽

10.1155/2019/2976373 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

Maria Nowacka-Zawisza ◽

Agata Raszkiewicz ◽

Tomasz Kwasiborski ◽

Ewa Forma ◽

Magdalena Bryś ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Strand Break ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Dna Double Strand Break ◽

Repair Efficiency ◽

Increased Risk ◽

Pcr Rflp ◽

Repair Genes

Genetic polymorphisms in DNA repair genes may affect DNA repair efficiency and may contribute to the risk of developing cancer. The aim of our study was to investigate single nucleotide polymorphisms (SNPs) in RAD51 (rs2619679, rs2928140, and rs5030789) and XRCC3 (rs1799796) involved in DNA double-strand break repair and their relationship to prostate cancer. The study group included 99 men diagnosed with prostate cancer and 205 cancer-free controls. SNP genotyping was performed using the PCR-RFLP method. A significant association was detected between RAD51 rs5030789 polymorphism and XRCC3 rs1799796 polymorphism and an increased risk of prostate cancer. Our results indicate that RAD51 and XRCC3 polymorphism may contribute to prostate cancer.

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Single nucleotide polymorphisms for DNA repair genes in breast cancer patients

Clinica Chimica Acta ◽

10.1016/j.cccn.2005.03.047 ◽

2005 ◽

Vol 359 (1-2) ◽

pp. 150-155 ◽

Cited By ~ 59

Author(s):

Lianping Zhang ◽

Zhenzhong Zhang ◽

Wenhai Yan

Keyword(s):

Breast Cancer ◽

Dna Repair ◽

Single Nucleotide Polymorphisms ◽

Cancer Patients ◽

Dna Repair Genes ◽

Nucleotide Polymorphisms ◽

Breast Cancer Patients ◽

Single Nucleotide ◽

Repair Genes

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Single nucleotide polymorphisms (SNPs) of hOGG1 and XRCC1 DNA repair genes and the risk of ovarian cancer in Polish women

Tumor Biology ◽

10.1007/s13277-015-3707-5 ◽

2015 ◽

Vol 36 (12) ◽

pp. 9457-9463 ◽

Cited By ~ 8

Author(s):

Magdalena M. Michalska ◽

Dariusz Samulak ◽

Hanna Romanowicz ◽

Jan Bieńkiewicz ◽

Maciej Sobkowski ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Repair ◽

Single Nucleotide Polymorphisms ◽

Dna Repair Genes ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Repair Genes

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Single Nucleotide Polymorphisms of RecQ1, RAD54L, and ATM Genes Are Associated With Reduced Survival of Pancreatic Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2005.04.4206 ◽

2006 ◽

Vol 24 (11) ◽

pp. 1720-1728 ◽

Cited By ~ 96

Author(s):

Donghui Li ◽

Marsha Frazier ◽

Douglas B. Evans ◽

Kenneth R. Hess ◽

Christopher H. Crane ◽

...

Keyword(s):

Pancreatic Cancer ◽

Overall Survival ◽

Dna Repair ◽

Single Nucleotide Polymorphisms ◽

Cox Regression ◽

Dna Repair Genes ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Clinical Prognosis ◽

Repair Genes

Purpose Our goal was to determine whether single nucleotide polymorphisms (SNPs) in DNA repair genes influence the clinical outcome of pancreatic cancer. Patients and Methods We evaluated 13 SNPs of eight DNA damage response and repair genes in 92 patients with potentially resectable pancreatic adenocarcinoma. All patients were treated with neoadjuvant concurrent gemcitabine and radiotherapy with or without a component of induction gemcitabine/cisplatin at The University of Texas M.D. Anderson Cancer Center (Houston, TX) from February 1999 to August 2004 and observed through August 2005. Response to the pretreatment was assessed by evaluating time to tumor progression and overall survival. Kaplan-Meier plot, log-rank test, and Cox regression were used to compare survival of patients according to genotype. Results The RecQ1 A159C, RAD54L C157T, XRCC1 R194W, and ATM T77C genotypes had a significant effect on the overall survival with log-rank P values of .001, .004, .001, and .02, respectively. A strong combined effect of the four genotypes was observed. Patients with none of the adverse genotypes had a mean survival time of 62.1 months, and those with one, two, or three or more at-risk alleles had median survival times of 27.5, 14.4, and 9.9 months, respectively (log-rank P < .001). There is a significant interaction between the RecQ1 gene and other genotypes. All four genes except XRCC1 remained as independent predictors of survival in multivariate Cox regression models adjusted for other clinical predictors. Conclusion These observations support the hypothesis that polymorphic variants of DNA repair genes affect clinical prognosis of patients with pancreatic cancer.

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