The ADPRT V762A genetic variant contributes to prostate cancer susceptibility and deficient enzyme function

Kristin L. Lockett, M. Craig Hall, Jianfeng Xu, S. Zheng, Marianne Berwick, Shu Chun Chuang, Peter E. Clark, Scott D. Cramer, Kurt Lohman, Jennifer Hu

Research output: Contribution to journalArticle

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Abstract

The ADP-ribosyltransferase (ADPRT) gene encodes a zinc-finger DNA-binding protein, poly(ADP-ribose) polymerase-1 (PARP-1), that modifies various nuclear proteins by poly(ADP-ribosyl)ation and functions as a key enzyme in the base excision repair pathway. We have conducted two studies to test whether an amino acid substitution variant, ADPRT V762A (T2444C), is associated with prostate cancer (CaP) risk and decreased enzyme function. The first study used genomic DNA samples from an ongoing, clinic-based case-control study (488 cases and 524 controls) to show that a higher percentage of the CaP cases carried the ADPRT 762 AA genotype than controls (4% versus 2%). In Caucasians, the AA genotype was significantly associated with increased CaP risk [odds ratio (OR), 2.65; 95% confidence interval (CI), 1.08-6.49], and the VA genotype was associated with a slight but not significantly increased CaP risk (OR, 1.18; 95% CI, 0.85-1.64) using VV as the referent group after adjustment for age, benign prostatic hyperplasia, and family history. Furthermore, this association was stronger in younger (<65) men (OR, 4.77; 95% CI, 1.01-22.44) than older (≥65) men (OR, 1.78; 95% CI, 0.55-5.82). The second study used freshly isolated peripheral lymphocytes from 354 cancer-free subjects to demonstrate that the ADPRT 762 A allele contributed to significantly lower adenosine diphosphate ribosyl transferase (ADPRT)/PARP-1 activities in response to H2O2 in a gene dosage-dependent manner (P < 0.0001, test for linear trend). The PARP-1 activities (mean ± SD dpm/106 cells) were 18,554 ± 9,070 (n = 257), 14,847 ± 7,082 (n = 86), and 12,155 ± 6,334 (n = 11) for VV, VA, and AA genotypes, respectively. This study is the first to provide evidence that the ADPRT V762A-genetic variant contributes to CaP susceptibility and altered ADPRT/PARP-1 enzyme function in response to oxidative damage.

Original languageEnglish
Pages (from-to)6344-6348
Number of pages5
JournalCancer Research
Volume64
Issue number17
DOIs
StatePublished - Sep 1 2004
Externally publishedYes

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ADP Ribose Transferases
Prostatic Neoplasms
Odds Ratio
Enzymes
Genotype
Confidence Intervals
Adenosine Diphosphate
Gene Dosage
Zinc Fingers
DNA-Binding Proteins
Prostatic Hyperplasia
Amino Acid Substitution
Transferases
Nuclear Proteins
DNA Repair
Case-Control Studies
Alleles
Lymphocytes
Poly (ADP-Ribose) Polymerase-1
DNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

The ADPRT V762A genetic variant contributes to prostate cancer susceptibility and deficient enzyme function. / Lockett, Kristin L.; Hall, M. Craig; Xu, Jianfeng; Zheng, S.; Berwick, Marianne; Chuang, Shu Chun; Clark, Peter E.; Cramer, Scott D.; Lohman, Kurt; Hu, Jennifer.

In: Cancer Research, Vol. 64, No. 17, 01.09.2004, p. 6344-6348.

Research output: Contribution to journalArticle

Lockett, KL, Hall, MC, Xu, J, Zheng, S, Berwick, M, Chuang, SC, Clark, PE, Cramer, SD, Lohman, K & Hu, J 2004, 'The ADPRT V762A genetic variant contributes to prostate cancer susceptibility and deficient enzyme function', Cancer Research, vol. 64, no. 17, pp. 6344-6348. https://doi.org/10.1158/0008-5472.CAN-04-0338
Lockett, Kristin L. ; Hall, M. Craig ; Xu, Jianfeng ; Zheng, S. ; Berwick, Marianne ; Chuang, Shu Chun ; Clark, Peter E. ; Cramer, Scott D. ; Lohman, Kurt ; Hu, Jennifer. / The ADPRT V762A genetic variant contributes to prostate cancer susceptibility and deficient enzyme function. In: Cancer Research. 2004 ; Vol. 64, No. 17. pp. 6344-6348.
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abstract = "The ADP-ribosyltransferase (ADPRT) gene encodes a zinc-finger DNA-binding protein, poly(ADP-ribose) polymerase-1 (PARP-1), that modifies various nuclear proteins by poly(ADP-ribosyl)ation and functions as a key enzyme in the base excision repair pathway. We have conducted two studies to test whether an amino acid substitution variant, ADPRT V762A (T2444C), is associated with prostate cancer (CaP) risk and decreased enzyme function. The first study used genomic DNA samples from an ongoing, clinic-based case-control study (488 cases and 524 controls) to show that a higher percentage of the CaP cases carried the ADPRT 762 AA genotype than controls (4{\%} versus 2{\%}). In Caucasians, the AA genotype was significantly associated with increased CaP risk [odds ratio (OR), 2.65; 95{\%} confidence interval (CI), 1.08-6.49], and the VA genotype was associated with a slight but not significantly increased CaP risk (OR, 1.18; 95{\%} CI, 0.85-1.64) using VV as the referent group after adjustment for age, benign prostatic hyperplasia, and family history. Furthermore, this association was stronger in younger (<65) men (OR, 4.77; 95{\%} CI, 1.01-22.44) than older (≥65) men (OR, 1.78; 95{\%} CI, 0.55-5.82). The second study used freshly isolated peripheral lymphocytes from 354 cancer-free subjects to demonstrate that the ADPRT 762 A allele contributed to significantly lower adenosine diphosphate ribosyl transferase (ADPRT)/PARP-1 activities in response to H2O2 in a gene dosage-dependent manner (P < 0.0001, test for linear trend). The PARP-1 activities (mean ± SD dpm/106 cells) were 18,554 ± 9,070 (n = 257), 14,847 ± 7,082 (n = 86), and 12,155 ± 6,334 (n = 11) for VV, VA, and AA genotypes, respectively. This study is the first to provide evidence that the ADPRT V762A-genetic variant contributes to CaP susceptibility and altered ADPRT/PARP-1 enzyme function in response to oxidative damage.",
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AU - Berwick, Marianne

AU - Chuang, Shu Chun

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N2 - The ADP-ribosyltransferase (ADPRT) gene encodes a zinc-finger DNA-binding protein, poly(ADP-ribose) polymerase-1 (PARP-1), that modifies various nuclear proteins by poly(ADP-ribosyl)ation and functions as a key enzyme in the base excision repair pathway. We have conducted two studies to test whether an amino acid substitution variant, ADPRT V762A (T2444C), is associated with prostate cancer (CaP) risk and decreased enzyme function. The first study used genomic DNA samples from an ongoing, clinic-based case-control study (488 cases and 524 controls) to show that a higher percentage of the CaP cases carried the ADPRT 762 AA genotype than controls (4% versus 2%). In Caucasians, the AA genotype was significantly associated with increased CaP risk [odds ratio (OR), 2.65; 95% confidence interval (CI), 1.08-6.49], and the VA genotype was associated with a slight but not significantly increased CaP risk (OR, 1.18; 95% CI, 0.85-1.64) using VV as the referent group after adjustment for age, benign prostatic hyperplasia, and family history. Furthermore, this association was stronger in younger (<65) men (OR, 4.77; 95% CI, 1.01-22.44) than older (≥65) men (OR, 1.78; 95% CI, 0.55-5.82). The second study used freshly isolated peripheral lymphocytes from 354 cancer-free subjects to demonstrate that the ADPRT 762 A allele contributed to significantly lower adenosine diphosphate ribosyl transferase (ADPRT)/PARP-1 activities in response to H2O2 in a gene dosage-dependent manner (P < 0.0001, test for linear trend). The PARP-1 activities (mean ± SD dpm/106 cells) were 18,554 ± 9,070 (n = 257), 14,847 ± 7,082 (n = 86), and 12,155 ± 6,334 (n = 11) for VV, VA, and AA genotypes, respectively. This study is the first to provide evidence that the ADPRT V762A-genetic variant contributes to CaP susceptibility and altered ADPRT/PARP-1 enzyme function in response to oxidative damage.

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