Sequence Variant Discovery in DNA Repair Genes from Radiosensitive and Radiotolerant Prostate Brachytherapy Patients

Sequence Variant Discovery in DNA Repair Genes from Radiosensitive and Radiotolerant Prostate Brachytherapy Patients

Purpose: The presence of intrinsic radiosensitivity within prostate cancer patients may be an important factor contributing to development of radiation toxicity. We investigated whether variants in genes responsible for detecting and repairing DNA damage independently contribute to toxicity followin...

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Bibliographic Details
Published in:Clinical cancer research Vol. 15; no. 15; pp. 5008 - 5016
Main Authors: PUGH, TrevorJ, KEYES, Mira, JIM MORRIS, W, OLIVE, Peggy L, MARRA, MarcoA, MOORE, Richard A, BARCLAY, Lorena, DELANEY, Allen, KRZYWINSKI, Martin, THOMAS, Dallas, NOVIK, Karen, YANG, Cindy, AGRANOVICH, Alexander, MCKENZIE, Michael
Format: Journal Article
Language:English
Published: Philadelphia, PA American Association for Cancer Research 01-08-2009
Subjects:
Antineoplastic agents
Biological and medical sciences
Brachytherapy - adverse effects
DNA Repair - genetics
DNA repair genes
Exons - genetics
Humans
Male
Medical sciences
Mutation, Missense
Pharmacology. Drug treatments
Polymorphism, Single Nucleotide
prostate brachytherapy
prostate cancer
Prostatic Neoplasms - genetics
Prostatic Neoplasms - radiotherapy
Radiation Tolerance - genetics
radiosensitivity
sequencing
toxicity
Human
Treatment
Genetic variability
DNA
Patient
Radiotherapy
Urogenital system
Curietherapy
Prostate
DNA repair
Repair gene
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Summary:Purpose: The presence of intrinsic radiosensitivity within prostate cancer patients may be an important factor contributing to development of radiation toxicity. We investigated whether variants in genes responsible for detecting and repairing DNA damage independently contribute to toxicity following prostate brachytherapy. Experimental Design: Genomic DNA was extracted from blood samples of 41 prostate brachytherapy patients, 21 with high and 20 with low late toxicity scores. For each patient, 242 PCR amplicons were generated containing 173 exons of eight candidate genes: ATM, BRCA1, ERCC2, H2AFX, LIG4, MDC1, MRE11A , and RAD50 . These amplicons were sequenced and all sequence variants were subjected to statistical analysis to identify those associated with late radiation toxicity. Results: Across 41 patients, 239 sites differed from the human genome reference sequence; 170 of these corresponded to known polymorphisms. Sixty variants, 14 of them novel, affected protein coding regions and 43 of these were missense mutations. In our patient population, the high toxicity group was enriched for individuals with at least one LIG4 coding variant ( P = 0.028). One synonymous variant in MDC1 , rs28986317, was associated with increased radiosensitivity ( P = 0.048). A missense variant in ATM , rs1800057, associated with increased prostate cancer risk, was found exclusively in two high toxicity patients but did not reach statistical significance for association with radiosensitivity ( P = 0.488). Conclusions: Our data revealed new germ-line sequence variants, indicating that existing sequence databases do not fully represent the full extent of sequence variation. Variants in three DNA repair genes were linked to increased radiosensitivity but require validation in larger populations.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-08-3357