Abstract
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. 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. 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). 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.
Highlights
The presence of intrinsic radiosensitivity within prostate cancer patients may be an important factor contributing to development of radiation toxicity
Across 41 patients, 239 sites were shown to differ from the human genome reference sequence and 170 of these corresponded to known variants listed in dbSNP.7
Variants within exon splicing sites were rare and only a single variant fell within fell within 2 bp of an annotated exon end, a novel intronic MRE11A variant located at chr11:93,866,690 in a single heterozygous low toxicity individual
Summary
The presence of intrinsic radiosensitivity within prostate cancer patients may be an important factor contributing to development of radiation toxicity. In an expanded search for variants predictive of radiosensitivity, we sequenced the coding and flanking intronic regions of eight DNA repair genes, including ATM, in 41 prostate brachytherapy patients. Through this in-depth survey, genetic variants in three DNA repair genes were identified that may be able to predict late side effects of radiation treatment.Validation of such variants in larger patient populations may lead to prognostic tests to identify radiosensitive cancer patients before treatment. The clinical course of these patients could be altered to consider their treatment with nonradiation therapies
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