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. Author manuscript; available in PMC: 2014 Sep 28.
Published in final edited form as: Cancer Lett. 2013 Apr 11;338(2):267–270. doi: 10.1016/j.canlet.2013.04.001

Pyrimidine Base Damage Is Increased in Women with BRCA Mutations

Edwin E Budzinski 1, Helen B Patrzyc 1, Jean B Dawidzik 1, Harold G Freund 1, Peter Frederick 2, Heidi E Godoy 2, Nicoleta C Voian 3, Kunle Odunsi 2, Harold C Box 1
PMCID: PMC3750071  NIHMSID: NIHMS477265  PMID: 23583677

Abstract

Oxidatively-induced DNA damage was measured in the DNA of WBC from two groups of women: carriers of a BRCA mutation, but asymptomatic for disease, and healthy controls. Two oxidatively induced lesions were measured: a formamide remnant of pyrimidine base and the glycol modification of thymine. These lesions, employed previously in studies of the effects of smoking, antioxidant usage and ovarian cancer, are proving valuable indicators of oxidative stress. The BRCA carriers of mutations, with no overt sign of cancer, nevertheless had significantly higher levels of DNA damage than the controls. The level measured for the formamide lesion was 5.9 ± 1.0 (femtomoles/μg of DNA ± SEM) compared with 2.4 ± 0.3 in controls. The level of the glycol lesion was 2.9 ± 0.4 compared with 1.8 ± 0.2 in controls. The experimental design utilized DNA from WBC and employed LC-MS/MS to detect the lesions.

1. INTRODUCTION

There are persistent reports that oxidatively induced DNA damage is significantly higher in cancer patients compared with healthy controls. The base modification 8-oxo-7,8-dihydroguanine, a biomarker for oxidative stress, was found to be elevated in the DNA of WBC from patients with cancer at a variety of sites: lung [1,2], lymphocytic leukemia [3], colorectum [4], bladder [5], breast [6] and esophagus [7]. Somewhat disconcerting, mean values from healthy controls reported by these various laboratories varied by more than two orders of magnitude. Moreover, all of the reported control values exceeded the maximum value (4.3 dGh/106dG) considered credible by the European Standards Committee for Oxidative DNA Damage [8]. Higher values are presumed caused mainly by inadvertent oxidation of guanine during the preparation of the DNA sample. A variety of mechanisms may generate 8-oxo-7,8-dihydroguanine including hydroxyl radical reactions, one-electron oxidations and singlet oxygen reactions [9]. Concerns over inadvertent loss of 8-oxo-7,8-dihydroguanine, which has an even lower redox potential than guanine, contribute to the uncertainty of 8-oxy-7,8-dihydroguanine measurements [10,11]. Pyrimidine bases, on the other hand, have a higher redox potential than purines and are less prone to artifactual oxidation [12].

The problems associated with measurements of oxidative damage can largely be avoided using a different biomarker for oxidative stress. We previously proposed two pyrimidine oxidation products as preferable biomarkers of oxidative stress, namely a glycol modification of thymine and a formamido remnant of the pyrimidine bases. The lesions are shown in Fig. 1 in the dimer form in which they were measured. The assay has been applied in a study of women with ovarian cancer [13]. These lesions, derived from the DNA of WBC of women with ovarian cancer, were found to have significantly higher levels compared with controls.

Fig. 1.

Fig. 1

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The formamide and thymine glycol lesions shown incorporated in dinucleoside monophosphates, the form in which they are actually measured.

The variety of risk factors associated with higher levels of the formamide and thymine glycol biomarkers continues to grow. In addition to demonstrating higher levels of oxidative DNA damage in women with ovarian cancer, it has been shown that former smokers have a lower level of these lesions after quitting [14]. Also, antioxidant users were shown to have significantly lower levels of formamide and thymine glycol damage than non-users [15]. Furthermore, antioxidants further reduced DNA damage in former smokers independently of the decrease due to quitting (unpublished results). Women harboring a BRCA mutation, but asymptomatic for disease, have significantly higher levels of pyrimidine lesions than healthy controls as reported herein.

In the present investigation two groups of women were studied: (a) women carrying either a BRCA1 or a BRCA2 mutation, but having no overt signs of cancer, and (b) healthy adult female controls. The BRCA group, composed of women having no overt signs of disease, had a significantly higher level of damage than the healthy control group. This finding is consistent with BRCA1’s growing reputation as the “master regulator” for maintaining the integrity of the genome. Perhaps it should be expected that women with a defective BRCA1 gene would exhibit higher levels of damage prior to manifesting cancer (see Discussion). It may be appropriate to consider whether a high level of oxidatively induced DNA damage could serve as an early clinical indicator of cancer susceptibility.

2. MATERIALS AND METHODS

Blood donors were recruited under an approved protocol (RPCI I-03007). Donors harboring a BRCA1 mutation, but asymptomatic for cancer, were recruited from the Gynecology Clinic at RPCI. These women did not have ovarian, primary peritoneal or fallopian tube cancer. The mutational status of the BRCA genes was determined by Myriad Genetics (Overland, WS ) [16]. The analysis by Myriad consisted of a full sequence analysis of BRCA1 and BRCA2 in both forward and reverse directions of, respectively, 22 coding exons (approximately 5000 base pairs and 750 adjacent base pairs) and 26 coding exons (approximately 10,200 base pairs and 900 adjacent base pairs).

DNA was extracted from WBC of whole blood samples using a ZeptoMetrix kit that is based on the chaotropic method of sample preparation. Sample prepration methods, important in measurements oxidative DNA damage, have been thoroughly investigated by Ames and coworkers (17). The chaotropic method was strongly endorsed. Also, the practice of adding desferal to the DNA sample as a precaution against artifactual oxidation, typically at 0.1 mM concentration, has been recommended (17,18). Adhering to these advisements the extracted DNA was denatured and subjected to enzynmatic hydrolysis at 37°C using nuclease P1 and alkaline phosphatase as described previously (14). The lesions of interest inhibit the hydrolysis by nuclease P1 of the phosphoester bond 3′ to the modified nucleoside [19]. Consequently, the lesions tend to accumulate in a nuclease P1-alkaline phosphatase hydrolysate of DNA as modified dinucleoside monophoshates. A significant advantage accrues from LC-MS/MS measurements made at the dimer level. Due to the presence of the phosphodiester bond, detection sensitivity is better. For example, the thymine glycol lesion is detected seven fold more sensitively at the dimer level than as a monomer [20]. An internal standard in the form of a labeled modified oligomer, d(GAAPfA*) and d(GTgA*C) where A* stands for universally 15N-labeled deoxyadenosine, is added to the DNA sample prior to digest in order to be able to account for any loss of modified dinucleoside monophosphate during digestion. The standard sample amount was 100 μg, a substantial amount, advantageous for guarding against inaccuracies that become more troublesome in small samples (17).

There were some differences between methods used in this study and the methods employed in our earlier study (13). Sample preparation was simplified by elimination of the HPLC step after hydrolysis of the DNA and prior to LC-MS/MS analysis. The HPLC step was used to remove normal 2′-deoxyribonucleosides, the bulk of the DNA sample, before LC-MS/MS analysis. It was found that the entire hydrolyzed sample could be injected into the spectrometer without serious compromise of detection sensitivity. Another difference from the previous study was the instrumentation. An AB Sciex Qtrap 5500 LC-MS/MS was employed in this study. Internal standards were added to the DNA sample prior to enzymatic digest. The internal standards and the DNA were hydrolyzed concomitantly.

3. RESULTS

The observed levels of d(PfpA) and d(TgpA) are plotted as a function of age of the donor in Figs 2 and 3 respectively for BRCA mutation carriers and for healthy controls. The specific mutations identified by Myriad are listed in Table 1.

Fig. 2.

Fig. 2

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Levels of d(PfpA) (fmol/ug DNA) versus age in carriers of BRCA mutations (empty circles) and healthy controls (filled circles).

Fig. 3.

Fig. 3

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Levels of d(TgpA) (fmol/ug DNA) versus age in carriers of BRCA mutations (empty circles) and healthy controls (filled circles).

Table 1.

Mutations in BRCA 1 and BRCA 2 genes, as determined by Myriad Genetic Laboratories, in women with no overt indication of disease. For mutation nomenclature see Beaudet and Tsui [11].

Sample # Gene Analyzed Mutation
100821906 BRCA1 387del4
102982219 BRCA1 C61G (300T>G)
102982177 BRCA1 C61G (300T>G)
111570319 BRCA1 exon 13 ins 6kb
113251661 BRCA2 F1870X
113111361 BRCA2 4206ins4
113080701 BRCA1 K679X (2154A>T)
102180275 BRCA2 7218del5
093132179 BRCA2 N31241 (9599A>T)
071791068 BRCA2 G1529R
071501608 BRCA1 K679X
113461439 BRCA2 G1529R
113461401 BRCA2 5385insC
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The scatter plots in Figs. 2 and 3 indicate some dependence of DNA damage levels on age but over and above any age dependence a risk factor effect is clearly discernible. The mean values of the formamide and thymine glycol lesions measured in the BRCA carriers and healthy control groups are listed in Table 2. The levels observed in the carrier group, composed of women having no overt signs of the disease, were 5.9 × 10−15 mol d(PfpA)/μg of DNA and 2.9 × 10−15 mol d(TgpA)/μg of DNA. These levels are significantly higher than the levels observed in the healthy control group, namely 2.4 × 10−15 mol d(PfpA)/μg DNA and 1.8 × 10−15 mol d(TgpA)/μg DNA. The p values for the significance of the differences in the mean damage levels between carriers and controls are <.01.

Table 2.

Levels of pyrimidine base damage are listed in terms of femtomoles of lesion per microgram of DNA ± SEM. The number in parenthesis is the number of participants in the group.*

d(PfpA) d(TgpA)
BRCA mutation carriers (14) 5.9 ±1.0 2.9 ± 0.4
Healthy controls (18) 2.4 ± 0.3 1.8 ± 0.2
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*

Two data points are omitted from Figs. 2 and 3 because participants did not disclose their age.

The results may be stated in terms of DNA lesions per 106 nucleotides. For example, the value 5.9 × 10−15 mol d(PfpA)/μg of DNA converts to 6.0 mol dPf/106 nucleotides. The conversion is based on the expectation that the molar abundaces of d(PfpA), d(PfpC), d(PfpT) and d(PfpG) in the sample are in the ratios 3/2/3/2. The value for the healthy control group is 2.5 dPf/106 nucleotides.

In our previous study the d(PfpA) and d(TgpA) lesions were measured in ovarian cancer patients versus healthy controls using a somewhat different methodology and technology as noted above in Methods. For comparison purposes those results are reproduced in Table 3.

Table 3.

Levels of pyrimidine base damage are listed in terms of femtomoles of lesion per microgram of DNA ± SEM. The number in parenthesis is the number of participants in the group.

Ovarian Cancer Patients (19) 6.3 ± 0.8 2.8 ± 0.5
Controls (16) 5.5 ± 0.8 2.2± 0.4
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That study did not include any known carriers of BRCA mutations. The present study is constituted of a completely separate set of measurements. Our conclusion is that BRCA mutations in the absence of disease raise the level of oxidative DNA damage to approximately the same level as actual cancer.

4. DISCUSSION

Oxidative stress and oxidatively induced DNA damage are recurrent themes in cancer research [21]. BRCA mutations are the focus for many of these investigations. It was recognized early that cells containing mutated BRCA1 are hypersensitive to radiation [22]. The purview accorded BRCA1 has continued to expand as new functions are discovered. The mechanism of BRCA1 control is, at least in part, transcription coupled. New insights have come from the realization that BRCA1 forms multiple complexes containing a BARDI component [23]. The BRCA1/BARDI complex is a participant in larger protein complexes that are involved in checkpoint control or DNA repair [24]. Thus, BRCA1 may be regarded as the “master regulator” of genome integrity [25,26]. It is well known that the glycosylase endo III excises the formamide and thymine glycol lesions from DNA [27]. More recently it has been shown that NTH1, a homolog of endonuclease III, is stimulated by BRCA1 [26]. Thus, a connection between BRCA1 function and the lesions observed in this study is clearly indicated.

Carriers of a BRCA1 or a BRCA2 gene have a lifetime risk of breast cancer of up to 80% as well as an increased risk of ovarian cancer (28 ). It was found in the present study that women who carry a BRCA mutation, but who are asymptomatic for cancer, have, on average, higher levels of DNA damage than healthy controls. This observation suggests that the oxidative DNA damage is not consequent to the disease but rather is precursor to the disease. Since the genomic defect is inherited, affected women are probably under lifelong oxidative stress. The higher incidence of cancer among these women can logically be attributed to mutations consequent to BRCA deficiency. One may speculate whether DNA damage measurements could become useful clinically and whether the prospects of affected women could be improved by taking antioxidants.

Multiple studies of the 8-oxo-7.8-dihydroguanine lesion (1–7, 13) have reported higher levels of oxidative DNA damage in WBC of cancer patients. The present study is unique in associating elevated levels of oxidative DNA damage with a high probability of developing the disease. BRCA1 and BRCA2 are tumor suppressor genes. Since their gene products participate in multiple cell functions including maintenance of genome integrity and DNA repair, it should not be surprising that, even in the absence of cancer, germ line carriers of a BRCA mutation exhibit higher levels of oxidative DNA damage. Presumably, the higher level of damage is due to one allele being dysfunctional. Both alleles must be dysfunctional for cancer to develop [29].

The equally famous mutated p53 cancer susceptibility gene produces effects similar to mutated BRCA genes. The p53 tumor suppressor also possesses antioxidant functions [30, 31] Studies of oxidative DNA damage in germ line carriers of p53 mutations have been few and focused mainly on the 8-oxo-7,8-dihydroguanine lesion. It would seem worthwhile to investigate more thoroughly the effect of germ line mutations in relation to oxidative damage and cancer.

Higher levels of the formamide and thymine glycol lesions have recently been associated with other risk factors for cancer. In addition to carriers of BRCA mutations, higher levels of formamide and thymine glycol lesions have also been associated with smoking [14] and poor antioxidant status [15].

This study is similar to that of Dziaman et al [32] who measured oxidative DNA damage in three groups of women with the differences from our study in that the control group was composed of relatives of BRCA1 carriers and the cancer patients were also carriers. These investigators measured the 8-oxo-7,8-dihydroguanine biomarker. An observation of these investigators was, also, that BRCA carriers have a higher level of oxidative damage than healthy controls.

Acknowledgments

The work was supported by grant RO3 CA139513 from the National Cancer Institute. Mass spectrometer facilities are shared resources supported by NCI grant CA 016056.

Footnotes

Conflict of Interest Statement

None

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