Radiation clastogenesis and cell cycle checkpoint function as functional markers of breast cancer risk

Filatov, Leonid V.; Oglesbee, Stephen E.; Simpson, Dennis A.; Lotano, Marc A.; McKeen, Hayley D.; Sawyer, Lynda R.; Moore, Dominic T.; Millikan, Robert C.; Cordeiro‐Stone, Marila; Carey, Lisa A.

doi:10.1093/carcin/bgl103

Cited by 13 publications

(19 citation statements)

References 51 publications

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“…Two hundred microliters of blood was eluted in a final volume of 200 µl that, according to the manufacturer, yields 15-60 ng/µl of DNA. DNA from UNC breast cancer patient samples were obtained from lymphoblastoid cell lines as described previously (39). Paraffin-embedded tissue (PET) samples from breast cancer patients were used for DNA isolation in the event there was insufficient DNA isolated from the blood samples.…”

Section: Genotype Analysismentioning

confidence: 99%

Polymorphisms in CYP1B1, GSTM1, GSTT1 and GSTP1, and susceptibility to breast cancer

Emburgh

Hu²,

Levine³

et al. 2008

Oncol Rep

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Polymorphisms in the cytochrome P450 1B1 (CYP1B1) and glutathione S-transferase (GST) drug metabolic enzymes, which are responsible for metabolic activation/detoxification of estrogen and environmental carcinogens, were analyzed for their association with breast cancer risk in 541 cases and 635 controls from a North Carolina population. Each polymorphism, altering the catalytic function of their respective enzymes, was analyzed in Caucasian and African-American women. As reported in previous studies, individual polymorphisms did not significantly impact breast cancer risk in either Caucasian or African-American women. However, African-American women exhibited a trend towards a protective effect when they had at least one CYP1B1 119S allele (OR=0.53; 95% CI=0.20-1.40) and increased risk for those women harboring at least one CYP1B1 432V allele (OR=5.52; 95% CI=0.50-61.37). Stratified analyses demonstrated significant interactions in younger (age ≤60) Caucasian women with the CYP1B1 119SS genotype (OR=3.09; 95% CI=1.22-7.84) and younger African-American women with the GSTT1 null genotype (OR=4.07; 95% CI=1.12-14.80). A notable trend was also found in Caucasian women with a history of smoking and at least one valine allele at GSTP1 114 (OR=2.12; 95% CI=1.02-4.41). In Caucasian women, the combined GSTP1 105IV/VV and CYP1B1 119AA genotypes resulted in a near 2-fold increase in risk (OR=1.96; 95% CI=1.04-3.72) and the three way combination of GSTP1 105IV/VV, CYP1B1 119AS/SS and GSTT1 null genotypes resulted in an

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Section: Genotype Analysismentioning

confidence: 99%

Polymorphisms in CYP1B1, GSTM1, GSTT1 and GSTP1, and susceptibility to breast cancer

Emburgh

Hu²,

Levine³

et al. 2008

Oncol Rep

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“…Nevertheless, the involvement of these two genes in DNA DSB repair provides some clue to the etiology of the remaining 95% of breast cancers. Ionizing radiation and other endogenous factors can cause DSBs [15,16] that could increase risk for breast cancer [9][10][11]17]. If any impairment exists in the H2AFX gene, it is possible that DSBs could not be repaired correctly or efficiently, leading to chromosomal breaks and genomic instability and thus predisposition to cancer.…”

Section: Introductionmentioning

confidence: 99%

Genetic variants in the H2AFX promoter region are associated with risk of sporadic breast cancer in non-Hispanic white women aged ≤55 years

Wei

Bondy

Brewster

et al. 2007

Breast Cancer Res Treat

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The histone protein family member X (H2AFX) is important in maintaining chromatin structure and genetic stability. Genetic variants in H2AFX may alter protein functions and thus cancer risk. In this case-control study, we genotyped four common single nucleotide polymorphisms (i.e., −1654A > G [rs643788], −1420G > A [rs8551], and −1187T > C [rs7759] in the H2AFX promoter region and 1057C > T [rs7350] in the 3′ untranslated region (UTR)) in 467 patients with sporadic breast cancer and 488 cancer-free controls. All female subjects were non-Hispanic whites aged ≤55 years. We found that significantly increased risk of breast cancer was associated with variant genotypes in the H2AFX promoter: adjusted odds ratio [OR] = 1.80, 95% confidence interval [CI] = 1.38-2.34 for −1654AG/GG; OR = 1.40, 95% CI = 1.07-1.83 for −1420GA/AA; and OR = 1.65, 95% CI = 1.26-2.16 for −1187TC/CC. Furthermore, the number of variant alleles in the promoter haplotypes was associated with increased risks of breast cancer in a dose-response manner (OR = 6.08, 95% CI = 3.25-11.38; OR = 6.83, 95% CI = 3.83-12.18; and OR = 23.61, 95% CI = 3.95-140.99 for one, two, and three variant alleles, respectively) (P trend < 0.0001). Age at onset of breast cancer significantly decreased as the number of variant alleles increased (P trend = 0.024). However, these effects were not observed in the 3′UTR 1057C > T polymorphism. Therefore, we believe that H2AFX promoter polymorphisms may contribute to the etiology of

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“…Some of the conflicting results in the literature may be related to: (1) study sample size and related statistical power, (2) PHA-induced PBLs vs lymphoblastoid cell lines, and (3) parameters used for interpreting the study results. 5,9,15,16 Another interesting finding in this study is that response of PBLs to PHA is lower in breast cancer cases compared to that in controls. Several earlier studies reported that PBLs from cancer patients are less responsive to mitogenic stimulation by PHA and other plant lectins compared to healthy controls.…”

Section: Discussionmentioning

confidence: 53%

“…12,15,16,23 Mutations in BRCA1 or ATM are risk factors for breast and ovarian cancers. 2,24 The results from recent studies suggest that BRCA1 plays critical roles in Cell cycle delay in breast cancer risk and radiosensitivity Dovepress submit your manuscript | www.dovepress.com Dovepress DNA repair, recombination, checkpoint control of the cell cycle, transcription, and S-and G 2 -phase checkpoints in response to IR.…”

Section: Discussionmentioning

confidence: 99%

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Validation of the cell cycle G2 delay assay in assessing ionizing radiation sensitivity and breast cancer risk

Hill¹,

Hu²

2009

CMR

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Genetic variations in cell cycle checkpoints and DNA repair genes are associated with prolonged cell cycle G 2 delay following ionizing radiation (IR) treatment and breast cancer risk. However, different studies reported conflicting results examining the association between post-IR cell cycle delay and breast cancer risk utilizing four different parameters: cell cycle G 2 delay index, %G 2 -M, G 2 /G 0 -G 1 , and (G 2 /G 0 -G 1 )/S. Therefore, we evaluated whether different parameters may influence study results using a data set from 118 breast cancer cases and 225 controls as well as lymphoblastoid and breast cancer cell lines with different genetic defects. Our results suggest that cell cycle G 2 delay index may serve as the best parameter in assessing breast cancer risk, genetic regulation of IR-sensitivity, and mutations of ataxia telangiectasia mutated (ATM) and TP53. Cell cycle delay in 21 lymphoblastoid cell lines derived from BRCA1 mutation carriers was not different from that in controls. We also showed that IR-induced DNA-damage signaling, as measured by phosphorylation of H2AX on serine 139 (γ-H2AX) was inversely associated with cell cycle G 2 delay index. In summary, the cellular responses to IR are extremely complex; mutations or genetic variations in DNA damage signaling, cell cycle checkpoints, and DNA repair contribute to cell cycle G 2 delay and breast cancer risk. The cell cycle G 2 delay assay characterized in this study may help identify subpopulations with elevated risk of breast cancer or susceptibility to adverse effects in normal tissue following radiotherapy.

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Radiation clastogenesis and cell cycle checkpoint function as functional markers of breast cancer risk

Abstract: Constitutive radiation hypersensitivity in blood lymphocytes and lymphoblasts was not a useful biomarker for identifying women at increased risk of breast cancer.

Cited by 13 publications

References 51 publications

Polymorphisms in CYP1B1, GSTM1, GSTT1 and GSTP1, and susceptibility to breast cancer

Polymorphisms in CYP1B1, GSTM1, GSTT1 and GSTP1, and susceptibility to breast cancer

Genetic variants in the H2AFX promoter region are associated with risk of sporadic breast cancer in non-Hispanic white women aged ≤55 years

Validation of the cell cycle G2 delay assay in assessing ionizing radiation sensitivity and breast cancer risk

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