Reduced DNA repair synthesis in healthy women having first degree relatives with breast cancer

doi:10.1016/0277-5379(87)90358-0

European Journal of Cancer and Clinical Oncology

Volume 23, Issue 7, July 1987, Pages 1051-1057

European Journal of ...

https://doi.org/10.1016/0277-5379(87)90358-0 Get rights and content

Abstract

The DNA repair synthesis induced by UV-C irradiation was studied in unstimulated lymphocytes of 64 healthy women whose mothers, or sisters, or mothers and sisters had had breast cancer. For comparison we took 48 control women. As the parameter for the determination of DNA repair synthesis the incorporation of [³H]thymidine in the presence of 2 mM hydroxyurea was taken. The levels of [³H]thymidine incorporation were reduced by 19 of the 29 women whose mothers, in 17 of the 25 women whose sisters and in nine of the 10 women whose mothers and sisters had had breast cancer. By comparison a decreased level was found in only seven of the 48 control women. This difference between the controls and women having first degree relatives with breast cancer was significant in each group. In an earlier study a redued DNA repair synthesis in breast cancer patients was established. The present findings suggest that DNA repair synthesis may be one of the factors involved in the genesis of breast cancer.

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35 cases of 27-68years old breast cancer individuals and 15 female individuals of FDFRS formed the material for the current study. An equal number of normal healthy females controls were also included to investigate the extent of DNA damaged in cases, FDFRs and controls. 'Comet assay' was done by conventional methods with slight modifications. For Comet metrics, a Trinocular research microscope, Nikkon Optiphot model with automatic photomicrograph attachment was used. Thus quantification of the DNA damage was done by measuring comet tail length in all the three groups (cases, FDFRs and controls).
There was significant increase in the mean comet tail length from controls to FDFRs (p<0.0001) and from FDFRs to cases (p<0.0001). In other words the DNA damage significantly increased from controls to FDFRs and from FDFRs to cases. It was also observed that among various stages of cases the mean comet tail length increased significantly from stage II A to stage III B.
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The majority of human cancers result from exposure to environmental carcinogens. Epidemiologic studies, as well as studies in animal models of cancer, have demonstrated a wide range of responses to carcinogen exposure and it is now clear that common allelic variants within the genome are responsible for this interindividual variation. Identification of specific genes that modify the response to carcinogen exposure has been difficult. However, new approaches in both human and animal studies have improved the likelihood that cancer modifier genes will be identified. Importantly, many of the modifier genes identified in animal models have been shown to modify cancer risk in humans, demonstrating the utility of animal studies. The identification of cancer modifier genes will ultimately lead to the development of new cancer risk models, the detection of individuals at high risk for cancer development, and improved prevention strategies.
Polymorphisms of XRCC1 and risk of esophageal and gastric cardia cancer
2004, Cancer Letters
Background: Linxian, a rural county in North Central China, has among the highest rates of esophageal squamous cell carcinoma and gastric cardia adenocarcinoma in the world. In a nested case-cohort study that originated from two cancer prevention trials in Linxian, we examined the relationship between these cancers and two polymorphisms in the DNA repair gene XRCC1.
Methods: We conducted a case-cohort study among individuals in the cohort who were alive and cancer free in 1991, and had blood samples for DNA extraction. Real time Taqman analyses were conducted to genotype incident cancer cases (n=221, 131 esophageal and 90 gastric cardia cancer cases) that developed through May 1996, and on an age- and sex-matched reference cohort (n=454). We used Cox proportional hazard models to estimate relative risks (RR) and 95% confidence intervals (95% CI).
Results: We observed no association between the variant genotype in XRCC1 Arg194Trp (codon 194 arganine to tryptophan substitution) and esophageal or gastric cardia cancer. However, carrying at least one copy of the variant allele in XRCC1 Arg399Gln (codon 399 arganine to glutamine substitution) was associated with reduced risk of gastric cardia cancer (RR: 0.60, 95% CI: 0.37–0.97) and the combined category esophageal/gastric cancer (RR: 0.67, 95% CI: 0.48–0.95). In combined polymorphisms analyses, we observed a significant reduction in risk of combined esophageal/gastric cancer among individuals that had both the XRCC1 Arg194Trp and Arg399Gln variant genotyopes (RR: 0.47, 95% CI: 0.26–0.84).
Conclusions: Our results suggest that the XRCC1 Arg399Gln variant genotype is associated with reduced risk of upper GI cancer and that individuals with both XRCC1 variant genotypes are also at significantly reduced risk of upper GI cancer in this high-risk Chinese population.
Unique tissue-specific level of DNA nucleotide excision repair in primary human mammary epithelial cultures
2003, Experimental Cell Research
DNA repair is essential for the maintenance of genomic integrity and stability. Nucleotide excision repair (NER) is a major pathway responsible for remediation of damage caused by UV light, bulky adducts, and cross-linking agents. We now show that NER capacity is differentially expressed in human tissues. We established primary cultures of peripheral blood lymphocytes (PBLs: N = 33) and foreskin fibroblasts (FF: N = 6), as well as adult breast tissue (N = 22) using a unique culture system, and measured their NER capacity using the unscheduled DNA synthesis (UDS) functional assay. Relative to FF, primary cultures of breast cells exhibited only 24.6 ± 2.1% of NER capacity and PBLs only 8.9 ± 1.2%. Cells from the breast therefore have a unique and distinctive DNA repair capacity. The NER capacities of all three cell types had similar coefficients of variation in the range of 10%–15%, which should be taken into account when running controls for this contextual assay. Unlike previous studies and speculation in the field, we found that NER was not affected by cell morphology, donor age, or proliferation as measured by the S phase index. While the NER capacity of the transformed lymphoblastoid cell line TK6 was within the range of our PBL samples, the breast tumor-derived MDA MB-231 cell line was four-fold higher than normal breast tissue. These studies show that analysis of baseline DNA repair in normal human cell types is critical as a basis for evaluation of the effects of “mutator” genes as etiological factors in the development of cancer.
p53-Degradation by HPV-16 E6 preferentially affects the removal of cyclobutane pyrimidine dimers from non-transcribed strand and sensitizes mammary epithelial cells to UV-irradiation
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Nucleotide excision repair (NER), the most versatile and ubiquitous mechanism for DNA repair, operates to remove many types of DNA base lesions. We have studied the role of p53 function in modulating the repair of DNA damage following UV irradiation in normal and p53-compromised human mammary epithelial cells (HMEC). The effect of UV-induced DNA damage on cellular cytotoxicity and apoptosis was determined in conjunction with global, gene- and strand-specific repair. Cytotoxicity studies, using clonogenic survival and MTT assays, showed that HPV-16 E6-expressing HMEC were more UV sensitive than p53-WT cell lines. High apoptotic index obtained with p53-compromised cells was in conformity to both the low clonogenic survival and the low cellular viability. No discernible differences in the formation of initial UV-induced cyclobutane pyrimidine dimers (CPD) were observed in the cell lines of varying p53 functional status. However, the extent and the rate of damage removal from genome overall were highest for p53-WT cells. Further examination of strand-specific repair in the p53 gene revealed that the removal of CPD in the non-transcribed strand (NTS) was slower in p53-compromised cells compared to the normal p53-WT cell lines. These results suggest that loss of p53 function, in the absence of other genetic alterations, decreased both overall amount of CPD repaired and their removal rate from the genome. Additionally, normal function of p53 is required for the repair of the NTS, but not of the transcribed strand (TS) in genomic DNA in human epithelial cells. Thus, failure of quantitative removal of CPD by global genomic repair (GGR), due to loss of p53 function, causes the enhanced UV sensitivity and increased damage-induced apoptosis via a p53-independent pathway. Nevertheless, recovery of cells from UV damage requires normal p53 function and efficient GGR.
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Reduced DNA repair synthesis in healthy women having first degree relatives with breast cancer

Abstract

Lancet

J Invest Dermatol

Eur J Cancer Clin Oncol

Mutat Res

Biochim Biophys Acta

Biochim Biophys Acta

Family history of breast cancer as a risk indicator for the disease

Am J Epidemiol

Genetic study of breast cancer: identification of a high risk group

Cancer

Cancer-associated human genetic diseases with defects in DNA repair

J Cancer Res Clin Oncol

Heritable diseases with increased sensitivity to cellular injury

Reduced capacity for DNA repair synthesis in patients with or genetically predisposed to colorectal cancer

J Nat Cancer Inst

use of hydroxyurea in the measurement of DNA repair by the BND cellulose method

Environ Mutagen