Reduced DNA Repair Capacity in Breast Cancer Patients and Unaffected Individuals from Breast Cancer Families

Rao, Nanyan; Pai, Sanjay A; Shinde, Shashank R.; Ghosh, Soumendra N.

doi:10.1016/s0165-4608(97)00303-8

Cited by 20 publications

(11 citation statements)

References 22 publications

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“…Several observations indicate that reduced DNA repair capacity may be a predisposing factor for familiar breast cancer (Helzlsouer et al, 1996;Parshad et al, 1996;Rao et al, 1998). A functional role of the breast cancer predisposing genes BRCA1 and BRCA2 in DNA repair has also been repeatedly suggested (Scully et al, 1997;Sharan et al, 1997;Bertwistle and Ashworth,1998;Shen et al, 1998;Zhang et al, 1998).…”

Section: Discussionmentioning

confidence: 97%

“…More than 75% of women with newly diagnosed breast cancer have no identifiable risk factors (Cady et al, 1998). Defective DNA repair has been suggested as a possible predisposing factor Rao et al, 1998). The breast cancer predisposing genes BRCA1 and BRCA2 code for proteins likely to be involved in DNA repair (Bertwistle and Ashworth,1998; Gowen et al, 1998;Shen et al, 1998;Zhang et al, 1998).…”

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confidence: 99%

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Analysis of repair of abasic sites in early onset breast cancer patients

et al. 2000

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Section: Discussionmentioning

confidence: 97%

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confidence: 99%

Analysis of repair of abasic sites in early onset breast cancer patients

et al. 2000

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“…Chromosomal sensitivity to radiation and chemical mutagens has been proposed as a marker for low penetrance predisposition to various common cancers including breast cancer (Baria et al, 2001b). Breast cancer patients have been tested for mutagen sensitivity in various studies (Helzlsouer et al, 1995(Helzlsouer et al, , 1996Parshad et al, 1996;Patel et al, 1997;Rao et al, 1998;Scott et al, 1998Scott et al, , 1999Roberts et al, 1999;Burrill et al, 2000;Rothfuss et al, 2000;Roy et al, 2000;Baria et al, 2001a, b;Baeyens et al, 2002;Buchholz et al, 2002;Trenz et al, 2002Trenz et al, , 2003b. Compared with normal healthy controls, a clearly increased portion of breast cancer patients has an enhanced sensitivity to the chromosome-damaging effects of ionizing radiation and other mutagens.…”

confidence: 99%

Chromosomal mutagen sensitivity associated with mutations in BRCA genes

Speit

Trenz²

2004

Cytogenet Genome Res

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Chromosomal mutagen sensitivity is a common feature of cells from patients with different kinds of cancer. A portion of breast cancer patients also shows an elevated sensitivity to the induction of chromosome damage in cells exposed to ionizing radiation or chemical mutagens. Segregation analysis in families of patients with breast cancer indicated heritability of mutagen sensitivity. It has therefore been suggested that mutations in low-penetrance genes which are possibly involved in DNA repair predispose a substantial portion of breast cancer patients. Chromosomal mutagen sensitivity has been determined with the G₂ chromosome aberration test and the G₀ micronucleus test (MNT). However, there seems to be no clear correlation between the results from the two tests, indicating that the inherited defect leading to enhanced G₀ sensitivity is different from that causing G₂ sensitivity. Less than 5% of breast cancer patients have a familial form of the disease due to inherited mutations in the breast cancer susceptibility genes BRCA1 or BRCA2. Heterozygous mutations in BRCA1 or BRCA2 in lymphocytes from women with familial breast cancer are also associated with mutagen sensitivity. Differentiation between mutation carriers and controls seems to be much better with the MNT than with the G₂ assay. Mutagen sensitivity was detected with the MNT not only after irradiation but also after treatment with chemical mutagens including various cytostatics. The enhanced formation of micronuclei after exposure of lymphocytes to these substances suggests that different DNA repair pathways are affected by a BRCA1 mutation in accordance with the proposed central role of BRCA1 in maintaining genomic integrity. Mutations in BRCA1 and BRCA2 seem to predispose cells to an increased risk of mutagenesis and transformation after exposure to radiation or cytostatics. This raises a question about potentially increased risks by mammography and cancer therapy in women carrying a mutation in one of the BRCA genes. Lymphoblastoid cell lines (LCLs) from breast cancer patients have been used to study the mechanisms and genetic changes associated with tumorigenesis. With respect to mutagen sensitivity, conflicting results have been reported. In particular enhanced induction of micronuclei does not seem to be a general feature of LCLs with a BRCA1 mutation in contrast to lymphocytes with the same mutation. Therefore, LCLs are of limited utility for studying the mechanisms underlying chromosomal mutagen sensitivity.

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“…There are few studies to date assessing the role of DRC in breast cancer. Studies from India found increased sensitivity to bleomycin, X-rays, aphidicolin, or N-methyl N-nitro Nnitrosoguanidin (MNNG) in lymphocytes of familial breast cancer patients and/or unaffected relatives compared to controls [Jyothish et al, 1998;Rao et al, 1998;Rajeswari et al, 2000]. All mutagens used in those studies are not ambient environment contaminants but were used to trigger DNA damage to investigate overall DRC.…”

Section: Figmentioning

confidence: 99%

Removal of benzo(a)pyrene diol epoxide (BPDE)‐DNA adducts as a measure of DNA repair capacity in lymphoblastoid cell lines from sisters discordant for breast cancer

Motykiewicz

Faraglia

Wang

et al. 2002

Environ and Mol Mutagen

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The mutagen sensitivity assay is one of the approaches used to investigate individual DNA repair capacity. This method is based on the premise that after in vitro treatment with a test mutagen, DNA from subjects with defective repair will be more damaged than DNA from those with an efficient repair system. However, very little is known about unmeasured processes that occur between cell treatment and final assessment of DNA damage. To develop a more precise assay, we modified the traditional mutagen sensitivity assay to also include measurement of DNA damage after culturing cells in the absence of mutagen. First, we treated apparently normal and xeroderma pigmentosum lymphoblastoid cell lines with various doses of benzo(a)pyrene diol epoxide (BPDE) and harvested cells at different time points. A polyclonal antiserum against BPDE-DNA was used to quantitate levels of adducts by immunoslot-blot and immunohistochemistry. Selected conditions included treatment with 10 microM BPDE, a 4-hr culture in mutagen-free medium, and immunohistochemical measurement of BPDE-DNA adducts. The method was then applied in a pilot study to 50 lymphoblastoid lines from sisters discordant for breast cancer. There was no significant difference between cases and controls in the level of BPDE-DNA adducts in lymphoblasts harvested immediately after BPDE treatment. However, after a 4-hr culture in mutagen-free medium, the level of adducts was significantly higher (P = 0.006) among cases than in controls. There was a two-fold increase in mean adduct removal in lines from nonaffected as compared to affected sisters (44% and 22% decrease, respectively). DNA repair capacity was predictive of case status (P = 0.04) in logistic regression analysis. This method, which can be easily applied to large numbers of samples, should be useful in studies to investigate the role of DNA repair in cancer risk.

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Reduced DNA Repair Capacity in Breast Cancer Patients and Unaffected Individuals from Breast Cancer Families

Cited by 20 publications

References 22 publications

Analysis of repair of abasic sites in early onset breast cancer patients

Analysis of repair of abasic sites in early onset breast cancer patients

Chromosomal mutagen sensitivity associated with mutations in BRCA genes

Removal of benzo(a)pyrene diol epoxide (BPDE)‐DNA adducts as a measure of DNA repair capacity in lymphoblastoid cell lines from sisters discordant for breast cancer

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