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Joanna Trubicka,
Ewa Grabowska-Kłujszo,
Janina Suchy,
Bartłomiej Masojć,
Pablo Serrano-Fernandez,
Grzegorz Kurzawski,
Cezary Cybulski,
Bohdan Górski,
Tomasz Huzarski,
Tomasz Byrski,
Jacek Gronwald,
Elzbieta Złowocka,
Józef Kładny,
Zbigniew Banaszkiewicz,
Rafał Wiśniowski, Elzbieta Kowalska,
Jan Lubinski,
Rodney J Scott
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ABSTRACT: CYP1B1 is a P450 enzyme which is involved in the activation of pro-carcinogens to carcinogens as well as sex hormone metabolism. Because differences in the activity of the enzyme have been correlated with variant alleles of single nucleotide polymorphisms (SNPs), it represents an attractive candidate gene for studies into colorectal cancer susceptibility.
We genotyped 597 cancer patients and 597controls for three CYP1B1 SNPs, which have previously been shown to be associated with altered enzymatic activity. Using the three SNPs, eight different haplotypes were constructed. The haplotype frequencies were estimated in cases and controls and then compared. The odds ratio for each tumour type, associated with each haplotype was estimated, with reference to the most common haplotype observed in the controls.
The three SNPs rs10012, rs1056827 and rs1056836 alone did not provide any significant evidence of association with colorectal cancer risk. Haplotypes of rs1056827 and rs10012 or rs1056827 and rs1056836 revealed an association with colorectal cancer which was significantly stronger in the homozygous carriers. One haplotype was under represented in the colorectal cancer patient group compared to the control population suggesting a protective effect.
Genetic variants within the CYP1B1 that are associated with altered function appear to influence susceptibility to a colorectal cancer in Poland. Three haplotypes were associated with altered cancer risk; one conferred protection and two were associated with an increased risk of disease. These observations should be confirmed in other populations.
BMC Cancer 01/2010; 10:420. · 3.01 Impact Factor
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Anna Jakubowska,
Cezary Cybulski,
Anna Szymańska,
Tomasz Huzarski,
Tomasz Byrski,
Jacek Gronwald,
Tadeusz Debniak,
Bohdan Górski, Elzbieta Kowalska,
Steven A Narod,
Jan Lubiński
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ABSTRACT: To investigate whether or not a genetic variant in BARD1 (Cys557Ser) contributes to early-onset breast cancer in Poland, or modifies the risk of breast cancer in women with an inherited predisposition to breast cancer.
We studied 3,188 unselected Polish women with breast cancer and 1,038 healthy controls. All women were genotyped for the BARD1 Cys557Ser variant and for known founder mutations in BRCA1 (three mutations), CHEK2 (four mutations), and NBS1 (one mutation).
A BARD1 variant was seen in 150 of 3,188 breast cancer cases (4.7%) and in 40 of 1,038 controls (3.8%) (OR = 1.2; 95% CI = 0.9-1.7). The risk associated with the BARD1 variant was not significantly greater in women with familial cancer (OR = 1.5; 95% CI = 0.8-2.7), or with an inherited mutation in BRCA1 (OR = 0.9; 95% CI = 0.4-2.2), CHEK2 (OR = 1.0; 95% CI = 0.5-2.1), or NBS1 (OR = 1.3; 95% CI = 0.2-10.2). Modest associations were observed among the subgroups of women with very early onset breast cancer (OR = 2.9; 95% CI = 1.2-7.1) and with medullary breast cancer (OR = 1.8; 95% CI = 0.9-3.7).
There was no clear association between the presence of the BARD1 Cys557Ser allele and breast cancer in Poland. Furthermore, the BARD1 Cys557Ser allele does not appear to modify the risk of breast cancers among carriers of BRCA1 mutations, or of other predisposing mutations. The allele may predispose to breast cancers of certain histologic subtypes, but further studies are needed to confirm these findings.
Breast Cancer Research and Treatment 02/2008; 107(1):119-22. · 4.43 Impact Factor
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Tadeusz Debniak,
Cezary Cybulski,
Bohdan Górski,
Tomasz Huzarski,
Tomasz Byrski,
Jacek Gronwald,
Anna Jakubowska, Elzbieta Kowalska,
Oleg Oszurek,
Steven A Narod,
Jan Lubiński
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ABSTRACT: To investigate the contribution of CDKN2A A148T common variant to early-onset breast cancer in Poland, and to establish the characteristic features of these cancers.
We studied 3,069 women diagnosed with breast cancer under the age of 51 and 3,493 population controls. CDKN2A variant were detected using RFLP-PCR and confirmed by genomic sequencing. Clinical and pathological features of CDKN2A-positive cases and CDKN2A-negative cases were compared.
A148T variant was identified in 157 of 3,069 women with breast cancer (5.1%). Overall, the odds ratio for early-onset breast cancer, given a CDKN2A variant was 1.4 (95% CI 1.075-1.725; P = 0.012). Breast tumors in women with the CDKN2A variant were more commonly intraductal cancers (DCIS) with micro-invasion (14.8% vs. 8.5%; P = 0.035). Carriers and non-carriers were similar with respect to tumor size, laterality, multicentricity, nodal status, family history and estrogen-receptor status.
The CDKN2A A148T variant seems to contribute to early-onset breast cancer in Poland. Breast tumors which arise in carriers of A148T variant appear to be similar to those of breast cancers in the population at large.
Breast Cancer Research and Treatment 08/2007; 103(3):355-9. · 4.43 Impact Factor
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Cezary Cybulski,
Bohdan Górski,
Tomasz Huzarski,
Tomasz Byrski,
Jacek Gronwald,
Tadeusz Debniak,
Dominika Wokolorczyk,
Anna Jakubowska, Elzbieta Kowalska,
Oleg Oszurek,
Steven A Narod,
Jan Lubinski
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ABSTRACT: To investigate the contribution of CHEK2 mutations to early-onset breast cancer in Poland and to establish the characteristic features of these cancers.
We studied 3,228 women diagnosed with breast cancer under the age of 51 years and 5,496 population controls. CHEK2 mutations were detected by RFLP-PCR or allele-specific oligonucleotide-PCR assays. Clinical and pathologic features of CHEK2-positive cases and CHEK2-negative cases were compared.
A truncating CHEK2 mutation (1100delC or IVS2+1G>A) was seen in 47 of 3,228 cases and in 34 of 5,496 controls (odds ratio, 2.4; P = 0.0001). The CHEK2 I157T missense mutation was present in 207 of 3,228 cases, compared with 264 of 5,496 controls (odds ratio, 1.4; P = 0.002). Breast cancers in women with a CHEK2 mutation were more commonly of lobular histology (21.5% versus 15.8%; P = 0.05), of size >2 cm (54.8% versus 43.5%; P = 0.01), or of multicentric origin (28.7% versus 19.5%; P = 0.01) than were cancers from women without a CHEK2 mutation. Bilateral cancers were equally common in both subgroups.
Three founder alleles in CHEK2 contribute to early-onset breast cancer in Poland. Breast tumors which arise in carriers of CHEK2 mutations seem to be similar to those of breast cancers in the population at large.
Clinical Cancer Research 08/2006; 12(16):4832-5. · 7.74 Impact Factor
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Hereditary Cancer in Clinical Practice 01/2006; 4(1):58. · 1.68 Impact Factor
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ABSTRACT: Women who are born with constitutional heterozygous mutations of the BRCA1 gene face greatly increased risks of breast and ovarian cancer. The product of the BRCA1 gene is involved in the repair of double-stranded DNA breaks and it is believed that increased susceptibility to DNA breakage contributes to the cancer phenotype. It is hoped therefore that preventive strategies designed to reduce chromosome damage will also reduce the rate of cancer in these women. To test for increased mutagenicity of cells from BRCA1 carriers, the frequency of chromosome breaks was measured in cultured blood lymphocytes following in vitro exposure to bleomycin in female BRCA1 carriers and was compared with noncarrier relatives. The frequency of chromosome breaks was also measured in BRCA1 carriers following oral selenium supplementation. Carriers of BRCA1 mutations showed significantly greater mean frequencies of induced chromosome breaks per cell than did healthy noncarrier relatives (0.58 versus 0.39; P < 10(-4)). The frequency of chromosome breaks was greatly reduced following 1 to 3 months of oral selenium supplementation (mean, 0.63 breaks per cell versus 0.40; P < 10(-10)). The mean level of chromosome breaks in carriers following supplementation was similar to that of the noncarrier controls (0.40 versus 0.39). Oral selenium is a good candidate for chemoprevention in women who carry a mutation in the BRCA1 gene.
Cancer Epidemiology Biomarkers & Prevention 06/2005; 14(5):1302-6. · 4.12 Impact Factor
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ABSTRACT: An important aspect of the chemopreventive activity of isothiocyanates (ITC) is their ability to induce cell growth inhibition and apoptosis. In this study, the effect of two sulforaphane analogues, 2-oxoheksyl isothiocyanate and alyssin, on lymphoblastoid cells, derived from people carrying four different germ-line mutations in BRCA1 gene, was tested and compared to the effect on wild type cells. The mutations studied were: C61G; 3819del5; 4153delA, and 5382INSC. Changes in cell viability and density after 2-oxoheksyl isothiocyanate and alyssin treatment were evaluated, as well as cell cycle progression, mitochondrial membrane potential changes, and phosphatidylserine externalization. Both isothiocyanates were shown to reduce cell viability and density in all cell lines tested, as well as the change in cell cycle phase's distribution. The response of cells to two ITC tested was various, as well as mutation type-modulated. We found that change of cellular maintenance by chemopreventive agents can be modulated by single allele BRCA1 mutation. Drug Dev. Res. 65:84–92, 2005. © 2005 Wiley-Liss, Inc.
Drug Development Research 05/2005; 65(2):84 - 92. · 1.19 Impact Factor
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ABSTRACT: The important aspect of sulforaphane (SFN) chemopreventive activity is its ability to induce cell growth inhibition and apoptosis. In this study, the effect of SFN on lymphoblastoid cells derived from people carrying four different germ-line mutations in BRCA1 gene was tested and compared to the effect of SFN on wild-type cells. The mutations studied were C61G, 3819del5, 4153delA and 5382INSC. Changes in cell viability and density after SFN treatment were evaluated, as well as cell cycle progression, changes in mitochondrial membrane potential, and phosphatidylserine externalization. SFN was shown to reduce cell viability and density in all cell lines tested. Cell cycle block in S-phase and the occurence of simultaneous apoptosis were observed. The concentration of SFN needed to elicit a comparable effect on each cell line was varied. We found that the effect of SFN on cells carrying different inherited mutations depended on mutation type.
Oncology Reports 05/2005; 13(4):659-65. · 1.84 Impact Factor
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Bohdan Górski,
Anna Jakubowska,
Tomasz Huzarski,
Tomasz Byrski,
Jacek Gronwald,
Ewa Grzybowska,
Andrzej Mackiewicz,
Malgorzata Stawicka,
Marek Bebenek,
Dagmara Sorokin, [......],
Cezary Cybulski, Elzbieta Kowalska,
Aleksandra Tołoczko-Grabarek,
Stanisław Zajaczek,
Janusz Menkiszak,
Krzysztof Medrek,
Bartłomiej Masojć,
Marek Mierzejewski,
Steven Alexander Narod,
Jan Lubiński
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ABSTRACT: Three mutations in BRCA1 (5382insC, C61G and 4153delA) are common in Poland and account for the majority of mutations identified to date in Polish breast and breast-ovarian cancer families. It is not known, however, to what extent these 3 founder mutations account for all of the BRCA mutations distributed throughout the country. This question has important implications for health policy and the design of epidemiologic studies. To establish the relative contributions of founder and nonfounder BRCA mutations, we established the entire spectrum of BRCA1 and BRCA2 mutations in a large set of breast-ovarian cancer families with origins in all regions of Poland. We sequenced the entire coding regions of the BRCA1 and BRCA2 genes in 100 Polish families with 3 or more cases of breast cancer and in 100 families with cases of both breast and ovarian cancer. A mutation in BRCA1 or BRCA2 was detected in 66% of breast cancer families and in 63% of breast-ovarian cancer families. Of 129 mutations, 122 (94.6%) were in BRCA1 and 7 (5.4%) were in BRCA2. Of the 122 families with BRCA1 mutations, 119 (97.5%) had a recurrent mutation (i.e., one that was seen in at least 2 families). In particular, 111 families (91.0%) carried one of the 3 common founder mutations. The mutation spectrum was not different between families with and without ovarian cancer. These findings suggest that a rapid and inexpensive assay directed at identifying the 3 common founder mutations will have a sensitivity of 86% compared to a much more costly and labor-intensive full-sequence analysis of both genes. This rapid test will facilitate large-scale national epidemiologic and clinical studies of hereditary breast cancer, potentially including studies of chemoprevention.
International Journal of Cancer 08/2004; 110(5):683-6. · 5.44 Impact Factor
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ABSTRACT: The effect of sulforaphane on human lymphoblastoid cells originating from a patient of a high cancer risk was studied. Sulforaphane (SFN) is a naturally occurring substance of chemopreventive activity. In our study, changes in cell growth, induction of apoptosis and phase 2 enzymes as well as glutathione level were examined. Apoptosis was tested by confocal microscopy at three stages: change in mitochondrial membrane potential, caspase activation and phosphatidylserine externalization. We show that SFN increases the activity of the detoxification system: it increases quinone reductase activity at low concentration (0.5-1 microM) and raises glutathione level in a dose-dependent manner. At higher doses (2.5-10 microM) sulforaphane is a cell growth modulator, as it caused cell growth cessation (IC50 = 3.875 microM), and apoptosis inducer. The results obtained suggest that sulforaphane acts as a chemopreventive agent in human lymphoblastoid cells.
Acta biochimica Polonica 02/2004; 51(3):711-21. · 1.49 Impact Factor
