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T Byrski

Publications and source records attributed to T Byrski.

At least 19 recordsLinked to original sources
PubMed2006

XPD common variants and their association with melanoma and breast cancer risk.

There are suggestions in the literature that common variants in the XPD gene may be associated with an altered risk of melanoma and breast cancer. To establish if the XPD common variants Asp312Asn and Lys751Gln are associated with an increased melanoma or breast cancer risk we performed an association study based on genotyping 426 unselected patients with malignant melanoma (MM) and 1830 consecutive breast cancer cases and compared the results to 1262 geographically matched newborns, 621 adults from the region of Szczecin (unselected for age and cancer family history), 421 healthy adults age- and sex-matched with the melanoma cases and 511 healthy controls matched with the breast cancer patients from the region of Szczecin. Additionally we examined the prevalence of three additional XPD variants, Gly156Gly, Leu485Pro and Arg112His amongst the 421 unselected melanoma patients. All of the variants when evaluated singularly were found not to be associated either with melanoma or breast cancer risk in younger or older patients. A modest association was observed with breast cancer risk when the Lys751Gln_CC/Asp312Asn_AA genotype (OR=1.5, p<0.05) segregated together. Individuals harboring the Lys751Gln_CC/Gly156Gly_CC genotype were significantly over-represented among late-onset melanoma cases (OR=1.7, p<0.05). The results of analyses of linkage disequilibrium and haplotype frequency support the thesis that a combination of at least two SNPs (Lys751Gln_CC/Gly156Gly_CC or Lys751Gln_CC/Asp312Asn_AA) inherited as a haplotype was associated with disease. These two pairs of SNPs could therefore be regarded as a single hereditary unit that would have a very small probability of being disrupted by recombination. Additional studies are required to determine whether these particular changes can be associated with an increased risk of other malignancies at different sites of origin.

Adult↗
PubMed2006

BRCA1-positive breast cancers in young women from Poland.

We identified 4316 unselected incident cases of early-onset breast cancers (<51 ears of age at diagnosis) in 18 Polish hospitals between 1996 and 2003. We were able to obtain a blood sample for DNA analysis from 3472 of these (80.4%). All cases were tested for the presence of three founder mutations in BRCA1. The proportion of cases with a BRCA1 mutation was 5.7%. The hereditary proportions were higher than this for women with breast cancer diagnosed before age 40 (9%), for women with cancer of medullary or atypical medullary histology (28%), for those with bilateral cancer (29%) or with a family history of breast or ovarian cancer (13%). It is reasonable to offer genetic testing to women with early-onset breast cancer in Poland.

Adult↗
PubMed2006

Germline MSH2 and MLH1 mutational spectrum including large rearrangements in HNPCC families from Poland (update study).

Germline mutations in the DNA mismatch repair genes MSH2 and MLH1 account for a significant proportion of hereditary non-polyposis colorectal cancer (HNPCC) families. One approach by which development of an efficient DNA-testing procedure can be implemented is to describe the nature and frequency of common mutations in particular ethnic groups. Two hundred and twenty-six patients from families matching the Amsterdam II diagnostic criteria or suspected HNPCC criteria were screened for MSH2 and MLH1 germline mutations. Fifty different pathogenic mutations were found, 25 in MSH2 and 25 in MLH1. Twenty-four of these had not previously been described in other populations. Among our 78 families with MSH2 or MLH1 mutations, 54 (69.2%) were affected by recurrent mutations including 38 found at least twice in our own series. Two of the most frequent alterations were a substitution of A to T at the splice donor site of intron 5 of MSH2 and a missense change (A681T) of MLH1 found in 10 and eight families, respectively. Among large deletions detected by the multiplex ligation-dependent probe amplification assay, exon 9 deletions in the MSH2 gene were found in two families. Our results indicate that a screening protocol specific for the Polish population that is limited to the detection of all reported mutations will result in the identification of the majority of changes present in MLH1 and MSH2 genes in Polish HNPCC kindreds.

Adaptor Proteins, Signal Transducing↗
PubMed2006

A large germline deletion in the Chek2 kinase gene is associated with an increased risk of prostate cancer.

BACKGROUND: Germline mutations in the Chek2 kinase gene (CHEK2) have been associated with a range of cancer types. Recently, a large deletion of exons 9 and 10 of CHEK2 was identified in several unrelated patients with breast cancer of Czech or Slovak origin. The geographical and ethnic extent of this founder allele has not yet been determined. PARTICIPANTS AND METHODS: We assayed for the presence of this deletion, and of three other CHEK2 founder mutations, in 1864 patients with prostate cancer and 5496 controls from Poland. RESULTS: The deletion was detected in 24 of 5496 (0.4%) controls from the general population, and is the most common CHEK2 truncating founder allele in Polish patients. The deletion was identified in 15 of 1864 (0.8%) men with unselected prostate cancer (OR 1.9; 95% CI 0.97 to 3.5; p = 0.09) and in 4 of 249 men with familial prostate cancer (OR 3.7; 95% CI 1.3 to 10.8; p = 0.03). These ORs were similar to those associated with the other truncating mutations (IVS2+1G-->A, 1100delC). CONCLUSION: A large deletion of exons 9 and 10 of CHEK2 confers an increased risk of prostate cancer in Polish men. The del5395 founder deletion might be present in other Slavic populations, including Ukraine, Belarus, Russia, Baltic and Balkan countries. It will be of interest to see to what extent this deletion is responsible for the burden of prostate cancer in other populations.

Checkpoint Kinase 2↗
PubMed2005

A common variant of CDKN2A (p16) predisposes to breast cancer.

BACKGROUND: A common missense variant of the CDKN2A gene (A148T) predisposes to malignant melanoma in Poland. An association between malignant melanoma and breast cancer has been reported in several families with CDKN2A mutations, OBJECTIVE: To determine whether this variant also predisposes to breast cancer. METHODS: Genotyping was undertaken in 4209 cases of breast cancer, unselected for family history, from 18 hospitals throughout Poland and in 3000 controls. RESULTS: The odds ratio (OR) associated with the CDKN2A allele for women diagnosed with breast cancer before the age of 50 was 1.5 (p = 0.002) and after age 50 it was 1.3 (p = 0.2). The effect was particularly strong for patients diagnosed at or before the age of 30 (OR = 3.8; p = 0.0002). CONCLUSIONS: CDKN2A appears to be a low penetrance breast cancer susceptibility gene in Poland. The association should be confirmed in other populations.

Adult↗
PubMed2005

Breast cancer predisposing alleles in Poland.

Mutant alleles of several genes in the DNA repair pathway have been found to predispose women to breast cancer. From a public health perspective, the importance of a given allele in a population is determined by the frequency of the allele and by the relative risk of breast cancer that it confers. In Poland founder alleles of the BRCA1, CHEK2 and NBS1 genes have been associated with an increased risk of breast cancer, but the relative contribution of each of these alleles to the overall breast cancer burden has not yet been determined. We screened 2012 unselected cases of breast cancer and 4000 population controls for 7 different mutations in these genes. Overall, a mutation was found in 12% of the cases and in 6% of the controls. Mutations in BRCA1 and CHEK2 contributed in approximately equal measure to the burden of breast cancer in Poland. A BRCA1 mutation was present in 3% of the cases. The missense BRCA1 mutation C61G was associated with a higher odds ratio for breast cancer (OR=15) than were either of the truncating BRCA1 mutations 4153delA (OR=2.0) and 5382insC (OR=6.2). In contrast, a higher odds ratio was seen for truncating CHEK2 mutations (OR=2.1) than for the missense mutation I157T (OR=1.4). This study suggests that cancer risks may be specific for particular alleles of a susceptibility gene and that these different risks should be taken into account by genetic counselors.

Adult↗
PubMed2005

NOD2 variants and the risk of malignant melanoma.

Both hereditary and environmental factors are important in the aetiology of malignant melanoma. Among the risk factors for malignant melanoma are immunodeficiency and immunosuppression. The recently identified NOD2 gene is involved in the regulation of immune function through activation of the transcription factor nuclear factor-kappaB (NF-kappaB). Three common NOD2 mutations -- 3020insC, G908R and R702W -- have been shown to be associated with chronic inflammatory disease such as Crohn's disease, the 3020insC also with human malignancy colorectal cancer. We examined the frequency of the NOD2 variants in 424 patients with malignant melanoma and 649 controls. The 3020insC mutation was present in 6.9% of unselected cases and 7% of the controls (odds ratio (OR) 1.0; P not significant). The mutation was present in 6.8% of 162 cases diagnosed under the age of 50 and in 7.1% of cases diagnosed after the age of 50. A mutation was present in the index case in 5% of 40 familial melanomas (OR 0.7; P not significant). There were no statistically significant differences between prevalence of G908R and R702W in malignant melanoma patients and controls. In conclusion, the three common NOD2 mutations are not associated with increased risk of development of malignant melanoma.

Adult↗
PubMed2004

CHEK2 is a multiorgan cancer susceptibility gene.

A single founder allele of the CHEK2 gene has been associated with predisposition to breast and prostate cancer in North America and Europe. The CHEK2 protein participates in the DNA damage response in many cell types and is therefore a good candidate for a multisite cancer susceptibility gene. Three founder alleles are present in Poland. Two of these result in a truncated CHEK2 protein, and the other is a missense substitution of an isoleucine for a threonine. We ascertained the prevalence of each of these alleles in 4,008 cancer cases and 4,000 controls, all from Poland. The majority of the common cancer sites were represented. Positive associations with protein-truncating alleles were seen for cancers of the thyroid (odds ratio [OR] 4.9; P=.0006), breast (OR 2.2; P=.02), and prostate (OR 2.2; P=.04). The missense variant I157T was associated with an increased risk of breast cancer (OR 1.4; P=.02), colon cancer (OR 2.0; P=.001), kidney cancer (OR 2.1; P=.0006), prostate cancer (OR 1.7; P=.002), and thyroid cancer (OR 1.9; P=.04). The range of cancers associated with mutations of the CHEK2 gene may be much greater than previously thought.

Case-Control Studies↗
PubMed2004

Attitudes toward preventive oophorectomy among BRCA1 mutation carriers in Poland.

Currently genetic testing for BRCA1 and BRCA2 susceptibility genes is performed throughout Europe and North America. In Poland three founder mutations in BRCA1 account for 14% of all invasive ovarian cancers and oophorectomy is frequently recommended to mutation carriers as a preventive measure. The purpose of the present study was to evaluate patient acceptance of the recommendation for prophylactic oophorectomy in a hereditary cancer clinic. Seventy-two women over the age of 40 and who carried a BRCA1 mutation were advised to undergo prophylactic oophorectomy. After a mean follow-up period of 19 months, 43 of the women (60%) had undergone the procedure. Of the 29 women who had not had an oophorectomy, five indicated that they did not intend to do so, 19 indicated that they intended to have the operation in the near future and five were undecided. In conclusion, preventive oophorectomy is acceptable to most Polish women at high risk of hereditary ovarian cancer and should be among the range of services offered in cancer genetics clinics.

Adult↗
PubMed2004

Clinical features of familial ovarian cancer lacking mutations in BRCA1 or BRCA2.

PURPOSE OF INVESTIGATION: The purpose of the present study was to identify the clinical and pathologic features of ovarian cancers in patients who have a family history of breast or ovarian cancer but who do not have a mutation in the BRCA1 or BRCA2 gene. METHODS: 303 patients with ovarian cancer were reviewed for clinical features and for cancer family histories. After the exclusion of 51 patients known to carry BRCA1 or BRCA2 mutations, 24 patients with familial cancer were compared with 228 patients with non-familial cancer. RESULTS: Patients with familial cancer were more likely to have grade 2 tumors, Stage II disease and to present between ages 51 and 60 than were non-familial controls. Ten of 24 patients in the familial group presented between ages 51 and 60 with a grade 2 tumor compared to 3.0 expected (p = 0.001). CONCLUSIONS: Families of women who present with grade 2 ovarian cancer between the ages of 51 and 60 may have an unidentified ovarian cancer susceptibility gene.

Adult↗
PubMed2001

Detection of germline mutations in the BRCA1 gene by RNA-based sequencing.

BRCA1 mutation detection is expensive and has sensitivity limitations, which might at least partially be overcome by RNA-based sequencing. There are claims that RNA tests are unreliable due to differential splicing, exon skipping, or nonsense-mediated mRNA decay that results in either the absence or low expression of mRNA harboring mutations. The major aim of this study was to determine if the application of specific high temperature annealing primers can assure high sensitivity of detection of BRCA1 sequence alterations by cDNA sequencing. The study group comprised 21 Polish cancer families with aggregations of breast and/or ovarian cancer. We detected mutations in 10 out of 21 unrelated patients. These were: nucleotide substitutions (c.309T>C; c.300T>G); nucleotide insertions (c.5382insC) three cases; nucleotide deletions (c.4154delA) one case, (c. 185delAG) one case, (c.3819delGTAAA) two cases; and the deletion of the entire sequence of exon 22, one case. In addition, we identified three transcript variants resulting from alternative splice sites affecting the last six nucleotides of exon 1a (GTAAAG), and the first three nucleotides (CAG) of exon 8 and exon 14. In all cases these were cDNA heterozygous changes. Two of these splice site changes have not been previously described. Sequencing of genomic DNA "exon by exon" did not result in the detection of any additional abnormalities. The sensitivity of our analyses was sufficient to reliably detect mutations without the necessity of tissue culturing to obtain enough template cDNA for analysis.

Alternative Splicing↗
PubMed2001

Characterization of a familial RCC-associated t(2;3)(q33;q21) chromosome translocation.

A Polish family was identified in which multifocal clear cell renal carcinoma segregated with a balanced constitutional chromosome translocation, t(2:3)(q33;q21), similar to the renal cell cancer-associated t(2;3)(q35;q21) reported in a Dutch family. Bacterial artificial chromosome (BAC) contigs encompassing the 2q and 3q breakpoints were constructed and BACs crossing the breakpoints were partially sequenced. All known regional markers, genes, and expressed sequence tags (ESTs) were mapped relative to the contigs, as well as to the breakpoint sequences. Two single ESTs mapped within the 2q breakpoint BAC, whereas the repeat-rich 3q breakpoint region was gene poor. Physical mapping suggested that the 3q break was in 3q13, possibly near the border with 3q21. Physical mapping illustrated that the 2q break was closely telomeric to the 2q31 FRA2G site, consistent with the G-band assignment. Characterization of full-length cDNAs for the ESTs near the 2q break will determine if a gene(s) is altered by this familial translocation.

Carcinoma, Renal Cell↗
PubMed2001

The DIRC1 gene at chromosome 2q33 spans a familial RCC-associated t(2;3)(q33;q21) chromosome translocation.

A reciprocal, balanced, constitutional chromosome translocation, t(2;3)(q33;q21), which is associated with familial clear cell renal cancer, has been described and the genomic regions surrounding the 2q and 3q breakpoints have been characterized. Based on the genomic map of the 2q break, EST AI468595 was positioned near the 2q33 translocation and the full-length gene and cDNA were isolated. This 57-kb gene, designated the DIRC1 gene, was disrupted between exons 1 and 2 by the familial translocation. The 1.5-kb mRNA encodes an 11-kDa predicted protein of 104 amino acids. Low-level expression of DIRC1 was detected by reverse transcriptase-polymerase chain reaction amplification in adult placenta, testis, ovary, and prostate and in fetal kidney, spleen, and skeletal muscle. A GFP-Dirc1 fusion protein was expressed in vitro and a polyclonal anti-Dircl peptide serum was prepared. A panel of cancer and cancer-derived cell line DNAs was examined for DIRC1 mutations, but only a rare polymorphism was observed. Two familial tumors showed loss of the derivative 3 chromosome, as observed in a Dutch kindred with t(2;3)associated renal cancers. Mutations in the second DIRC1 allele were not detected. Further studies will be required to determine if disruption of the DIRC1 gene contributed to development of the associated familial clear cell renal cancers.

3T3 Cells↗