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A V Mitra,
C Jameson,
Y Barbachano, N Sodha,
Z Kote-Jarai,
A Javed,
E Bancroft,
A Fletcher,
C Cooper,
S Peock,
D Easton,
R Eeles,
C S Foster
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ABSTRACT: Prostate cancers in men with germline BRCA1 and BRCA2 mutations are more aggressive than morphologically similar cancers in men without these mutations. This study was performed to test the hypothesis that enhanced expression of Ki-67, as a surrogate of cell proliferation, is a characteristic feature of prostate cancers occurring in BRCA1 or BRCA2 mutation carriers. The study cohort comprised 20 cases of prostate cancer in mutation carriers and 126 control sporadic prostate cancers. Of the combined sample cohort, 65.7% stained only within malignant tissues while 0.7% stained in both malignant and benign tissues (p<0.001). Significantly increased expression of Ki-67 occurred in prostate cancers with higher Gleason score (p<0.001). Elevated Ki-67 expression was identified in 71% of prostate cancers in BRCA1 or BRCA2 mutation carriers and in 67% of the sporadic controls (p>0.5). Similar results were obtained when the data were analysed using a threshold set at 3.5 and 7.1%. This study shows that elevated expression of Ki-67 is associated both with aggressive prostate cancers and with high Gleason score irrespective of whether their occurrence is against a background of BRCA1 or BRCA2 mutations or as sporadic disease. The data suggest that, since elevated Ki-67 does not distinguish prostate cancers occurring in BRCA1 or BRCA2 mutation carriers from sporadic prostatic malignancies, the effects of these genetic mutations are probably independent. While all prostate cancers occurring in the presence of BRCA germline mutations are clinically aggressive, their potentially different phenotypes consistently involve maximal rates of cell proliferation.
Oncology Reports 02/2010; 23(2):299-305. · 1.84 Impact Factor
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ABSTRACT: Germline mutations in the TP53 tumour suppressor gene are associated with Li-Fraumeni syndrome, which is characterised by a spectrum of neoplasms occurring in children and young adults that predominantly include early-onset breast cancer, a variety of sarcomas, brain tumours and adrenocortical tumours. The identification of patients carrying TP53 mutations is primarily based on a positive family history of these early-onset characteristic cancer types. The aim of this study is to emphasize the importance of TP53 molecular testing in patients with very early onset breast cancer and no family history of cancer.
A young woman with no family history of cancer presented with bilateral breast cancer at the age of 27 years. Forty months later she developed malignant fibrous histiocytoma of the right clavicle and another primary left breast cancer. Molecular testing of mutations 185delAG, 5382insC in BRCA1 gene and 6174delT in BRCA2 gene was performed using multiplex PCR and separation on a denaturing polyacrylamide gel. TP53 molecular analysis was performed by PCR-SSCP analysis of the whole coding region of the TP53. Exon 8 PCR products were sequenced using an ABI dye terminator kit and examined on an ABI 3100 automated sequencer.
Molecular testing of peripheral blood DNA did not reveal mutations in BRCA1 or BRCA2 genes. A novel germline TP53 mutation, c.G841C, p.D281N, was identified. The detected mutation is a missense substitution, c.G841C, resulting in the substitution of the amino acid aspartate to asparagine, p.D281N. Molecular analysis in her parents showed that neither of them carried the mutation.
We describe a novel 'de novo'TP53 mutation and discuss the importance of molecular testing in early-onset breast cancer patients and its effect on the management and outcome of the disease.
Clinical Oncology 10/2007; 19(7):490-3. · 2.07 Impact Factor
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N Sodha,
S Bullock,
R Taylor,
G Mitchell,
B Guertl-Lackner,
R D Williams,
S Bevan,
K Bishop,
S McGuire,
R S Houlston,
R A Eeles
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ABSTRACT: We have recently shown that the CHEK2*1100delC mutation acts as a low penetrance breast cancer susceptibility allele. To investigate if other CHEK2 variants confer an increased risk of breast cancer, we have screened an affected individual with breast cancer from 68 breast cancer families. Five of these individuals were found to harbour germline variants in CHEK2. Three carried the 1100delC variant (4%). One of these three individuals also carried the missense variant, Arg180His. In the other two individuals, missense variants, Arg117Gly and Arg137Gln, were identified. These two missense variants reside within the Forkhead-associated domain of CHEK2, which is important for the function of the expressed protein. None of these missense variants were present in 300 healthy controls. Microdissected tumours with a germline mutation showed loss of the mutant allele suggesting a mechanism for tumorigenesis other than a loss of the wild type allele. This study provides further evidence that sequence variation in CHEK2 is associated with an increased risk of breast cancer, and implies that tumorigenesis in association with CHEK2 mutations does not involve loss of the wild type allele.
British Journal of Cancer 01/2003; 87(12):1445-8. · 5.04 Impact Factor
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Science 08/2000; 289(5478):359. · 31.20 Impact Factor
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ABSTRACT: We have tested two rapid assays of p53 function, namely the apoptotic assay and the FASAY as means of detecting germline p53 mutations in members of Li-Fraumeni and Li-Fraumeni-like families. Results of the functional assays have been compared with direct sequencing of all 11 exons of the p53 gene. The results show good agreement between the two functional assays and between them and sequencing. No false-positives or negatives were seen with either functional assay although the apoptotic assay gave one borderline result for an individual without a mutation. As an initial screen the apoptotic assay is not only rapid but inexpensive and very simple to perform. It would be expected to detect any germline defect that leads to loss of p53 function. The apoptotic assay could be ideal as a means of prescreening large numbers of samples and identifying those that require further investigation. The FASAY detects mutations in exons 4-10, is rapid and distinguishes between functionally important and silent mutations.
British Journal of Cancer 04/2000; 82(6):1145-8. · 5.04 Impact Factor
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ABSTRACT: The Li-Fraumeni syndrome (LFS) is a dominant disease whose hallmark is an increased risk of breast cancers, brain tumours, sarcomas, leukaemia and adrenal carcinoma. Some, but not all LFS and Li-Fraumeni-like (LFL) families are caused by TP53 mutations. Bcl10 is a recently identified tumour suppressor reported to be commonly mutated in a wide range of cancers. To investigate the possibility that Bcl10 is a susceptibility gene for LFS and LFL we have analysed 27 LFS/LFL families. No mutations were observed. This indicates that Bcl10 is unlikely to act as a susceptibility gene for LFS and LFL.
Cancer Letters 01/2000; 147(1-2):181-5. · 4.24 Impact Factor
