Publications (5)10.22 Total impact
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Article: Full sequencing of TP53 identifies identical mutations within in situ and invasive components in breast cancer suggesting clonal evolution.
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ABSTRACT: In breast cancer, previous studies have suggested that somatic TP53 mutations are likely to be an early event. However, there are controversies regarding the cellular origin and linear course of breast cancer. The purpose of this study was to investigate tumor evolution in breast cancer by analyzing TP53 mutation status in tumors from various stages of the disease. The entire coding sequence of TP53 was sequenced in a cohort of pure ductal carcinoma in situ (DCIS), pure invasive cancer (≤15mm) and mixed lesions (i.e. invasive cancer with an in situ component). Of 118 tumor samples, 19 were found to harbor a TP53 mutation; 5 (15.6%) of the pure DCIS, 4 (10.5%) of the pure invasive cancers and 10 (20.8%) of the mixed lesions. In the mixed lesions, both the invasive and the DCIS components showed the same mutation in all 5 cases where the two components were successfully microdissected. Presence of the same mutation in both DCIS and invasive components from the same tumor indicates same cellular origin. The role of mutant TP53 in the progression of breast cancer is less clear and may vary between subtypes.Molecular oncology 04/2009; 3(3):214-9. · 4.10 Impact Factor -
Article: TP53 mutations in synchronous and metachronous bilateral breast carcinomas.
Cancer genetics and cytogenetics 08/2008; 184(2):119-21. · 1.54 Impact Factor -
Article: A comparison between p53 accumulation determined by immunohistochemistry and TP53 mutations as prognostic variables in tumours from breast cancer patients.
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ABSTRACT: p53 accumulation and TP53 mutations are known prognostic markers for breast cancer. To clarify their interrelationship and the importance of different TP53 mutation types, these markers were investigated in tumours from 630 patients with breast cancer. Tumour sections were stained for p53 and scored based on staining intensity and percentages of invasive tumour cells with nuclear staining. TP53 mutations were identified by sequencing. Patient cohorts were from the DBCG (Danish Breast Cancer Cooperative Group) protocols DBCG82 and DBCG89. TP53 was mutated in 29% of the patients. The disease-specific survival (DSS) at 15 years of follow-up for patients with missense mutations directly involved in DNA or zinc binding was 21+/-8%. Patients with the remaining missense mutations within the structural/conserved domains and patients with null mutations had a DSS of 36+/-6% and 31+/-17%, respectively. For patients without TP53 mutations and patients with mutations affecting amino acids outside these domains, the 15 year DSS was 51+/-3% and 71+/-10%, respectively. p53 accumulation was successfully scored in 567 patients and categorized into three groups. Tumours with no p53 expression had a high frequency of null mutations (37% compared to 10% in the whole cohort), and tumours with high p53 expression contained 82% of the missense mutations inside structural/conserved domains including those directly involved in DNA or zinc binding. The clinical outcome for breast cancer patients is significantly different for different TP53 mutation types, but further functional studies are required to clarify the exact role of these mutation types. Most of the mutations that lead to mutant p53 protein accumulation can be detected by immunohistochemistry but the specificity is low. Samples showing lack of detectable p53 protein should be considered as an indication of a possible null mutation.Acta oncologica (Stockholm, Sweden) 02/2008; 47(4):600-7. · 2.27 Impact Factor -
Article: Linkage disequilibrium pattern of the ATM gene in breast cancer patients and controls; association of SNPs and haplotypes to radio-sensitivity and post-lumpectomy local recurrence.
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ABSTRACT: The ATM protein is activated as a result of ionizing radiation, and genetic variants of the ATM gene may therefore affect the level of radiation-induced damage. Individuals heterozygous for ATM mutations have been reported to have an increased risk of malignancy, especially breast cancer. Norwegian breast cancer patients (272) treated with radiation (252 of which were evaluated for radiation-induced adverse side effects), 95 Norwegian women with no known history of cancer and 95 American breast cancer patients treated with radiation (44 of which developed ipsilateral breast tumour recurrence, IBTR) were screened for sequence variations in all exons of the ATM gene as well as known intronic variants by denaturating high performance liquid chromatography (dHPLC) followed by sequencing to determine the nature of the variant. A total of 56 variants were identified in the three materials combined. A borderline significant association with breast cancer risk was found for the 1229 T>C (Val>Ala) substitution in exon 11 (P-value 0.055) between the Norwegian controls and breast cancer patients as well as a borderline significant difference in haplotype distribution (P-value 0.06). Adverse side effects, such as: development of costal fractures and telangiectasias, subcutaneous and lung fibrosis, pleural thickening and atrophy were evaluated in the Norwegian patients. Significant associations were found for several of the identified variants such as rs1800058 (Leu > Phe) where a decrease in minor allele frequency was found with increasing level of adverse side effects for the clinical end-points pleural thickening and lung fibrosis, thus giving a protective effect. Overall our results indicate a role for variation in the ATM gene both for risk of developing breast cancer, and in radiation induced adverse side effects. No association could be found between risk of developing ipsilateral breast tumour recurrence and any of the sequence variants found in the American patient material.Radiation Oncology 02/2007; 2:25. · 2.32 Impact Factor -
Article: Mutation screening of the TP53 gene by temporal temperature gradient gel electrophoresis.
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ABSTRACT: A protocol for detection of mutations in the TP53 gene using temporal temperature gradient gel electrophoresis (TTGE) is described. TTGE is a mutation detection technique that separates DNA fragments differing by single base pairs according to their melting properties in a denaturing gel. It is based on constant denaturing conditions in the gel combined with a temperature gradient during the electrophoretic run. This method combines some of the advantages of the related techniques denaturing gradient gel electrophoresis (DGGE) and constant denaturant gel electrophoresis (CDGE) and eliminates some of the problems. The result is a rapid and sensitive screening technique that is robust and easily set up in smaller laboratory environments.Methods in molecular biology (Clifton, N.J.) 02/2005; 291:207-16.
