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1. Breast cancer risk and the BRCA1 interacting protein CTIP.

Author

Gorringe KL, Choong DY, Lindeman GJ, Visvader JE, and Campbell IG

Subjects
Australia, Breast Neoplasms ethnology, DNA Mutational Analysis, Endodeoxyribonucleases, Family Health, Female, Genetic Predisposition to Disease, Humans, Male, Mass Screening methods, Microsatellite Repeats, Risk, BRCA1 Protein genetics, BRCA1 Protein physiology, Breast Neoplasms genetics, Breast Neoplasms metabolism, Carrier Proteins genetics, Carrier Proteins physiology, Genes, BRCA1, Mutation, Nuclear Proteins genetics, Nuclear Proteins physiology
Abstract

Mutations in BRCA1 predispose to breast cancer. CTIP interacts with BRCA1 and so could also be associated with increased risk. We screened CTIP for germline mutations in 210 probands of breast cancer families including 129 families with no mutations in BRCA1 or BRCA2. No coding variants were detected in CTIP, therefore, it is unlikely to be involved in breast cancer risk.

Published
2008
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2. Genetic, functional, and histopathological evaluation of two C-terminal BRCA1 missense variants.

Author

Lovelock PK, Healey S, Au W, Sum EY, Tesoriero A, Wong EM, Hinson S, Brinkworth R, Bekessy A, Diez O, Izatt L, Solomon E, Jenkins M, Renard H, Hopper J, Waring P, Tavtigian SV, Goldgar D, Lindeman GJ, Visvader JE, Couch FJ, Henderson BR, Southey M, Chenevix-Trench G, Spurdle AB, and Brown MA

Subjects
Adult, Aged, Australia, Breast Neoplasms pathology, Centrosome metabolism, Female, Genes, Reporter genetics, Humans, Loss of Heterozygosity genetics, Middle Aged, Models, Molecular, Protein Processing, Post-Translational, Protein Transport, RNA Splicing genetics, RNA Stability genetics, Transcription, Genetic, Transcriptional Activation genetics, BRCA1 Protein chemistry, BRCA1 Protein genetics, Mutation, Missense genetics
Abstract

Background: The vast majority of BRCA1 missense sequence variants remain uncharacterized for their possible effect on protein expression and function, and therefore are unclassified in terms of their pathogenicity. BRCA1 plays diverse cellular roles and it is unlikely that any single functional assay will accurately reflect the total cellular implications of missense mutations in this gene., Objective: To elucidate the effect of two BRCA1 variants, 5236G>C (G1706A) and 5242C>A (A1708E) on BRCA1 function, and to survey the relative usefulness of several assays to direct the characterisation of other unclassified variants in BRCA genes., Methods and Results: Data from a range of bioinformatic, genetic, and histopathological analyses, and in vitro functional assays indicated that the 1708E variant was associated with the disruption of different cellular functions of BRCA1. In transient transfection experiments in T47D and 293T cells, the 1708E product was mislocalised to the cytoplasm and induced centrosome amplification in 293T cells. The 1708E variant also failed to transactivate transcription of reporter constructs in mammalian transcriptional transactivation assays. In contrast, the 1706A variant displayed a phenotype comparable to wildtype BRCA1 in these assays. Consistent with functional data, tumours from 1708E carriers showed typical BRCA1 pathology, while tumour material from 1706A carriers displayed few histopathological features associated with BRCA1 related tumours., Conclusions: A comprehensive range of genetic, bioinformatic, and functional analyses have been combined for the characterisation of BRCA1 unclassified sequence variants. Consistent with the functional analyses, the combined odds of causality calculated for the 1706A variant after multifactorial likelihood analysis (1:142) indicates a definitive classification of this variant as "benign". In contrast, functional assays of the 1708E variant indicate that it is pathogenic, possibly through subcellular mislocalisation. However, the combined odds of 262:1 in favour of causality of this variant does not meet the minimal ratio of 1000:1 for classification as pathogenic, and A1708E remains formally designated as unclassified. Our findings highlight the importance of comprehensive genetic information, together with detailed functional analysis for the definitive categorisation of unclassified sequence variants. This combination of analyses may have direct application to the characterisation of other unclassified variants in BRCA1 and BRCA2.

Published
2006
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3. Frequency of the ATM IVS10-6T-->G variant in Australian multiple-case breast cancer families.

Author

Lindeman GJ, Hiew M, Visvader JE, Leary J, Field M, Gaff CL, Gardner RJ, Trainor K, Cheetham G, Suthers G, and Kirk J

Subjects
Adult, Aged, Ataxia Telangiectasia genetics, Ataxia Telangiectasia Mutated Proteins, Australia epidemiology, Cell Cycle Proteins, DNA-Binding Proteins, Female, Genes, BRCA1, Genes, BRCA2, Genetic Carrier Screening, Genetic Testing, Humans, Introns genetics, Male, Middle Aged, Ovarian Neoplasms genetics, Retrospective Studies, Tumor Suppressor Proteins, Breast Neoplasms genetics, Breast Neoplasms, Male genetics, Gene Frequency genetics, Germ-Line Mutation genetics, Protein Serine-Threonine Kinases genetics
Abstract

Background: Germline mutations in the genes BRCA1 and BRCA2 account for only a proportion of hereditary breast cancer, suggesting that additional genes contribute to hereditary breast cancer. Recently a heterozygous variant in the ataxia-telangiectasia mutated (ATM) gene, IVS10-6T-->G, was reported by an Australian multiple-case breast cancer family cohort study (the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer) to confer a substantial breast cancer risk. Although this variant can result in a truncated ATM product, its clinical significance as a high-penetrance breast cancer allele or its role as a low-penetrance risk-modifier is controversial., Methods: We determined the frequency of ATM IVS10-6T-->G variants in a cohort of individuals affected by breast and/or ovarian cancer who underwent BRCA1 and BRCA2 genetic testing at four major Australian familial cancer clinics., Results: Seven of 495 patients (1.4%) were heterozygous for the IVS10-6T-->G variant; the carrier rate in unselected Australian women with no family history of breast cancer is reported to be 6 of 725 (0.83%) (P = 0.4). Two of the seven probands also harboured a pathogenic BRCA1 mutation and one patient had a BRCA1 unclassified variant of uncertain significance., Conclusion: These findings indicate that the ATM IVS10-6T-->G variant does not seem to occur at a significantly higher frequency in affected individuals from high-risk families than in the general population. A role for this variant as a low-penetrance allele or as a modifying gene in association with other genes (such as BRCA1) remains possible. Routine testing for ATM IVS10-6T-->G is not warranted in mutation screening of affected individuals from high-risk families.

Published
2004
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