Accurate Prediction of BRCA1 and BRCA2 Heterozygous Genotype Using Expression Profiling after Induced DNA Damage.

@article{citeulike:741325, abstract = {PURPOSE: In this study, the differential gene expression changes following radiation-induced DNA damage in healthy cells from BRCA1/BRCA1 mutation carriers have been compared with controls using high-density microarray technology. We aimed to establish if BRCA1/BRCA2 mutation carriers could be distinguished from noncarriers based on expression profiling of normal cells. EXPERIMENTAL DESIGN: Short-term primary fibroblast cultures were established from skin biopsies from 10 BRCA1 and 10 BRCA2 mutation carriers and 10 controls, all of whom had previously had breast cancer. The cells were subjected to 15 Gy ionizing irradiation to induce DNA damage. RNA was extracted from all cell cultures, preirradiation and at 1 hour postirradiation. For expression profiling, 15 K spotted cDNA microarrays manufactured by the Cancer Research UK DNA Microarray Facility were used. Statistical feature selection was used with a support vector machine (SVM) classifier to determine the best feature set for predicting BRCA1 or BRCA2 heterozygous genotype. To investigate prediction accuracy, a nonprobabilistic classifier (SVM) and a probabilistic Gaussian process classifier were used. RESULTS: In the task of distinguishing BRCA1 and BRCA2 mutation carriers from noncarriers and from each other following radiation-induced DNA damage, the SVM achieved 90\%, and the Gaussian process classifier achieved 100\% accuracy. This effect could not be achieved without irradiation. In addition, the SVM identified a set of BRCA genotype predictor genes. CONCLUSIONS: We conclude that after irradiation-induced DNA damage, BRCA1 and BRCA2 mutation carrier cells have a distinctive expression phenotype, and this may have a future role in predicting genotypes, with application to clinical detection and classification of mutations.}, address = {Authors' Affiliations: Translational Cancer Genetics Team and Sections of Molecular Carcinogenesis and Paediatric Oncology, The Institute of Cancer Research, Sutton, Surrey, United Kingdom.}, author = {Kote-Jarai, Zsofia and Matthews, Lucy and Osorio, Ana and Shanley, Susan and Giddings, Ian and Moreews, Francois and Locke, Imogen and Evans, D Gareth G. and Eccles, Diana and Williams, Richard D D. and Girolami, Mark and Campbell, Colin and Eeles, Ros }, citeulike-article-id = {741325}, doi = {10.1158/1078-0432.CCR-05-2805}, issn = {1078-0432}, journal = {Clin Cancer Res}, keywords = {microarray, prediction}, month = {July}, number = {13}, pages = {3896--3901}, posted-at = {2006-07-06 00:22:21}, priority = {2}, title = {Accurate Prediction of BRCA1 and BRCA2 Heterozygous Genotype Using Expression Profiling after Induced DNA Damage.}, url = {http://dx.doi.org/10.1158/1078-0432.CCR-05-2805}, volume = {12}, year = {2006} }

TY - JOUR ID - citeulike:741325 L3 - citeulike-article-id:741325 TI - Accurate Prediction of BRCA1 and BRCA2 Heterozygous Genotype Using Expression Profiling after Induced DNA Damage. JF - Clin Cancer Res VL - 12 IS - 13 SP - 3896 EP - 3901 AD - Authors' Affiliations: Translational Cancer Genetics Team and Sections of Molecular Carcinogenesis and Paediatric Oncology, The Institute of Cancer Research, Sutton, Surrey, United Kingdom. SN - 1078-0432 N2 - PURPOSE: In this study, the differential gene expression changes following radiation-induced DNA damage in healthy cells from BRCA1/BRCA1 mutation carriers have been compared with controls using high-density microarray technology. We aimed to establish if BRCA1/BRCA2 mutation carriers could be distinguished from noncarriers based on expression profiling of normal cells. EXPERIMENTAL DESIGN: Short-term primary fibroblast cultures were established from skin biopsies from 10 BRCA1 and 10 BRCA2 mutation carriers and 10 controls, all of whom had previously had breast cancer. The cells were subjected to 15 Gy ionizing irradiation to induce DNA damage. RNA was extracted from all cell cultures, preirradiation and at 1 hour postirradiation. For expression profiling, 15 K spotted cDNA microarrays manufactured by the Cancer Research UK DNA Microarray Facility were used. Statistical feature selection was used with a support vector machine (SVM) classifier to determine the best feature set for predicting BRCA1 or BRCA2 heterozygous genotype. To investigate prediction accuracy, a nonprobabilistic classifier (SVM) and a probabilistic Gaussian process classifier were used. RESULTS: In the task of distinguishing BRCA1 and BRCA2 mutation carriers from noncarriers and from each other following radiation-induced DNA damage, the SVM achieved 90%, and the Gaussian process classifier achieved 100% accuracy. This effect could not be achieved without irradiation. In addition, the SVM identified a set of BRCA genotype predictor genes. CONCLUSIONS: We conclude that after irradiation-induced DNA damage, BRCA1 and BRCA2 mutation carrier cells have a distinctive expression phenotype, and this may have a future role in predicting genotypes, with application to clinical detection and classification of mutations. KW - microarray KW - prediction AU - Kote-Jarai, Zsofia AU - Matthews, Lucy AU - Osorio, Ana AU - Shanley, Susan AU - Giddings, Ian AU - Moreews, Francois AU - Locke, Imogen AU - Evans, D Gareth AU - Eccles, Diana AU - Williams, Richard D AU - Girolami, Mark AU - Campbell, Colin AU - Eeles, Ros PY - 2006/07/01/ UR - http://dx.doi.org/10.1158/1078-0432.CCR-05-2805 ER -