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Accurate prediction of BRCA1 and BRCA2 heterozygous genotype using expression profiling after induced DNA damage

Accurate prediction of BRCA1 and BRCA2 heterozygous genotype using expression profiling after induced DNA damage
Accurate prediction of BRCA1 and BRCA2 heterozygous genotype using expression profiling after induced DNA damage
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
patterns, gene, brca1, cultures, breast-cancer, transcription, rad51, breast cancer, cell, cancer susceptibility, expression, mutations, genes, DNA, cells, mutation, irradiation, breast, cancer, gene-expression, classification, DNA-damage, prediction, brca2
1078-0432
3896-3901
Kote-Jarai, Zsofia
c5b0a417-48b3-4cd4-a242-8fad3f4d4bf6
Matthews, Lucy
ea0fa3fc-586b-4efe-a9c3-fc430ac44ac3
Osorio, Ana
5d37d9d7-d889-4e14-ad7c-7b7f73f6e299
Shanley, Susan
a0d8bf7d-730c-40ad-b9d0-d6e85f87fb95
Giddings, Ian
3a2ebe4a-6036-43e9-8c4f-13da9fd2a145
Moreews, Francois
a0570f18-bfe0-4cae-8580-1f2a6169dc1b
Locke, Imogen
ea9f3b84-f732-46f7-8180-664203c4594d
Evans, D. Gareth
314acefb-89fb-4eb7-a0e7-0a6949c9af6c
Eccles, Diana
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
Williams, Richard D.
1209c95e-6400-42df-8858-77fd23cbb301
Girolami, Mark
4feb7248-7beb-4edc-8509-139b4049d23b
Campbell, Colin
e9ed00aa-68df-413f-9a44-05273df75e73
Eeles, Ros
1101f5dc-f8ae-4102-99fb-f814695e5f9c
The Carrier Clinic Collaborators
Kote-Jarai, Zsofia
c5b0a417-48b3-4cd4-a242-8fad3f4d4bf6
Matthews, Lucy
ea0fa3fc-586b-4efe-a9c3-fc430ac44ac3
Osorio, Ana
5d37d9d7-d889-4e14-ad7c-7b7f73f6e299
Shanley, Susan
a0d8bf7d-730c-40ad-b9d0-d6e85f87fb95
Giddings, Ian
3a2ebe4a-6036-43e9-8c4f-13da9fd2a145
Moreews, Francois
a0570f18-bfe0-4cae-8580-1f2a6169dc1b
Locke, Imogen
ea9f3b84-f732-46f7-8180-664203c4594d
Evans, D. Gareth
314acefb-89fb-4eb7-a0e7-0a6949c9af6c
Eccles, Diana
5b59bc73-11c9-4cf0-a9d5-7a8e523eee23
Williams, Richard D.
1209c95e-6400-42df-8858-77fd23cbb301
Girolami, Mark
4feb7248-7beb-4edc-8509-139b4049d23b
Campbell, Colin
e9ed00aa-68df-413f-9a44-05273df75e73
Eeles, Ros
1101f5dc-f8ae-4102-99fb-f814695e5f9c

Kote-Jarai, Zsofia, Matthews, Lucy, Osorio, Ana, Shanley, Susan, Giddings, Ian, Moreews, Francois, Locke, Imogen, Evans, D. Gareth, Eccles, Diana, Williams, Richard D., Girolami, Mark, Campbell, Colin and Eeles, Ros , The Carrier Clinic Collaborators (2006) Accurate prediction of BRCA1 and BRCA2 heterozygous genotype using expression profiling after induced DNA damage. Clinical Cancer Research, 12 (13), 3896-3901.

Record type: Article

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

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More information

Published date: 1 July 2006
Keywords: patterns, gene, brca1, cultures, breast-cancer, transcription, rad51, breast cancer, cell, cancer susceptibility, expression, mutations, genes, DNA, cells, mutation, irradiation, breast, cancer, gene-expression, classification, DNA-damage, prediction, brca2

Identifiers

Local EPrints ID: 62819
URI: http://eprints.soton.ac.uk/id/eprint/62819
ISSN: 1078-0432
PURE UUID: 49c2f858-c41b-43d2-b233-ed166967e5a1

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Date deposited: 04 Sep 2008
Last modified: 13 Mar 2019 20:27

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Contributors

Author: Zsofia Kote-Jarai
Author: Lucy Matthews
Author: Ana Osorio
Author: Susan Shanley
Author: Ian Giddings
Author: Francois Moreews
Author: Imogen Locke
Author: D. Gareth Evans
Author: Diana Eccles
Author: Richard D. Williams
Author: Mark Girolami
Author: Colin Campbell
Author: Ros Eeles

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