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BRCA1 and BRCA2 missense variants of high and low clinical significance influence lymphoblastoid cell line post-irradiation gene expression

Waddell, N; Ten Haaf, A; Marsh, A; Johnson, J; Walker, LC; Gongora, M; Brown, M; ... kConFab Investigators, ; + view all (2008) BRCA1 and BRCA2 missense variants of high and low clinical significance influence lymphoblastoid cell line post-irradiation gene expression. PLOS GENET , 4 (5) , Article e1000080. 10.1371/journal.pgen.1000080. Green open access

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Abstract

The functional consequences of missense variants in disease genes are difficult to predict. We assessed if gene expression profiles could distinguish between BRCA1 or BRCA2 pathogenic truncating and missense mutation carriers and familial breast cancer cases whose disease was not attributable to BRCA1 or BRCA2 mutations (BRCAX cases). 72 cell lines from affected women in high-risk breast ovarian families were assayed after exposure to ionising irradiation, including 23 BRCA1 carriers, 22 BRCA2 carriers, and 27 BRCAX individuals. A subset of 10 BRCAX individuals carried rare BRCA1/2 sequence variants considered to be of low clinical significance (LCS). BRCA1 and BRCA2 mutation carriers had similar expression profiles, with some subclustering of missense mutation carriers. The majority of BRCAX individuals formed a distinct cluster, but BRCAX individuals with LCS variants had expression profiles similar to BRCA1/2 mutation carriers. Gaussian Process Classifier predicted BRCA1, BRCA2 and BRCAX status, with a maximum of 62% accuracy, and prediction accuracy decreased with inclusion of BRCAX samples carrying an LCS variant, and inclusion of pathogenic missense carriers. Similarly, prediction of mutation status with gene lists derived using Support Vector Machines was good for BRCAX samples without an LCS variant (82-94%), poor for BRCAX with an LCS (40-50%), and improved for pathogenic BRCA1/2 mutation carriers when the gene list used for prediction was appropriate to mutation effect being tested (71-100%). This study indicates that mutation effect, and presence of rare variants possibly associated with a low risk of cancer, must be considered in the development of array-based assays of variant pathogenicity.

Type: Article
Title: BRCA1 and BRCA2 missense variants of high and low clinical significance influence lymphoblastoid cell line post-irradiation gene expression
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pgen.1000080
Publisher version: http://dx.doi.org/10.1371/journal.pgen.1000080
Language: English
Additional information: Copyright: © 2008 Waddell et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This research was supported by a grant from the Susan G. Komen Breast Cancer Foundation, and the NHMRC. MG is an Engineering and Physical Sciences Research Council of the UK Advanced Research Fellow (EP/EO52029/1), GC-T is an NHMRC Senior Principal Research Fellow, SMG is an NHMRC Senior Research Fellow, and ABS is a recipient of an NHMRC Career Development Award. NW was supported by grant funding from the National Breast Cancer Foundation, and LCW was supported by grant funding from the NHMRC. The kConFab resource is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC) and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. Some kConFab data is derived from the kConFab Clinical Follow Up Study, funded by NHMRC grants.
Keywords: HEREDITARY BREAST-CANCER, DNA-SEQUENCE VARIANTS, OVARIAN-CANCER, FUNCTIONAL-ANALYSIS, IONIZING-RADIATION, MUTATION, RISK, CLASSIFICATION, SUBSTITUTIONS, PROFILES
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/1339732
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