DNA methylation profiling to assess pathogenicity of BRCA1 unclassified variants in breast cancer
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Published version
Author(s)
Type
Journal Article
Abstract
Germline pathogenic mutations in BRCA1 increase risk of developing breast cancer. Screening for mutations in BRCA1 frequently identifies sequence variants of unknown pathogenicity and recent work has aimed to develop methods for determining pathogenicity. We previously observed that tumor DNA methylation can differentiate BRCA1-mutated from BRCA1-wild type tumors. We hypothesized that we could predict pathogenicity of variants based on DNA methylation profiles of tumors that had arisen in carriers of unclassified variants. We selected 150 FFPE breast tumor DNA samples [47 BRCA1 pathogenic mutation carriers, 65 BRCAx (BRCA1-wild type), 38 BRCA1 test variants] and analyzed a subset (n=54) using the Illumina 450K methylation platform, using the remaining samples for bisulphite pyrosequencing validation. Three validated markers (BACH2, C8orf31, and LOC654342) were combined with sequence bioinformatics in a model to predict pathogenicity of 27 variants (independent test set). Predictions were compared with standard multifactorial likelihood analysis. Prediction was consistent for c.5194-12G>A (IVS 19-12 G>A) (P>0.99); 13 variants were considered not pathogenic or likely not pathogenic using both approaches. We conclude that tumor DNA methylation data alone has potential to be used in prediction of BRCA1 variant pathogenicity but is not independent of estrogen receptor status and grade, which are used in current multifactorial models to predict pathogenicity.
Date Issued
2016-02-01
Date Acceptance
2015-10-16
Citation
Epigenetics, 2016, 10 (12), pp.1121-1132
ISSN
1559-2308
Publisher
Taylor & Francis
Start Page
1121
End Page
1132
Journal / Book Title
Epigenetics
Volume
10
Issue
12
Copyright Statement
© Kirsty J Flower, Natalie S Shenker, Mona El-Bahrawy, David E Goldgar, Michael T Parsons, KConFab Investigators, Affect study group, Amanda B Spurdle, Joanna
R Morris, Robert Brown and James M Flanagan. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s)
have been asserted
R Morris, Robert Brown and James M Flanagan. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s)
have been asserted
License URL
Sponsor
Breast Cancer Care & Breast Cancer Now
Breast Cancer Care & Breast Cancer Now
Imperial College Healthcare NHS Trust- BRC Funding
Cancer Research UK
Imperial College Healthcare NHS Trust- BRC Funding
Identifier
https://www.tandfonline.com/doi/full/10.1080/15592294.2015.1111504
Grant Number
2009MaySF03
WSCC_P33227
RDB01 79560
13086
RDB01 79560
Subjects
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Genetics & Heredity
BRCA1
breast cancer
epigenetic
methylation
variants
RECEPTOR IMMUNOCYTOCHEMISTRY
MISSENSE SUBSTITUTIONS
CLINICAL-SIGNIFICANCE
MOLECULAR SUBTYPES
SEQUENCE VARIANTS
MUTATION STATUS
RISK
ESTROGEN
GENES
CLASSIFICATION
BRCA1
breast cancer
epigenetic
methylation
variants
Breast Neoplasms
Computational Biology
DNA Methylation
DNA Mutational Analysis
Female
Genes, BRCA1
Genetic Markers
Genetic Predisposition to Disease
Humans
KConFab Investigators
Affect Study Group
Humans
Breast Neoplasms
Genetic Predisposition to Disease
Genetic Markers
DNA Mutational Analysis
Computational Biology
DNA Methylation
Genes, BRCA1
Female
0601 Biochemistry and Cell Biology
0604 Genetics
1101 Medical Biochemistry and Metabolomics
Developmental Biology
Publication Status
Published
Date Publish Online
2016-01-04