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Functional disruptions of susceptibility genes by large genomic structure variant (SV) deletions in germlines are known to be associated with cancer risk. However, few studies have been conducted to systematically search for SV deletions in breast cancer susceptibility genes. We analysed deep (> 30x) whole-genome sequencing (WGS) data generated in blood samples from 128 breast cancer patients of Asian and European descent with either a strong family history of breast cancer or early cancer onset disease. To identify SV deletions in known or suspected breast cancer susceptibility genes, we used multiple SV calling tools including Genome STRiP, Delly, Manta, BreakDancer and Pindel. SV deletions were detected by at least three of these bioinformatics tools in five genes. Specifically, we identified heterozygous deletions covering a fraction of the coding regions of BRCA1 (with approximately 80kb in two patients), and TP53 genes (with ∼1.6 kb in two patients), and of intronic regions (∼1 kb) of the PALB2 (one patient), PTEN (three patients) and RAD51C genes (one patient). We confirmed the presence of these deletions using real-time quantitative PCR (qPCR). Our study identified novel SV deletions in breast cancer susceptibility genes and the identification of such SV deletions may improve clinical testing.

Original publication

DOI

10.1093/hmg/ddy005

Type

Journal article

Journal

Human molecular genetics

Publication Date

03/2018

Volume

27

Pages

853 - 859

Addresses

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, and Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37203, USA.

Keywords

Humans, Breast Neoplasms, Genetic Predisposition to Disease, Membrane Proteins, BRCA1 Protein, Sequence Deletion, Genome, Human, Female, Tumor Suppressor Protein p53, PTEN Phosphohydrolase, Rad51 Recombinase, High-Throughput Nucleotide Sequencing, Fanconi Anemia Complementation Group N Protein