Detecting Large Germline Rearrangements of BRCA1 by Next Generation Tumor Sequencing

A. Minucci, G. Mazzuccato, C. Marchetti, A. Pietragalla, G. Scambia, A. Fagotti, A. Urbani

Research output: Contribution to journalArticlepeer-review


Abstract: A majority of BRCA1/2 (BRCA) pathogenic variants (PVs) are single nucleotide substitutions or small insertions/deletions. Copy number variations (CNVs), also known as large genomic rearrangements (LGRs), have been identified in BRCA genes. LGRs detection is a mandatory analysis in hereditary breast and ovarian cancer families, if no predisposing PVs are found by sequencing. Next generation sequencing (NGS) may be used to detect structural variation, since quantitative analysis of sequencing reads, when coupled with appropriate bioinformatics tools, is capable of estimating and predicting germline LGRs (gLGRs). However, applying this approach to tumor tissue is challenging, and the pipelines for determination of CNV are yet to be optimized. The aim of this study was to validate the Next Generation Tumor Sequencing (NGTS) technology to detect various gLGRs of BRCA1 locus in surgical tumor tissue samples. In this study, seven different BRCA1 gLGRs, previously found in high-grade serous ovarian cancers (HGSOC) patients, were detected in tumor samples collected from the patients at a time of HGSOC surgery. This study demonstrated that NGS can accurately detect BRCA1 gLGRs in primary tumors, suggesting that gLGR evaluation in BRCA1 locus should be performed in cases when the screening for BRCA alterations starts from tumor instead of blood. NGS sequencing of tumor samples may become the preferred method to detect both somatic and germline gLGRs in BRCA-encoding loci.

Original languageEnglish
Pages (from-to)464-473
Number of pages10
JournalMolecular Biology
Issue number3
Publication statusPublished - May 1 2020


  • BRCA1/2 genes
  • copy number variations
  • high grade serous ovarian cancer
  • large genomic rearrangements
  • NGS sequencing of tumor DNA

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology


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