Detection of BRCA1/2 large genomic rearrangements in breast and ovarian cancer patients: an overview of the current methods

ABSTRACT

Introduction: Currently, genetic testing of BRCA1/2 genes includes screening for single-nucleotide variants, small insertions/deletions, and copy number variations (CNVs). In fact, many studies document the involvement of BRCA1/2 gene rearrangements in genetic predisposition to breast and ovarian cancer. Large genomic rearrangements (LGRs) of BRCA1 may account for up to one-third of all disease-causing alterations in various populations, while LGRs in BRCA2 are less frequently observed.

Areas covered: We aimed to present an overview of current technologies employed in molecular diagnosis of BRCA1/2 LGRs. The most relevant literature papers, showing the application of new strategies, were considered.

Expert opinion: Currently, the progress of next-generation sequencing (NGS) technologies allows for the validation of new pipelines able to provide rapid and effective results, ensuring the sensitivity and specificity requested for the detection of BRCA1/2 LGRs. Multiplex ligation-dependent probe amplification remains the gold standard to confirm NGS CNVs results and to perform fast screening in families where a pathogenic rearrangement has been detected in a proband.

KEYWORDS:

• Breast cancer
• BRCA1
• BRCA2
• large genomic rearrangements (LRGs)
• ovarian cancer

Article Highlights

• The prevalence of BRCA1/2 LGRs varies widely among different population, mainly due to the existence of founder rearrangements.

• The rapid evolution of NGS technologies allowed the search for small variants and CNVs with a single platform and workflow, providing high accuracy and an acceptable turn-around time for clinical decisions.

• All rearrangements identified by NGS analysis need to be confirmed using MLPA or MAQ. Currently, the MLPA technique represents the gold standard for a definitive molecular diagnosis.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewers Disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.