BRCA to the future: towards best testing practice in the era of personalised healthcare

Abstract

The year 2014 marked the twentieth anniversary of the discovery of the breast cancer susceptibility gene, BRCA1. 1,2 Since this discovery, our understanding of pathogenic BRCA variants and the associated increase in lifetime cancer risks has advanced significantly. 3,4 National guidelines have been developed to help clinicians identify patients with an increased risk of pathogenic BRCA mutations, and genetic counselling for risk assessment is now a routine practice. 5,6 The evolution of genetic counselling models has placed increasing importance on the use of multidisciplinary health-care teams, including medical geneticists, genetic counsellors, gynaecologists, surgeons, radiotherapists, medical oncologists and all other professionals involved in a patient's management. There has also been a surge of technological advances and new strategies allowing for the rapid turnaround of BRCA1 and BRCA2 mutation testing. In addition, evaluation of BRCA and other BRCA-like deleterious mutations as potentially actionable tumour targets are underway, such as the development of poly(ADP)-ribose polymerase (PARP) inhibitors in classes four or five BRCA mutation-positive cancers. [7][8][9] The present supplement contains review articles based on presentations from a scientific symposium focused on the evolving BRCA testing landscape (BRCA to the future: towards best testing practice in the era of personalised healthcare) held at the European Human Genetics Conference in Milan, June 2014.In the first review, Professor Dominique Stoppa-Lyonnet discusses the biological effects and clinical implications of pathogenic BRCA mutations. BRCA1 and BRCA2 have key roles in the repair of DNA double-strand breaks via the mechanism of homologous recombination (HR) and ensure genome stability. 10-13 Germline deleterious mutations in BRCA1 or BRCA2 are associated with elevated risk of developing breast and/or ovarian cancer, sometimes with a genotype-phenotype correlation. 3,4,14 BRCA pathogenic mutationpositive ovarian or breast cancers are susceptible to inhibitors of additional DNA damage repair pathways, such as PARP inhibitors. [7][8][9] As the presence of actionable BRCA mutations in patients with breast and/or ovarian cancer becomes increasingly important in clinical management decisions, there is increasing support to expand the screening criteria for BRCA mutation testing, including testing for pathogenic mutations in other HR-deficiency genes.In his review on BRCA testing, Dr Andrew Wallace covers the challenges of BRCA testing from the perspective of a diagnostic laboratory. Demand for BRCA testing is steadily increasing, placing a strain on diagnostics laboratories, particularly in those offering rapid genetic testing at the point of diagnosis. Increasingly, diagnostic laboratories are adopting next-generation sequencing (NGS) technology for BRCA testing, which offers the potential of fast, scalable, costefficient and comprehensive sequencing. [15][16][17][18][19] However, the choice and complexity surrounding NGS means that adopt...

Main implications related to the switch to BRCA1/2 tumor testing in ovarian cancer patients: a proposal of a consensus

“…Based on the above appraisals, tBRCA1/2 testing should be strongly harmonized worldwide [ 3 , 12 ] in order to: a) ensure best access to innovative therapies, b) identify in advance mutations that might involve the family, c) prevent the occurrence of a second cancer, d) facilitate the diagnostic process and family management [ 27 – 31 ]; e) improve results deriving from clinical ongoing and future trials [ 30 ]. In these regards, both germline and somatic BRCA1/2 assays have the same dignity and value: in fact, when these molecular assays are correctly performed, they can provide clinically useful information regarding both family risk and targeted treatment [ 1 , 4 , 7 ].…”

A Whole Germline BRCA2 Gene Deletion: How to Learn from CNV In Silico Analysis

“…Massive Parallel Sequencing technologies have increased the feasibility of molecular test screening in cancer diagnostics. Furthermore, several studies are ongoing in order to evaluate the benefits that are provided by this technology in routine diagnostics, above all in ovarian cancer BRCA1/2 assessment [ 13 , 14 , 15 , 16 , 17 ]. NGS platforms are able to provide reliable qualitative data: nevertheless, one of the main challenges regards its ability to precisely identify quantitative changes, like gain or loss in the genes investigated [ 18 , 19 ].…”

Germline BRCA 1-2 status prediction through ovarian ultrasound images radiogenomics: a hypothesis generating study (PROBE study)

“…All patients included in the study received oncogenetic counseling before BRCA testing and signed written informed consent for BRCA analysis. Standardized procedures according to previously published workflows were observed 34,35 .…”