Abstract
The aim of this study was to verify the reliability of a next generation sequencing (NGS)-based method as a strategy to detect all possible BRCA mutations, including large genomic rearrangements. Genomic DNA was obtained from a peripheral blood sample provided by a patient from Southern Italy with early onset breast cancer and a family history of diverse cancers. BRCA molecular analysis was performed by NGS, and sequence data were analyzed using two software packages. Comparative genomic hybridization (CGH) array was used as confirmatory method. A novel large duplication, involving exons 4–26, of BRCA2 was directly detected in the patient by NGS workflow including quantitative analysis of copy number variants. The duplication observed was also found by CGH array, thus confirming its extent. Large genomic rearrangements can affect the BRCA1/2 genes, and thus contribute to germline predisposition to familial breast and ovarian cancers. The frequency of these mutations could be underestimated because of technical limitations of several routinely used molecular analysis, while their evaluation should be included also in these molecular testing. The NGS-based strategy described herein is an effective procedure to screen for all kinds of BRCA mutations.
Highlights
Germline mutations in the BRCA genes confer an increased risk for breast and ovarian cancers [1]
Variants occurring on the wild type allele will have a frequency of about 33%, while variants occurring in the duplicated allele will have a frequency of about 66%: these are exactly the values we found in our patient
We report the identification of a large novel BRCA2 duplication in an hereditary breast and ovarian cancer (HBOC) patient obtaHineerde, wuseinrgepaonrtNthGeSid-beansteidficmateiothnoodf.aTlahregetenstoevdelpBaRtiCenAt2isduap4li3c-ayteioanr-oinldanwHomBOanC fpraotmienStooubthtaeirnned uIstianlgy awnhNo GhaSd-baanseedarmlyetohnosdet. bTrheeasttecsatendcepra(tuienndteris4a0 4y3e-ayresaor-foaldgew). oSminacen sfhroemhaSsoautfhaemrinlyIthailsytowryho had an early onset breast cancer
Summary
Germline mutations in the BRCA genes confer an increased risk for breast and ovarian cancers [1]. About 15% of all breast cancer cases fall within the hereditary breast and ovarian cancer (HBOC) syndrome, and BRCA1 and BRCA2 are the two major HBOC susceptibility genes identified so far [2]. BRCA mutations carriers have a higher lifetime risk of different types of cancers, which often occur at an earlier age with respect to the general population [1,2]. Most of the known BRCA1/2 mutations are single nucleotide substitutions or small insertions/deletions (https://research.nhgri.nih.gov/projects/bic/), detectable by DNA sequencing methods. Generally these methods are not able to identify large genomic rearrangements (LGRs) [7]
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