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New recurrent BRCA1/2 mutations in Polish patients with familial breast/ovarian cancer detected by next generation sequencing.

ABSTRACT: Targeted PCR-based genetic testing for BRCA1 and BRCA2 can be performed at a lower cost than full gene testing; however, it may overlook mutations responsible for familial breast and/or ovarian cancers. In the present study, we report the utility of next generation sequencing (NGS) to identify new pathogenic variants of BRCA1/2.BRCA1 and BRCA2 exons were amplified using the Ion AmpliSeq BRCA1/2 Panel and sequenced on the Ion Torrent PGM sequencer in 512 women with familial and/or only early onset breast and/or ovarian cancers who were negative for selected BRCA1/2 mutations.146 single nucleotide variants (SNVs) and 32 indels were identified. Of them, 14 SNVs and 17 indels were considered as pathogenic or likely pathogenic. One and 18 pathogenic mutations had been detected previously in the Polish and other populations, respectively, and 12 deleterious mutations were previously unknown. Eight mutations were recurrent; Q563X (BRCA1), N3124I (BRCA2) and c.4516delG (BRCA1) were found in eight, six and four patients, respectively, and two other mutations (c.9118-2A?>?G and c.7249delCA in BRCA2) were detected in three patients each. Altogether, BRCA1/2 pathogenic mutations were identified in 52 out of 512 (10%) patients.NGS substantially improved the detection rates of a wide spectrum of mutations in Polish patients with familial breast and/or ovarian cancer. Although targeted screening for specific BRCA1 mutations can be offered to all Polish breast or ovarian cancer patients, NGS-based testing is justified in patients with breast or ovarian cancer likely related to BRCA1/2 who test negative for the selected BRCA1/2 pathogenic mutations.

SUBMITTER: Kluska A

PROVIDER: S-EPMC4429836 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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New recurrent BRCA1/2 mutations in Polish patients with familial breast/ovarian cancer detected by next generation sequencing.

Kluska Anna A Balabas Aneta A Paziewska Agnieszka A Kulecka Maria M Nowakowska Dorota D Mikula Michal M Ostrowski Jerzy J

BMC medical genomics 20150507

<h4>Background</h4>Targeted PCR-based genetic testing for BRCA1 and BRCA2 can be performed at a lower cost than full gene testing; however, it may overlook mutations responsible for familial breast and/or ovarian cancers. In the present study, we report the utility of next generation sequencing (NGS) to identify new pathogenic variants of BRCA1/2.<h4>Methods</h4>BRCA1 and BRCA2 exons were amplified using the Ion AmpliSeq BRCA1/2 Panel and sequenced on the Ion Torrent PGM sequencer in 512 women w ...[more]

PMID: 25948282

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Project description:Hereditary mutations in BRCA1/2 genes increase the risk of breast cancer by 60-80% and ovarian cancer by about 20-40% in female carriers. Detection of inherited mutations in asymptomatic carriers allows for the implementation of appropriate preventive measures. BRCA1/2 genotyping is also important for poly(adenosine diphosphate)-ribose polymerase (PARP) inhibitor administration. This work addresses the need for next-generation sequencing (NGS) technology for the detection of BRCA1/2 mutations in Poland where until recently mostly founder mutations have been tested, and whether BRCA diagnostics should be extended beyond the panel of founder mutations in this population. The study comprises 2931 patients who were referred for genetic counseling and tested for founder and recurrent mutations in BRCA1 (5382insC (c.5266dupC; p.Gln1756Profs), c.5370C>T (c.5251C>T; p.R1751*), 300T>G (c.181T>G; p.Cys61Gly), 185delAG (c.68_69delAG; p.Glu23Valfs), and 4153delA (c.4035delA; p.Glu1346Lysfs)) by high-resolution melting/Sanger sequencing. A total of 103 (3.5%) mutations were detected, including 53 (51%) in healthy subjects and 50 (49%) in cancer patients. Then, based on more stringent clinical and pedigree criteria, sequencing of all BRCA1/2 exons was performed in 454 (16%) patients without founder mutations by NGS, which detected 58 mutations (12.8%), 40 (8.8%) of which were pathogenic. In 14 (3.1%) subjects, variants of uncertain significance (VUS) were detected, and in four (0.9%) subjects, the detected mutations were benign. In total, 161 mutations were detected using our two-step algorithm (founder test and NGS), of which 64% were founder mutations, 25% were NGS-detected pathogenic mutations, 9% were VUS, and 2% were benign. In addition, 38 mutations not yet reported in the Polish population were detected. In total, founder mutations accounted for only 64% of all detected mutations, and the remaining mutations (36%) were dispersed across the BRCA1/2 gene sequences. Thus, in Poland, testing for constitutional mutations in BRCA1/2 should be carried out in two stages, where NGS is performed in qualifying subjects if founder mutations are not identified.

Dataset Information

New recurrent BRCA1/2 mutations in Polish patients with familial breast/ovarian cancer detected by next generation sequencing.

Publications

New recurrent BRCA1/2 mutations in Polish patients with familial breast/ovarian cancer detected by next generation sequencing.

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