Multigene panel testing beyond BRCA1/2 in breast/ovarian cancer Spanish families and clinical actionability of findings
Few and small studies have been reported about multigene testing usage by massively parallel sequencing in European cancer families. There is an open debate about what genes should be tested, and the actionability of some included genes is under research.
We investigated a panel of 34 known high/moderate-risk cancer genes, including 16 related to breast or ovarian cancer (BC/OC) genes, and 63 candidate genes to BC/OC in 192 clinically suspicious of hereditary breast/ovarian cancer (HBOC) Spanish families without pathogenic variants in BRCA1 or BRCA2 (BRCA1/2).
We identified 16 patients who carried a high- or moderate-risk pathogenic variant in eight genes: 4 PALB2, 3 ATM, 2 RAD51D, 2 TP53, 2 APC, 1 BRIP1, 1 PTEN and 1 PMS2. These findings led to increased surveillance or prevention options in 12 patients and predictive testing in their family members. We detected 383 unique variants of uncertain significance in known cancer genes, of which 35 were prioritized in silico. Eighteen loss-of-function variants were detected in candidate BC/OC genes in 17 patients (1 BARD1, 1 ERCC3, 1 ERCC5, 2 FANCE, 1 FANCI, 2 FANCL, 1 FANCM, 1 MCPH1, 1 PPM1D, 2 RBBP8, 3 RECQL4 and 1 with SLX4 and XRCC2), three of which also carry pathogenic variants in known cancer genes.
Eight percent of the BRCA1/2 negative patients carry pathogenic variants in other actionable genes. The multigene panel usage improves the diagnostic yield in HBOC testing and it is an effective tool to identify potentially new candidate genes.
KeywordsBreast/ovarian hereditary cancer BRCA1 or BRCA2 negative Panel testing by massively parallel sequencing Clinical actionability
The authors acknowledge the Cellex Foundation for providing research facilities and equipment.
This work was supported by Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds: FIS PI12/02585 and PI15/00355 (to O Diez), PI13/01711 and PI16/01218 (to S. Gutiérrez-Enríquez). S. Gutiérrez-Enríquez and S. Bonache are supported by the Miguel Servet Progam (CPII16/00034) and AECC contract, respectively.
Compliance with ethical standards
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent, approved by the Clinical Research Ethics Committee of Vall d’Hebron Hospital from Barcelona, was obtained from all individual participants included in the study.
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