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. 2020 Aug 25;12(9):2415.
doi: 10.3390/cancers12092415.

Detection of Germline Mutations in a Cohort of 139 Patients with Bilateral Breast Cancer by Multi-Gene Panel Testing: Impact of Pathogenic Variants in Other Genes beyond BRCA1/2

Daniele Fanale  1 , Lorena Incorvaia  2 , Clarissa Filorizzo  1 , Marco Bono  1 , Alessia Fiorino  1 , Valentina Calò  1 , Chiara Brando  1 , Lidia Rita Corsini  1 , Nadia Barraco  1 , Giuseppe Badalamenti  1 , Antonio Russo  1 , Viviana Bazan  2
Affiliations

Detection of Germline Mutations in a Cohort of 139 Patients with Bilateral Breast Cancer by Multi-Gene Panel Testing: Impact of Pathogenic Variants in Other Genes beyond BRCA1/2

Daniele Fanale et al. Cancers (Basel). .

Abstract

Patients with unilateral breast cancer (UBC) have an increased risk of developing bilateral breast cancer (BBC). The annual risk of contralateral BC is about 0.5%, but increases by up to 3% in BRCA1 or BRCA2 pathogenic variant (PV) carriers. Our study was aimed to evaluate whether all BBC patients should be offered multi-gene panel testing, regardless their cancer family history and age at diagnosis. We retrospectively collected all clinical information of 139 BBC patients genetically tested for germline PVs in different cancer susceptibility genes by NGS-based multi-gene panel testing. Our investigation revealed that 52 (37.4%) out of 139 BBC patients harbored germline PVs in high- and intermediate-penetrance breast cancer (BC) susceptibility genes including BRCA1, BRCA2, PTEN, PALB2, CHEK2, ATM, RAD51C. Nineteen out of 53 positively tested patients harbored a PV in a known BC susceptibility gene (no-BRCA). Interestingly, in the absence of an analysis performed via multi-gene panel, a significant proportion (14.4%) of PVs would have been lost. Therefore, offering a NGS-based multi-gene panel testing to all BBC patients may significantly increase the detection rates of germline PVs in other cancer susceptibility genes beyond BRCA1/2, avoiding underestimation of the number of individuals affected by a hereditary tumor syndrome.

Keywords: ATM; BRCA1; BRCA2; CHECK2; PALB2; PTEN; bilateral breast cancer; breast cancer; germline pathogenic variants; multi-gene panel testing.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Distribution and frequency of variants of uncertain significance (VUS) identified in different genes of bilateral breast cancer patients. The OncoPrint, showing the identified VUS by heatmap, was obtained by the informatic tool Mutation Mapper-cBioPortal for Cancer Genomics.
Figure 2
Figure 2
BRCA1 functional domains and gene location of BRCA1 PVs in bilateral breast cancer patients. Abbreviations: BRCT, BRCA1 C-terminus domain; NLS, nuclear localization sequence; PVs, pathogenic variants; SCD, serine cluster domain. * This PV is present together with the BRCA2 PV named c.8331+2T>C in one patient showing double heterozygosity for BRCA1 and BRCA2 PVs.
Figure 3
Figure 3
BRCA2 functional domains and gene location of BRCA2 PVs in bilateral breast cancer patients. Abbreviations: NLS, nuclear localization sequence; OB, oligonucleotide binding; PVs, pathogenic variants. * This PV is present together with the BRCA1 PV named c.181T>G in one patient showing double heterozygosity for BRCA1 and BRCA2 PVs.
See this image and copyright information in PMC

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