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

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

doi:10.3390/cancers12092415

Cited by 47 publications

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“…Thirty-one percent (4/13) of patients with bilateral BC harbored PVs in non- BRCA genes ( CHEK2 , BARD1 and RAD51C ). These results are in concordance with previous studies [ 32 , 47 ].…”

Section: Discussionsupporting

confidence: 94%

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Germline molecular data in hereditary breast cancer in Brazil: Lessons from a large single-center analysis

et al. 2021

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Brazil is the largest country in South America and the most genetically heterogeneous. The aim of the present study was to determine the prevalence of germline pathogenic variants (PVs) in Brazilian patients with breast cancer (BC) who underwent genetic counseling and genetic testing at a tertiary Oncology Center. We performed a retrospective analysis of the medical records of Brazilian patients with BC referred to genetic counseling and genetic testing between August 2017 and August 2019. A total of 224 unrelated patients were included in this study. Premenopausal women represented 68.7% of the cohort. The median age at BC diagnosis was 45 years. Multigene panel testing was performed in 219 patients, five patients performed single gene analysis or family variant testing. Forty-eight germline PVs distributed among 13 genes were detected in 20.5% of the patients (46/224). Eighty-five percent of the patients (91/224) fulfilled NCCN hereditary BC testing criteria. Among these patients, 23.5% harbored PVs (45/191). In the group of patients that did not meet NCCN criteria, PV detection rate was 3% (1/33). A total of 61% of the patients (28/46) harbored a PV in a high-penetrance BC gene: 19 (8.5%) BRCA1/2, 8 (3.5%) TP53, 1 (0.5%) PALB2. Moderate penetrance genes (ATM, CHEK2) represented 15.2% (7/46) of the positive results. PVs detection was statistically associated (p<0.05) with BC diagnosis before age 45, high-grade tumors, bilateral BC, history of multiple primary cancers, and family history of pancreatic cancer. According to the current hereditary cancer guidelines, 17.4% (39/224) of the patients had actionable variants. Nine percent of the patients (20/224) had actionable variants in non-BRCA genes, it represented 43.5% of the positive results and 51.2% of the actionable variants. Considering the observed prevalence of PVs in actionable genes beyond BRCA1/2 (9%, 20/224), multigene panel testing may offer an effective first-tier diagnostic approach in this population.

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“…Thirty-one percent (4/13) of patients with bilateral BC harbored PVs in non- BRCA genes ( CHEK2 , BARD1 and RAD51C ). These results are in concordance with previous studies [ 32 , 47 ].…”

Section: Discussionsupporting

confidence: 94%

“…Patients with cancer predisposition syndromes have a higher risk of developing a second primary BC, especially for BRCA 1/2 mutation carriers [ 46 ]. Nevertheless, 8–36% of patients with bilateral BC harbor PVs in other genes beyond BRCA [ 32 , 47 , 48 ]. Bilateral BC represented 5.8% (13/224) of our cohort.…”

Section: Discussionmentioning

confidence: 99%

Germline molecular data in hereditary breast cancer in Brazil: Lessons from a large single-center analysis

et al. 2021

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“…Since the discovery of BRCA1 and BRCA2 genes, genetic testing requests have been steadily increasing. Inherited Pathogenic Variants (PVs) or Likely Pathogenic Variants (LPVs) detected in these major susceptibility genes have been shown to be involved in the Hereditary Breast and Ovarian Cancer syndrome (HBOC) (1)(2)(3)(4). However, these sequence variants confer in carriers an increased lifetime risk also to develop other tumors such as pancreatic carcinoma (5,6), prostate cancer (7)(8)(9), and melanoma (10).…”

Section: Introductionmentioning

confidence: 99%

Prevalence and Spectrum of Germline BRCA1 and BRCA2 Variants of Uncertain Significance in Breast/Ovarian Cancer: Mysterious Signals From the Genome

et al. 2021

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About 10–20% of breast/ovarian (BC/OC) cancer patients undergoing germline BRCA1/2 genetic testing have been shown to harbor Variants of Uncertain Significance (VUSs). Since little is known about the prevalence of germline BRCA1/2 VUS in Southern Italy, our study aimed at describing the spectrum of these variants detected in BC/OC patients in order to improve the identification of potentially high-risk BRCA variants helpful in patient clinical management. Eight hundred and seventy-four BC or OC patients, enrolled from October 2016 to December 2020 at the “Sicilian Regional Center for the Prevention, Diagnosis and Treatment of Rare and Heredo-Familial Tumors” of University Hospital Policlinico “P. Giaccone” of Palermo, were genetically tested for germline BRCA1/2 variants through Next-Generation Sequencing analysis. The mutational screening showed that 639 (73.1%) out of 874 patients were BRCA-w.t., whereas 67 (7.7%) were carriers of germline BRCA1/2 VUSs, and 168 (19.2%) harbored germline BRCA1/2 pathogenic/likely pathogenic variants. Our analysis revealed the presence of 59 different VUSs detected in 67 patients, 46 of which were affected by BC and 21 by OC. Twenty-one (35.6%) out of 59 variants were located on BRCA1 gene, whereas 38 (64.4%) on BRCA2. We detected six alterations in BRCA1 and two in BRCA2 with unclear interpretation of clinical significance. Familial anamnesis of a patient harboring the BRCA1-c.3367G>T suggests for this variant a potential of pathogenicity, therefore it should be carefully investigated. Understanding clinical significance of germline BRCA1/2 VUS could improve, in future, the identification of potentially high-risk variants useful for clinical management of BC or OC patients and family members.

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“…46,47 Rebbeck et al 21 The BRCA2-1466delT was more likely associated to HER2-negative BC with higher ER expression (range 70-95%), in patients who carried a high proportion of bilateral breast tumors. 51 In addition, as BRCA1-633delC has been infrequently observed in other Italian regions or in the world, this PV could be further investigated for a possible founder effect specific for the Sicilian population. 27 Understanding the mutational background underlying the phenotype of each tumor may have not only prognostic, but also preventive and therapeutic implications.…”

Section: Discussionmentioning

confidence: 99%

BRCA1/2 pathogenic variants in triple-negative versus luminal-like breast cancers: genotype–phenotype correlation in a cohort of 531 patients

et al. 2020

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Background: Several available data suggest the association between specific molecular subtypes and BRCA1/2 mutational status. Previous investigations showed the association between BRCA1/2 pathogenic variants (PVs) in specific genomic regions and phenotypic variations of cancer relative risk, while the role of PV type and location in determining the breast cancer (BC) phenotypic features remains still unclear. The aim of this research was to describe the germline BRCA1/2 PVs in triple-negative breast cancer (TNBC) versus luminal-like BC and their potential leverage on BC phenotype. Patients & methods: We retrospectively collected and analyzed all clinical information of 531 patients with BC genetically tested for germline BRCA1/2 PVs by Next-Generation Sequencing analysis at University Hospital Policlinico “P. Giaccone” of Palermo (Sicily) from January 2016 to February 2020. Results: Our results corroborate the evidence that BRCA1-related tumors often have a profile which resembles the TNBC subtype, whereas BRCA2-associated tumors have a profile that resembles luminal-like BC, especially the Luminal B subtype. Interestingly, our findings suggest that the PVs identified in TNBC were not largely overlapping with those in luminal-like tumors. Differences in the frequency of two PVs potentially associated with different molecular tumor subtypes were observed. BRCA1-633delC was detected with relatively higher prevalence in patients with TNBC, whereas BRCA2-1466delT was found mainly in Luminal B tumors, but in no TNBC patient. Conclusion: Future studies examining the type and location of BRCA1/2 PVs within different molecular subtypes are required to verify our hypothesis and could provide an interesting insight into the complex topic of genotype–phenotype correlations. Additionally, a more in-depth understanding of the potential correlations between BRCA PVs and clinical and phenotypic features of hereditary BC syndrome patients could be the key to develop better strategies of prevention and surveillance in BRCA-positive carriers without disease.

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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

Cited by 47 publications

References 46 publications

Germline molecular data in hereditary breast cancer in Brazil: Lessons from a large single-center analysis

Germline molecular data in hereditary breast cancer in Brazil: Lessons from a large single-center analysis

Prevalence and Spectrum of Germline BRCA1 and BRCA2 Variants of Uncertain Significance in Breast/Ovarian Cancer: Mysterious Signals From the Genome

BRCA1/2 pathogenic variants in triple-negative versus luminal-like breast cancers: genotype–phenotype correlation in a cohort of 531 patients

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