Novel and recurrent BRCA2 mutations in Italian breast/ovarian cancer families widen the ovarian cancer cluster region boundaries to exons 13 and 14

Coppa, Anna; Buffone, Amelia; Capalbo, Carlo; Nicolussi, Arianna; D’Inzeo, Sonia; Belardinilli, Francesca; Colicchia, Valeria; Petroni, Marialaura; Granato, Teresa; Midulla, C; Zani, Massimo; Ferraro, Sergio; Screpanti, Isabella; Gulino, Alberto; Giannini, Giuseppe

doi:10.1007/s10549-014-3196-z

Cited by 13 publications

(7 citation statements)

References 34 publications

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“…Two recurrent variants were detected ( BRCA1 : c.5329dup and BRCA2 : c.5796_5797del). Both have already been reported as recurrently found in a large cohort of individuals, particularly in Italian cohorts [ 34 , 35 , 36 , 37 , 38 ].…”

Section: Discussionmentioning

confidence: 84%

Beyond BRCA1/2: Homologous Recombination Repair Genetic Profile in a Large Cohort of Apulian Ovarian Cancers

Turchiano

Loconte

Nola

et al. 2022

Cancers

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Background: Pathogenic variants in homologous recombination repair (HRR) genes other than BRCA1/2 have been associated with a high risk of ovarian cancer (OC). In current clinical practice, genetic testing is generally limited to BRCA1/2. Herein, we investigated the mutational status of both BRCA1/2 and 5 HRR genes in 69 unselected OC, evaluating the advantage of multigene panel testing in everyday clinical practice. Methods: We analyzed 69 epithelial OC samples using an NGS custom multigene panel of the 5 HRR pathways genes, beyond the genetic screening routine of BRCA1/2 testing. Results: Overall, 19 pathogenic variants (27.5%) were detected. The majority (21.7%) of patients displayed a deleterious mutation in BRCA1/2, whereas 5.8% harbored a pathogenic variant in one of the HRR genes. Additionally, there were 14 (20.3%) uncertain significant variants (VUS). The assessment of germline mutational status showed that a small number of variants (five) were not detected in the corresponding blood sample. Notably, we detected one BRIP1 and four BRCA1/2 deleterious variants in the low-grade serous and endometrioid histology OC, respectively. Conclusion: We demonstrate that using a multigene panel beyond BRCA1/2 improves the diagnostic yield in OC testing, and it could produce clinically relevant results.

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Section: Discussionmentioning

confidence: 84%

Beyond BRCA1/2: Homologous Recombination Repair Genetic Profile in a Large Cohort of Apulian Ovarian Cancers

Turchiano

Loconte

Nola

et al. 2022

Cancers

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“…Mutations in the BRCA1 and BRCA2 genes are responsible for two thirds of hereditary BC, being the most well-known cause of inherited cancer predisposition. The cumulative risk of developing BC by the age of 70 for a BRCA mutation carrier is 65% for BRCA1 and 45% for BRCA2 [4,5].…”

Section: Introductionmentioning

confidence: 99%

Multi gene panel testing for hereditary breast cancer - is it ready to be used?

Cătană

Apostu

Antemie

2019

Medicine and Pharmacy Reports

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Breast cancer is one of the most common malignancies and the leading cause of death among women worldwide. About 20% of breast cancers are hereditary. Approximately 30% of the mutations have remained negative after testing BRCA1/2 even in families with a Mendelian inheritance pattern for breast cancer. Additional non-BRCA genes have been identified as predisposing for breast cancer. Multi gene panel testing tries to cover and explain the BRCA negative inherited breast cancer, improving efficiency, speed and costs of the breast cancer screening. We identified 23 studies reporting results from individuals who have undergone multi gene panel testing for hereditary breast cancer and noticed a prevalence of 1-12% of non-BRCA genes, but also a high level of variants of uncertain significance. A result with a high level of variants of uncertain significance is likely to be more costly than bring benefits, as well as increase the anxiety for patients. Regarding further development of multi gene panel testing, more research is required to establish both the optimal care of patients with cancer (specific treatments like PARP inhibitors) and the management of unaffected individuals (chemoprevention and/or prophylactic surgeries). Early detection in these patients as well as prophylactic measures will significantly increase the chance of survival. Therefore, multi gene panel testing is not yet ready to be used outside clear guidelines. In conclusion, studies on additional cohorts will be needed to better define the real prevalence, penetrance and the variants of these genes, as well as to describe clear evidence-based guidelines for these patients.

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“…The reported cumulative breast cancer risk by the age of 70 is 55–65% for BRCA1 and 45–47% for BRCA2 mutation carriers, while the ovarian cancer risk is 39% for BRCA1 and 11–17% for BRCA2 mutation carriers . Differences in mutation type and site may at least partially impact on cancer risk definition .…”

Section: Introductionmentioning

confidence: 99%

Optimizing the identification of risk‐relevant mutations by multigene panel testing in selected hereditary breast/ovarian cancer families

et al. 2017

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The introduction of multigene panel testing for hereditary breast/ovarian cancer screening has greatly improved efficiency, speed, and costs. However, its clinical utility is still debated, mostly due to the lack of conclusive evidences on the impact of newly discovered genetic variants on cancer risk and lack of evidence‐based guidelines for the clinical management of their carriers. In this pilot study, we aimed to test whether a systematic and multiparametric characterization of newly discovered mutations could enhance the clinical utility of multigene panel sequencing. Out of a pool of 367 breast/ovarian cancer families Sanger‐sequenced for BRCA1 and BRCA2 gene mutations, we selected a cohort of 20 BRCA1/2‐negative families to be subjected to the BROCA‐Cancer Risk Panel massive parallel sequencing. As a strategy for the systematic characterization of newly discovered genetic variants, we collected blood and cancer tissue samples and established lymphoblastoid cell lines from all available individuals in these families, to perform segregation analysis, loss‐of‐heterozygosity and further molecular studies. We identified loss‐of‐function mutations in 6 out 20 high‐risk families, 5 of which occurred on BRCA1,CHEK2 and ATM and are esteemed to be risk‐relevant. In contrast, a novel RAD50 truncating mutation is most likely unrelated to breast cancer. Our data suggest that integrating multigene panel testing with a pre‐organized, multiparametric characterization of newly discovered genetic variants improves the identification of risk‐relevant alleles impacting on the clinical management of their carriers.

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Novel and recurrent BRCA2 mutations in Italian breast/ovarian cancer families widen the ovarian cancer cluster region boundaries to exons 13 and 14

Cited by 13 publications

References 34 publications

Beyond BRCA1/2: Homologous Recombination Repair Genetic Profile in a Large Cohort of Apulian Ovarian Cancers

Beyond BRCA1/2: Homologous Recombination Repair Genetic Profile in a Large Cohort of Apulian Ovarian Cancers

Multi gene panel testing for hereditary breast cancer - is it ready to be used?

Optimizing the identification of risk‐relevant mutations by multigene panel testing in selected hereditary breast/ovarian cancer families

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