Germline variants in DNA repair genes associated with hereditary breast and ovarian cancer syndrome: analysis of a 21 gene panel in the Brazilian population

Carvalho, Simone da Costa e Silva; Cury, Nathália Moreno; Brotto, Danielle Barbosa; Araújo, Luíza Ferreira de; Rosa, Reginaldo Cruz Alves; Texeira, Lorena Alves; Plaça, Jéssica Rodrigues; Marques, Adriana Aparecida; Peronni, Kamila Chagas; Ruy, Patrícia de Cássia; Molfetta, Greice Andreotti de; Moriguti, Júlio C.; Carraro, Dirce Maria; Palmero, Edenir Inêz; Ashton‐Prolla, Patrícia; Ferraz, Victor Evangelista de Faria; Silva, Wilson A.

doi:10.1186/s12920-019-0652-y

Cited by 39 publications

(29 citation statements)

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“…Whereas, among 33 patients that did not met NCCN criteria, only one harbored a PV (3%). The detection rate of PVs was similar to other multigene panel testing studies based on hereditary breast and ovarian cancer (HBOC) criteria [ 5 , 13 , 14 , 31 – 33 ].…”

Section: Discussionsupporting

confidence: 83%

“…Most of these patients were tested using a 33-gene panel. A research group from the Brazilian Southeast region performed a 21-gene panel in 95 women with a personal history of BC or HBOC clinical suspicion based on family history criteria [ 14 ]. Twenty-three percent of the patients harbored a PV in BRCA1/2 and TP53 genes.…”

Section: Discussionmentioning

confidence: 99%

“…It was retrospective and had a limited sample size compared to multigene testing studies around the world. However, it represents the largest Brazilian BC cohort from a single institution tested using a multigene panel for hereditary BC [ 13 , 14 ]. It is also the first BC germline characterization from the Center-West of the country.…”

Section: Discussionmentioning

confidence: 99%

“…Even though there are published data on hereditary BC among Latin American countries [ 11 , 12 ], few studies have included non- BRCA genes and multigene panel testing [ 13 , 14 ]. Brazil is the largest country in South America and is the most genetically heterogeneous [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…Multi-gene panels that usually contain known high-risk cancer predisposing genes, such as BRCA1 and BRCA2 , were used to determine the prevalence and spectrum of variants in the genes in defined study groups for comparative purposes. Germline whole gene sequencing panels included 10–219 genes [ 16 , 18 , 19 , 20 , 21 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ] and whole exome sequencing strategies analyzed 10–832 genes [ 63 , 64 , 65 , 66 , 67 ]. These sequencing strategies were used in studies on BC and/or OC and male BC, the first being published in 2011 [ 61 ] ( Figure 1 ).…”

Section: Potentially Pathogenic Germline Bard1 mentioning

confidence: 99%

Literature Review of BARD1 as a Cancer Predisposing Gene with a Focus on Breast and Ovarian Cancers

Alenezi

Fierheller

Recio

et al. 2020

Genes

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Soon after the discovery of BRCA1 and BRCA2 over 20 years ago, it became apparent that not all hereditary breast and/or ovarian cancer syndrome families were explained by germline variants in these cancer predisposing genes, suggesting that other such genes have yet to be discovered. BRCA1-associated ring domain (BARD1), a direct interacting partner of BRCA1, was one of the earliest candidates investigated. Sequencing analyses revealed that potentially pathogenic BARD1 variants likely conferred a low–moderate risk to hereditary breast cancer, but this association is inconsistent. Here, we review studies of BARD1 as a cancer predisposing gene and illustrate the challenge of discovering additional cancer risk genes for hereditary breast and/or ovarian cancer. We selected peer reviewed research articles that focused on three themes: (i) sequence analyses of BARD1 to identify potentially pathogenic germline variants in adult hereditary cancer syndromes; (ii) biological assays of BARD1 variants to assess their effect on protein function; and (iii) association studies of BARD1 variants in family-based and case-control study groups to assess cancer risk. In conclusion, BARD1 is likely to be a low–moderate penetrance breast cancer risk gene.

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BRCA1, BRCA2, and TP53 germline and somatic variants and clinicopathological characteristics of Brazilian patients with epithelial ovarian cancer

Richau,

Scherer,

Matta

et al. 2024

Cancer Medicine

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BackgroundApproximately 3/4 of ovarian cancers are diagnosed in advanced stages, with the high‐grade epithelial ovarian carcinoma (EOC) accounting for 90% of the cases. EOC present high genomic instability and somatic loss‐of‐function variants in genes associated with homologous recombination mutational repair pathway (HR), such as BRCA1 and BRCA2, and in TP53. The identification of germline variants in HR genes in EOC is relevant for treatment of platinum resistant tumors and relapsed tumors with therapies based in synthetic lethality such as PARP inhibitors. Patients with somatic variants in HR genes may also benefit from these therapies. In this work was analyzed the frequency of somatic variants in BRCA1, BRCA2, and TP53 in an EOC cohort of Brazilian patients, estimating the proportion of variants in tumoral tissue and their association with progression‐free survival and overall survival.MethodsThe study was conducted with paired blood/tumor samples from 56 patients. Germline and tumoral sequences of BRCA1, BRCA2, and TP53 were obtained by massive parallel sequencing. The HaplotypeCaller method was used for calling germline variants, and somatic variants were called with Mutect2.ResultsA total of 26 germline variants were found, and seven patients presented germline pathogenic or likely pathogenic variants in BRCA1 or BRCA2. The analysis of tumoral tissue identified 52 somatic variants in 41 patients, being 43 somatic variants affecting or likely affecting protein functionality. Survival analyses showed that tumor staging was associated with overall survival (OS), while the presence of somatic mutation in TP53 was not associated with OS or progression‐free survival.ConclusionFrequency of pathogenic or likely pathogenic germline variants in BRCA1 and BRCA2 (12.5%) was lower in comparison with other studies. TP53 was the most altered gene in tumors, with 62.5% presenting likely non‐functional or non‐functional somatic variants, while eight 14.2% presented likely non‐functional or non‐functional somatic variants in BRCA1 or BRCA2.

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Germline variants in DNA repair genes associated with hereditary breast and ovarian cancer syndrome: analysis of a 21 gene panel in the Brazilian population

Cited by 39 publications

References 100 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

Literature Review of BARD1 as a Cancer Predisposing Gene with a Focus on Breast and Ovarian Cancers

BRCA1, BRCA2, and TP53 germline and somatic variants and clinicopathological characteristics of Brazilian patients with epithelial ovarian cancer

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