Prevalence of germline variants in consensus moderate-to-high-risk predisposition genes to hereditary breast and ovarian cancer in BRCA1/2-negative Brazilian patients

Gomes, Rachel Novaes; Spinola, Pricila da Silva; Brant, Ayslan Castro; Matta, Bruna Palma; Nascimento, Caroline Macedo; Paes, Silvia Maria de Aquino; Bonvicino, Cibele Rodrigues; Santos, Anna Cláudia Evangelista dos; Moreira, Miguel Ângelo Martins

doi:10.1007/s10549-020-05985-9

Cited by 8 publications

(4 citation statements)

References 61 publications

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“…Multiplex PCR-based assays were performed on 158 unpaired tumor samples, designed to cover the entire coding regions and flanking splicing sites of BRCA1, BRCA2, PALB2, TP53, and RAD51D (25). Tumor DNA sequencing was prepared with Nextera XT DNA Kit (Illumina, San Diego, CA, USA) and performed in three independent runs, using paired-end methodology on MiSeq Genome Analyzer (Illumina), with up to 150 bp of reading length.…”

Section: Sample Preparation and Next-generation Sequencing Of Unpaire...mentioning

confidence: 99%

Somatic DNA Damage Response and Homologous Repair Gene Alterations and Its Association With Tumor Variant Burden in Breast Cancer Patients With Occupational Exposure to Pesticides

et al. 2022

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Homologous recombination is a crucial pathway that is specialized in repairing double-strand breaks; thus, alterations in genes of this pathway may lead to loss of genomic stability and cell growth suppression. Pesticide exposure potentially increases cancer risk through several mechanisms, such as the genotoxicity caused by chronic exposure, leading to gene alteration. To analyze this hypothesis, we investigated if breast cancer patients exposed to pesticides present a different mutational pattern in genes related to homologous recombination (BRCA1, BRCA2, PALB2, and RAD51D) and damage-response (TP53) concerning unexposed patients. We performed multiplex PCR-based assays and next-generation sequencing (NGS) of all coding regions and flanking splicing sites of BRCA1, BRCA2, PALB2, TP53, and RAD51D in 158 unpaired tumor samples from breast cancer patients on MiSeq (Illumina) platform. We found that exposed patients had tumors with more pathogenic and likely pathogenic variants than unexposed patients (p = 0.017). In general, tumors that harbored a pathogenic or likely pathogenic variant had a higher mutational burden (p < 0.001). We also observed that breast cancer patients exposed to pesticides had a higher mutational burden when diagnosed before 50 years old (p = 0.00978) and/or when carrying BRCA1 (p = 0.0138), BRCA2 (p = 0.0366), and/or PALB2 (p = 0.00058) variants, a result not found in the unexposed group. Our results show that pesticide exposure impacts the tumor mutational landscape and could be associated with the carcinogenesis process, therapy response, and disease progression. Further studies should increase the observation period in exposed patients to better evaluate the impact of these findings.

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Section: Sample Preparation and Next-generation Sequencing Of Unpaire...mentioning

confidence: 99%

Somatic DNA Damage Response and Homologous Repair Gene Alterations and Its Association With Tumor Variant Burden in Breast Cancer Patients With Occupational Exposure to Pesticides

et al. 2022

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“…Genomic DNA was isolated from peripheral blood samples using salting out method 73 . Multiplex PCR-based assays were designed and performed as described by Gomes et al 17 ; TP53 findings for 67 patients from the present study (out of 257) were published in this previous study 17 . Briefly, PCR primers were designed to amplify the full coding regions of BRCA1 (NG_005905.2), BRCA2 (NG_012772.…”

Section: Methodsmentioning

confidence: 98%

“…We followed the guidelines of the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) for classification and interpretation of clinical significance of the germline variants 80 using the VarSome variant search engine version 8.4.6 as a guide 81 . Each automated ACMG/AMP criterion used by VarSome was carefully revised, as thoroughly described by Gomes et al 17 and in the legend of Supplementary Table S2 (see the Supplementary Information S1). Additional databases assessed for variant classification were ClinVar (https:// www.…”

Section: Variants Classificationmentioning

confidence: 99%

Familial history and prevalence of BRCA1, BRCA2 and TP53 pathogenic variants in HBOC Brazilian patients from a public healthcare service

Matta

Gomes

Mattos

et al. 2022

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Several studies have demonstrated the cost-effectiveness of genetic testing for surveillance and treatment of carriers of germline pathogenic variants associated with hereditary breast/ovarian cancer syndrome (HBOC). In Brazil, seventy percent of the population is assisted by the public Unified Health System (SUS), where genetic testing is still unavailable. And few studies were performed regarding the prevalence of HBOC pathogenic variants in this context. Here, we estimated the prevalence of germline pathogenic variants in BRCA1, BRCA2 and TP53 genes in Brazilian patients suspected of HBOC and referred to public healthcare service. Predictive power of risk prediction models for detecting mutation carriers was also evaluated. We found that 41 out of 257 tested patients (15.9%) were carriers of pathogenic variants in the analyzed genes. Most frequent pathogenic variant was the founder Brazilian mutation TP53 c.1010G > A (p.Arg337His), adding to the accumulated evidence that supports inclusion of TP53 in routine testing of Brazilian HBOC patients. Surprisingly, BRCA1 c.5266dupC (p.Gln1756fs), a frequently reported pathogenic variant in Brazilian HBOC patients, was not observed. Regarding the use of predictive models, we found that familial history of cancer might be used to improve selection or prioritization of patients for genetic testing, especially in a context of limited resources.

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“…Other well-recognized risk factors are gene mutations and hereditary syndromes that represent the most notable predisposing causes for the development of ovarian cancer ( 14 ). A growing body of literature has demonstrated that individuals harboring germline mutations affecting BRCA1 and BRCA2 genes have an increased risk of breast and ovarian cancer ( 15 - 18 ). Overall, ~25% of ovarian cancer tumors are positive for BRCA1 or BRCA2 mutations ( 19 ).…”

Section: Risk and Protective Factors For Ovarian Cancermentioning

confidence: 99%

A multidisciplinary approach remains the best strategy to improve and strengthen the management of ovarian cancer (Review)

et al. 2021

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Ovarian cancer represents one of the most aggressive female tumors worldwide. Over the decades, the therapeutic options for the treatment of ovarian cancer have been improved significantly through the advancement of surgical techniques as well as the availability of novel effective drugs able to extend the life expectancy of patients. However, due to its clinical, biological and molecular complexity, ovarian cancer is still considered one of the most difficult tumors to manage. In this context, several studies have highlighted how a multidisciplinary approach to this pathology improves the prognosis and survival of patients with ovarian cancer. On these bases, the aim of the present review is to present recent advantages in the diagnosis, staging and treatment of ovarian cancer highlighting the benefits of a patient-centered care approach and on the importance of a multidisciplinary team for the management of ovarian cancer.

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Prevalence of germline variants in consensus moderate-to-high-risk predisposition genes to hereditary breast and ovarian cancer in BRCA1/2-negative Brazilian patients

Cited by 8 publications

References 61 publications

Somatic DNA Damage Response and Homologous Repair Gene Alterations and Its Association With Tumor Variant Burden in Breast Cancer Patients With Occupational Exposure to Pesticides

Somatic DNA Damage Response and Homologous Repair Gene Alterations and Its Association With Tumor Variant Burden in Breast Cancer Patients With Occupational Exposure to Pesticides

Familial history and prevalence of BRCA1, BRCA2 and TP53 pathogenic variants in HBOC Brazilian patients from a public healthcare service

A multidisciplinary approach remains the best strategy to improve and strengthen the management of ovarian cancer (Review)

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