Comprehensive analysis of germline mutations in northern Brazil: a panel of 16 genes for hereditary cancer-predisposing syndrome investigation

Vidal, Amanda Ferreira; Ferraz, Rafaella Sousa; El-Husny, Antonette; Silva, Caio Santos; Vinasco-Sandoval, Tatiana; Magalhães, Leandro; Raiol-Moraes, Milene; Barra, Williams Fernandes; Pereira, Cynthia Lara Brito Lins; Assumpção, Paulo Pimentel de; Brito, Leonardo Miranda; Vialle, Ricardo Assunção; Santos, Sidney Emanuel Batista dos; Ribeiro-dos-Santos, Ândrea

doi:10.1186/s12885-021-08089-9

Cited by 7 publications

(4 citation statements)

References 50 publications

(32 reference statements)

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“…In this study, we have provided the genetic information for 19 individuals/families that will benefit from personalized cancer medicine. We demonstrated a rate of pathogenic variants (23%) within the reported range from other populations [ 20 , 21 , 22 ]. Interestingly, a high number of VUS was identified in this study that suggest a need for their clinical significance classification.…”

Section: Discussionsupporting

confidence: 76%

Genetic Characterization in High-Risk Individuals from a Low-Resource City of Peru

Zavaleta-Lopez¹,

Solis²,

Palacios

et al. 2022

Cancers

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Background: Genetic testing for hereditary cancers is inconsistently applied within the healthcare systems in Latin America. In Peru, the prevalence and spectrum of cancer-predisposing germline variants is thus poorly characterized. Purpose: To determine the spectrum and prevalence of cancer-predisposing germline variants and variants of uncertain significance (VUS) in high-risk individuals located in a Peruvian low-resource setting city. Methods: Individuals presenting clinical criteria for hereditary cancer syndromes or being unaffected with familial history of cancer were included in the study. Samples from a total of 84 individuals were subjected to a high-throughput DNA sequencing assay that targeted a panel of 94 cancer predisposition genes. The pathogenicity of detected germline variants was classified according to the established American College of Medical Genetics and Genomics (ACMG) criteria. All pathogenic variants were validated by cycling temperature capillary electrophoresis. Results: We identified a total of eight pathogenic variants, found in 19 out of 84 individuals (23%). Pathogenic variants were identified in 24% (10/42) of unaffected individuals with family history of cancer and in 21% (9/42) of individuals with a cancer diagnosis. Pathogenic variants were identified in eight genes: RET (3), BRCA1 (3), SBDS (2), SBDS/MLH1 (4), MLH1 (4), TP53 (1), FANCD2 (1), DDB2/FANCG (1). In cancer cases, all colon cancer cases were affected by pathogenic variants in MLH1 and SBDS genes, while 20% (2/10) of the thyroid cancer cases by RET c.1900T>C variants were affected. One patient with endometrial cancer (1/3) had a double heterozygous pathogenic variant in DDB2 and FANCG genes, while one breast cancer patient (1/14) had a pathogenic variant in TP53 gene. Overall, each individual presented at least 17 VUS, totaling 1926 VUS for the full study population. Conclusion: We describe the first genetic characterization in a low-resource setting population where genetic testing is not yet implemented. We identified multiple pathogenic germline variants in clinically actionable predisposition genes, that have an impact on providing an appropriate genetic counselling and clinical management for individuals and their relatives who carry these variants. We also reported a high number of VUS, which may indicate variants specific for this population and may require a determination of their clinical significance.

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Section: Discussionsupporting

confidence: 76%

Genetic Characterization in High-Risk Individuals from a Low-Resource City of Peru

Zavaleta-Lopez¹,

Solis²,

Palacios

et al. 2022

Cancers

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“…Similarly, the c.1961delA mutation is associated with a 2.8-fold rise in CRC risk when compared to controls. Notably, this mutation's implications extend to breast, ovarian, and hereditary cancer syndromes, as observed in South Korea [ 45 ], Baltic [ 46 ] and Brazil populations [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Deleterious and ethnic-related BRCA1/2 mutations in tissue and blood of Egyptian colorectal cancer patients and its correlation with human papillomavirus

Youssef,

Zekri,

Mohanad

et al. 2023

Clin Exp Med

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This study aimed to identify BRCA1/2 mutational patterns in the tissue and blood of Egyptian colorectal cancer (CRC) patients and to study the possible correlation of this mutational pattern with Human papillomavirus (HPV) infection. Eighty-two colonoscopic biopsies and forty-six blood samples were collected from Egyptian CRC patients, as well as blood samples of age and sex-matched healthy controls (n = 43) were enrolled. The libraries were performed using Qiaseq Human BRCA1 and BRCA2 targeted DNA panel and sequenced via Ion proton sequencer. Also, the CRC tissues were subjected to conventional PCR targeting the HPV Late 1 (L1) region. Our analysis revealed that the BRCA-DNA damage pathway had been altered in more than 65% of the CRC patients. Comparing tissue and blood samples from CRC patients, 25 somatic mutations were found exclusively in tissue, while 41 germline mutations were found exclusively in blood. Additionally, we identified 23 shared BRCA1/2 pathogenic (PVs) mutations in both blood and tissue samples, with a significantly higher frequency in blood samples compared to tissue samples. The most affected exon in BRCA1 was exon 10, while the most affected exons in BRCA2 were 11, 14, 18, 24, and 27 exons. Notably, we revealed an ethnic-related cluster of polymorphism variants in our population closely related to South Asian and African ethnicities. Novel PVs were identified and submitted to the ClinVar database. HPV was found in 23.8% of the CRC tissues, and 54% of HPV-positive cases had somatic BRCA1/2 PVs. The results of this research point to a possible connection between infection with HPV and BRCA1/2 mutations in the occurrence of colorectal cancer in the Egyptian population, which has a mixed ethnic background. Our data also indicate that liquid biopsy (blood samples) may be more representative than tissue samples for detecting BRCA1/2 mutations. These findings may have implications for cancer screening and the development of personalized, targeted therapies, such as PARP inhibitors, which can effectively target BRCA1/2 mutations.

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“…The prevalence of P/LP variants in this cohort was 27.3% (97/355), higher than that described in the most recent studies using multigene panel testing in the Brazilian population. Recent data from diverse regions of the country estimated a detection rate of P/LP variants of 16.9% in the Northern ( 14 ); 20.8% in the Northeast ( 15 ), 20.5% in the Central-west ( 16 ) and 23.4% in Southern Brazil ( 17 ). Also, in the largest nationwide cohort of Brazilian breast cancer patients, the prevalence of germline P/LP variants was 20.1% ( 18 ).…”

Section: Discussionmentioning

confidence: 99%

Hereditary Breast Cancer in the Brazilian State of Ceará (The CHANCE Cohort): Higher-Than-Expected Prevalence of Recurrent Germline Pathogenic Variants

Gifoni

Gifoni²,

Wotroba³

et al. 2022

Front. Oncol.

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PurposeThere is a significant lack of epidemiological data on hereditary cancer in Northeast Brazil. This is the largest study on the prevalence and mutational spectrum of cancer predisposition genes conducted in this region and the first in the State of Ceará.MethodsPatients ≥18 years of age that were referred to CHANCE (Grupo de Câncer Hereditário do Ceará) from March 2014 to December 2020 with testing criteria for breast cancer susceptibility genes according to NCCN v.1.2021 were eligible to participate. The inclusion of patients was limited to one individual per family and to those born in the State of Ceará. All patients underwent a hereditary cancer panel testing with at least 30 genes.ResultsA total of 355 patients were included, and 97 (27.3%) carried a P/LP germline variant in 18 different genes. Among the 97 P/LP carriers, BRCA1 (31, 31.9%) and BRCA2 (25, 25.7%) were the most frequently mutated genes, followed by PALB2 (10, 10.3%), CHEK2 (7, 7.2%) and ATM (4, 4.1%). A small number of recurrent variants (detected in three or more individuals) in BRCA1, BRCA2, CHEK2 and ATM represented the majority of the P/LP variants described in this cohort.ConclusionIn this cohort, the prevalence of L/PL was high, particularly involving the BRCA1, BRCA2, PALB2, CHEK2 and ATM genes and, to a lesser extent than expected, the TP53 gene. A high frequency of recurrent variants was also observed, for which further and larger analyses should clarify the presence of any possible founder effect. Characterizing the mutational profile of cancer predisposition genes in diverse populations may contribute to cancer prevention and therapeutic management.

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Comprehensive analysis of germline mutations in northern Brazil: a panel of 16 genes for hereditary cancer-predisposing syndrome investigation

Cited by 7 publications

References 50 publications

Genetic Characterization in High-Risk Individuals from a Low-Resource City of Peru

Genetic Characterization in High-Risk Individuals from a Low-Resource City of Peru

Deleterious and ethnic-related BRCA1/2 mutations in tissue and blood of Egyptian colorectal cancer patients and its correlation with human papillomavirus

Hereditary Breast Cancer in the Brazilian State of Ceará (The CHANCE Cohort): Higher-Than-Expected Prevalence of Recurrent Germline Pathogenic Variants

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