Germline copy number variations in BRCA1/2 negative families: Role in the molecular etiology of hereditary breast cancer in Tunisia

Boujemaa, Maroua; Hamdi, Yosr; Mejri, Nesrine; Romdhane, Lilia; Ghedira, Kaïs; Benna, Houda El; Labidi, Soumaya; Dallali, Hamza; Jaïdane, Olfa; Nasr, S. Ben; Haddaoui, A.; Rahal, Khaled; Abdelhak, Sonia; Boussen, Hamouda; Boubaker, Mohamed Samir

doi:10.1371/journal.pone.0245362

Cited by 10 publications

(8 citation statements)

References 75 publications

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“…These findings could be explained by the significant variability in GC frequency worldwide as well as risk factors [ 1 ]. Our findings highlight the particular genetic background of the Tunisian population compared to others [ 55 , 56 , 57 , 58 , 59 ].…”

Section: Discussionsupporting

confidence: 57%

CDH1 Germline Variants in a Tunisian Cohort with Hereditary Diffuse Gastric Carcinoma

Aissa-Haj

Kabbage

Othman

et al. 2022

Genes

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Mutational screening of the CDH1 gene is a standard treatment for patients who fulfill Hereditary Diffuse Gastric Cancer (HDGC) testing criteria. In this framework, the classification of variants found in this gene is a crucial step for the clinical management of patients at high risk for HDGC. The aim of our study was to identify CDH1 as well as CTNNA1 mutational profiles predisposing to HDGC in Tunisia. Thirty-four cases were included for this purpose. We performed Sanger sequencing for the entire coding region of both genes and MLPA (Multiplex Ligation Probe Amplification) assays to investigate large rearrangements of the CDH1 gene. As a result, three cases, all with the HDGC inclusion criteria (8.82% of the entire cohort), carried pathogenic and likely pathogenic variants of the CDH1 gene. These variants involve a novel splicing alteration, a missense c.2281G > A detected by Sanger sequencing, and a large rearrangement detected by MLPA. No pathogenic CTNNA1 variants were found. The large rearrangement is clearly pathogenic, implicating a large deletion of two exons. The novel splicing variant creates a cryptic site. The missense variant is a VUS (Variant with Uncertain Significance). With ACMG (American College of Medical Genetics and Genomics) classification and the evidence available, we thus suggest a revision of its status to likely pathogenic. Further functional studies or cosegregation analysis should be performed to confirm its pathogenicity. In addition, molecular exploration will be needed to understand the etiology of the other CDH1- and CTNNA1-negative cases fulfilling the HDGC inclusion criteria.

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Section: Discussionsupporting

confidence: 57%

CDH1 Germline Variants in a Tunisian Cohort with Hereditary Diffuse Gastric Carcinoma

Aissa-Haj

Kabbage

Othman

et al. 2022

Genes

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“…Our results highlight the particular genetic background of the Tunisian population compared to others. Indeed, several papers published in Tunisia have reported the particular genetic background of our population [58][59][60][61].…”

Section: Discussionmentioning

confidence: 97%

CDH1 and CTNNA1 Genetic Screening in Tunisian Patients with Hereditary Diffuse Gastric Carcinoma

Aissa-Haj

Kabbage

Othmen

et al. 2021

Preprint

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Background: Mutational screening of the CDH1 gene is a standard treatment for patients who meet the criteria for Hereditary Diffuse Gastric Cancer (HDGC). In this framework, the classification of variants found in this gene is a crucial step for the clinical management of patients at high risk for HDGC. The aim of this study was to identify CDH1 as well as CTNNA1 mutation profiles predisposing to HDGC from Tunisia. Methods: Thirty four cases were included for this purpose with a mean age at diagnosis of 48 years old. We performed Sanger Sequencing for the entire coding sequence of both genes and MLPA (Multiplex Ligation Probe Amplification) assay to investigate large rearrangements of the CDH1 gene. Results: As a result, three cases (8.82%) carried probably pathogenic variants in the CDH1 gene. These variants involves a novel splice alteration, a missense located in exon 14 detected by Sanger Sequencing and a large rearrangement detected by MLPA assay.Conclusion: Our results suggest that the CDH1 p.G761R variant is probably pathogenic and involved in the conformational space shift of the protein. Molecular modeling analysis highlights a putative influence on the conformational properties of the Juxta-Membrane Domain core (JMD) that could result in destabilizing the protein-protein complexes and therefore impacting the downstream pathways. Also, a large deletion from the 5' locus including exons 1 and 2 of the CDH1 gene implicating the signal peptide and a part of the precursor domain of the protein. These findings highlight the critical importance of screening for large CDH1 rearrangements as well as mutations for the management of HDGC families and individuals at high risk for more personalised medicine. We therefore suggest a revision of the status of p.G761R mutation from Variant of Unknown Significance (VUS) to likely pathogenic.

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“…In neighboring North African region, the frequency of BRCA1/2 pathogenic variants in Moroccan population varied from 16.7 to 31.6% [23]. In Tunisia, 25% of hereditary BC patients carried a BRCA1/2 gene pathogenic variant [24]. The BRCA1/2 variant ratio we found (1:1.18) was also consistent with the fraction reported by these different studies which confirmed the significant contribution of BRCA1/2 germline variant in BC risk among North African populations [25 26].…”

Section: Discussionmentioning

confidence: 99%

Screening of BRCA1/2 variants in Mauritanian breast cancer patients

Brahim

Zein²,

Bonnet³

et al. 2022

BMC Cancer

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Background and study aim Carrying a pathogenic BRCA1/2 variant increases greatly young women’s risk of developing breast cancer (BC). This study aimed to provide the first genetic data on BC in Mauritania. Methods Using NGS based screening; we searched for BRCA1/2 variants in DNA samples from 137 patients diagnosed for hereditary BC. Results We identified 16 pathogenic or likely pathogenic (PV) variants carried by 38 patients. Two predominant BRCA1 PV variants were found: c.815_824dup and c.4986 + 6 T > C in 13 and 7 patients, respectively. Interestingly, three novels BRCA1/2 predicted pathogenic variants have also been detected. Notably, no specific distribution of BRCA1/2 variants was observed regarding triple negative breast cancer (TNBC) or patient gender status. Conclusions In this first genetic profiling of BC in Mauritania, we identified a substantial number of BRCA1/2 pathogenic variants. This finding could be important in the future diagnosis and prevention policy of hereditary BC in Mauritania.

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Germline copy number variations in BRCA1/2 negative families: Role in the molecular etiology of hereditary breast cancer in Tunisia

Cited by 10 publications

References 75 publications

CDH1 Germline Variants in a Tunisian Cohort with Hereditary Diffuse Gastric Carcinoma

CDH1 Germline Variants in a Tunisian Cohort with Hereditary Diffuse Gastric Carcinoma

CDH1 and CTNNA1 Genetic Screening in Tunisian Patients with Hereditary Diffuse Gastric Carcinoma

Screening of BRCA1/2 variants in Mauritanian breast cancer patients

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