A novel frequent BRCA1 recurrent variant c.5117G &gt; A (p.Gly1206Glu) identified after 20 years of BRCA1/2 research in the Baltic region: cohort study and literature review

Loza, P.; Irmejs, Arvids; Daneberga, Zanda; Miklaševičs, Edvīns; Berga-Švītiņa, Egija; Subatniece, Signe; Maksimenko, Jelena; Trofimovics, Genadijs; Tauvena, Elina; Ukleikins, S.; Gardovskis, Jānis

doi:10.1186/s13053-021-00168-z

Cited by 4 publications

(8 citation statements)

References 28 publications

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“…Remarkably, the c.1961delA variant demonstrates a noteworthy co-occurrence with the c.1016delA and c.3329delA variants, suggesting potential interactions or relationships among BRCA1 PVs that could influence disease development or other genetic outcomes. The observed significant association between specific somatic BRCA1 PVs namely, c.1961dupA and c.3329dupA in CRC patients in our results align with previous studies that have documented significant associations among these BRCA1 PVs not only in breast cancer cases [ 46 , 48 ] but also in ovarian cancer contexts [ 49 , 50 ] . This suggests a potential implication of these co-occurring PVs across different malignancies, pointing towards potentially underlying mechanisms or vulnerabilities linked to these genetic alterations.…”

Section: Discussionsupporting

confidence: 91%

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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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Section: Discussionsupporting

confidence: 91%

“…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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“…Another common mutation BRCA1 c.3756_3759delGTCT has been detected in some populations, such as Thai [55], Polish [56], Belarusian [57], Italian [58], French-Canadian [59], and Czech populations [60]. BRCA1 c.4065_4068del has been detected in some populations [61][62][63]. Another study showed that c.4065_4068del is one of the three most common BRCA1 variants in Chinese ovarian cancer patients [47].…”

Section: Discussionmentioning

confidence: 99%

Germline variants profiling of BRCA1 and BRCA2 in Chinese Hakka breast and ovarian cancer patients

Zhang

et al. 2022

BMC Cancer

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Objective To investigate the prevalence and spectrum of BRCA1 and BRCA2 mutations in Chinese Hakka patients with breast and ovarian cancer. Methods A total of 1,664 breast or ovarian cancer patients were enrolled for genetic testing at our hospital. Germline mutations of the BRCA gene were analysed by next-generation sequencing, including the coding regions and exon intron boundary regions. Results The 1,664 patients included 1,415 (85.04%) breast cancer patients and 245 (14.72%) ovarian cancer patients, while four (0.24%) patients had both the breast and ovarian cancers. A total of 151 variants, including 71 BRCA1 variants and 80 BRCA2 variants, were detected in the 234 (14.06%) patients. The 151 variants included 58 pathogenic variants, 8 likely pathogenic variants, and 85 variants of unknown significance (VUS). A total of 56.25% (18/32) and 65.38% (17/26) of pathogenic variants (likely pathogenic variants are not included) were distributed in exon 14 of BRCA1 and exon 11 of BRCA2, respectively. The most common pathogenic variants among this Hakka population are c.2635G > T (p.Glu879*) (n = 7) in the BRCA1 gene and c.5164_5165del (p.Ser1722Tyrfs*4) (n = 7) in the BRCA2 gene among the Hakka population. A hotspot mutation in the Chinese population, the BRCA1 c.5470_5477del variant was not found in this Hakka population. The prevalence and spectrum of variants in the BRCA genes in the Hakka patients are different from that in other ethnic groups. Conclusions The most common pathogenic variant in this population is c.2635G > T in the BRCA1 gene, and c.5164_5165delAG in the BRCA2 gene in this population. The prevalence and spectrum of variants in the BRCA1 and BRCA2 genes in the Hakka patients from southern China are different from those in other ethnic groups.

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“…This variant was also detected by Yang et al among Malaysian BC patients in two different cases: the first one had a family history and was diagnosed at a very early age (23 years), and the other one had no family history and was diagnosed at 42 years old [42]. Furthermore, we also identified the c.1961delA (p.Lys654fs) BRCA1 pathogenic variant in seven patients, and it was previously reported as a recurrent founder mutation in BC patients in different countries and worldwide [43][44][45][46]. On the other hand, we identified eight different deleterious mutations in the BRCA2 gene.…”

Section: Discussionmentioning

confidence: 58%

Frequency of Pathogenic Germline Mutations in Early and Late Onset Familial Breast Cancer Patients Using Multi-Gene Panel Sequencing: An Egyptian Study

Nassar

Zekri

Kamel

et al. 2022

Genes

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Background: Precision oncology has been increasingly used in clinical practice and rapidly evolving in the oncology field. Thus, this study was performed to assess the frequency of germline mutations in early and late onset familial breast cancer (BC) Egyptian patients using multi-gene panel sequencing to better understand the contribution of the inherited germline mutations in BC predisposition. Moreover, to determine the actionable deleterious mutations associated with familial BC that might be used as biomarker for early cancer detection. Methods: Whole blood samples were collected from 101 Egyptian patients selected for BC family history, in addition to 50 age-matched healthy controls. A QIAseq targeted DNA panel (human BC panel) was used to assess the frequency of germline mutations. Results: A total of 58 patients (57.4%) out of 101 were found to have 27 deleterious germline mutations in 11 cancer susceptibility genes. Of them, 32 (31.6%) patients carried more than one pathogenic mutation and each one carried at least one pathogenic mutation. The major genes harboring the pathogenic mutations were: ATM, BRCA2, BRCA1, VHL, MSH6, APC, CHEK2, MSH2, MEN1, PALB2, and MUTYH. Thirty-one patients (30.6%) had BRCA2 mutations and twenty (19.8%) had BRCA1 mutations. Our results showed that exon 10 and exon 11 harbored 3 and 5 mutations, respectively, in BRCA1 and BRCA2 genes. Our analysis also revealed that the VHL gene significantly co-occurred with each of the BRCA2 gene (p = 0.003, event ratio 11/21), the MSH2 gene (p = 0.01, 4/10), the CHEK2 gene (p = 0.02, 4/11), and the MSH6 gene (p = 0.04, 4/12). In addition, the APC gene significantly co-occurred with the MSH2 gene (p = 0.01, 3/7). Furthermore, there was a significant mutually exclusive event between the APC gene and the ATM gene (p = 0.04, 1/36). Interestingly, we identified population specific germline mutations in genes showing potentials for targeted therapy to meet the need for incorporating precision oncology into clinical practice. For example, the mutations identified in the ATM, APC, and MSH2 genes. Conclusions: Multi-gene panel sequencing was used to detect the deleterious mutations associated with familial BC, which in turns mitigate the essential need for implementing next generation sequencing technologies in precision oncology to identify cancer predisposing genes. Moreover, identifying DNA repair gene mutations, with focus on non-BRCA genes, might serve as candidates for targeted therapy and will be increasingly used in precision oncology.

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A novel frequent BRCA1 recurrent variant c.5117G > A (p.Gly1206Glu) identified after 20 years of BRCA1/2 research in the Baltic region: cohort study and literature review

Cited by 4 publications

References 28 publications

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

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

Germline variants profiling of BRCA1 and BRCA2 in Chinese Hakka breast and ovarian cancer patients

Frequency of Pathogenic Germline Mutations in Early and Late Onset Familial Breast Cancer Patients Using Multi-Gene Panel Sequencing: An Egyptian Study

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