BRCA1 promoter hypermethylation is not associated with germline variants in Polish breast cancer patients
Abstract Background Methylation of BRCA1 has been associated with an increased risk of breast cancer and specific clinical characteristics of the disease. In the British population, the genetic alteration c.-107 A/T has been shown to cause allelic methylation, leading to familial breast and ovarian...
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BMC
2025-06-01
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| Series: | Hereditary Cancer in Clinical Practice |
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| Online Access: | https://doi.org/10.1186/s13053-025-00317-8 |
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| author | Karolina Prajzendanc Paweł Domagała Jolanta Hybiak Wojciech Kluźniak Cezary Cybulski Katarzyna Białkowska Alicja Ogrodniczak Janusz Ryś Aleksandra Sejda Marek Szwiec Joanna Tomiczek-Szwiec Tomasz Kluz Roksana Dwornik Dagmara Cylwik Jacek Gronwald Jan Lubiński Anna Jakubowska |
| author_facet | Karolina Prajzendanc Paweł Domagała Jolanta Hybiak Wojciech Kluźniak Cezary Cybulski Katarzyna Białkowska Alicja Ogrodniczak Janusz Ryś Aleksandra Sejda Marek Szwiec Joanna Tomiczek-Szwiec Tomasz Kluz Roksana Dwornik Dagmara Cylwik Jacek Gronwald Jan Lubiński Anna Jakubowska |
| author_sort | Karolina Prajzendanc |
| collection | DOAJ |
| description | Abstract Background Methylation of BRCA1 has been associated with an increased risk of breast cancer and specific clinical characteristics of the disease. In the British population, the genetic alteration c.-107 A/T has been shown to cause allelic methylation, leading to familial breast and ovarian cancer. However, this variant has not been detected in Polish population. Nonetheless, other genetic variants may still be associated with BRCA1 methylation, highlighting the need for further research. Aim of study This study aimed to analyze BRCA1 promoter region to identify germline alterations associated with BRCA1 methylation in peripheral blood DNA. Additionally, the correlation between the detected variants and breast cancer incidence, as well as clinical characteristics, was assessed. Materials and methods One hundred breast cancer patients with BRCA1 methylation were analyzed using pyrosequencing to quantify methylation levels. Immunohistochemistry (IHC) was performed on formalin-fixed paraffin-embedded (FFPE) tumor tissue samples from these patients to assess BRCA1 expression. In 47 patients with the highest BRCA1 methylation and decreased BRCA1 expression, Sanger sequencing was performed encompassing 643 bp of BRCA1 promoter to identify potential variants associated with methylation and/or breast cancer. A variant was identified and genotyped in multiple patient groups, including 336 BRCA1 methylation-positive women, 1898 unselected breast cancer cases, 2234 healthy controls, and 309 BRCA1 pathogenic variant (PV) carriers. Statistical analyses were performed using Fisher’s exact test and Chi-square test in Stata/IC version 16.1. Results The study identified BRCA1 c.20 + 101 C/G (rs799905) in the promoter region of the gene. However, no significant association was found between rs799905 and BRCA1 methylation or breast cancer risk. Nevertheless, a borderline association was observed between rs799905 and the occurrence of triple-negative breast cancer (TNBC) (p = 0.048) as well as lymph node (LN) metastases (p = 0.046). Among BRCA1 PV carriers, the GG genotype was significantly more frequent, while the CC genotype was 10 times less common compared to non-carriers (p = 0.003). Conclusion Rs799905 variant is not associated with BRCA1 methylation breast cancer risk. However, it may be linked to the occurrence of TNBC and LN metastases. Additionally, rs799905 may be associated to some extent with BRCA1 PVs, though further research is needed to clarify the nature of this potential correlation. |
| format | Article |
| id | doaj-art-c4b511edec8e4b76b3415370c747e9ad |
| institution | OA Journals |
| issn | 1897-4287 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
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| series | Hereditary Cancer in Clinical Practice |
| spelling | doaj-art-c4b511edec8e4b76b3415370c747e9ad2025-08-20T02:07:45ZengBMCHereditary Cancer in Clinical Practice1897-42872025-06-012311710.1186/s13053-025-00317-8BRCA1 promoter hypermethylation is not associated with germline variants in Polish breast cancer patientsKarolina Prajzendanc0Paweł Domagała1Jolanta Hybiak2Wojciech Kluźniak3Cezary Cybulski4Katarzyna Białkowska5Alicja Ogrodniczak6Janusz Ryś7Aleksandra Sejda8Marek Szwiec9Joanna Tomiczek-Szwiec10Tomasz Kluz11Roksana Dwornik12Dagmara Cylwik13Jacek Gronwald14Jan Lubiński15Anna Jakubowska16Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical UniversityDepartment of Clinical Genetics and Pathology, University of Zielona GóraDepartment of Pathology, Pomeranian Medical UniversityDepartment of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical UniversityDepartment of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical UniversityDepartment of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical UniversityDepartment of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical UniversityDepartment of Tumor Pathology, Maria Skłodowska-Curie Memorial Centre and Institute of OncologyDepartment of Pathomorphology and Forensic Medicine, University of Warmia and MazuryDepartment of Surgery and Oncology, University of Zielona GóraClinical Department of Oncological Gynecology at the Oncology Centre in Opole, University of OpoleInstitute of Obstetric and Emergency Medicine, Faculty of Medicine, University of RzeszowDepartment of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical UniversityDepartment of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical UniversityDepartment of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical UniversityDepartment of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical UniversityDepartment of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical UniversityAbstract Background Methylation of BRCA1 has been associated with an increased risk of breast cancer and specific clinical characteristics of the disease. In the British population, the genetic alteration c.-107 A/T has been shown to cause allelic methylation, leading to familial breast and ovarian cancer. However, this variant has not been detected in Polish population. Nonetheless, other genetic variants may still be associated with BRCA1 methylation, highlighting the need for further research. Aim of study This study aimed to analyze BRCA1 promoter region to identify germline alterations associated with BRCA1 methylation in peripheral blood DNA. Additionally, the correlation between the detected variants and breast cancer incidence, as well as clinical characteristics, was assessed. Materials and methods One hundred breast cancer patients with BRCA1 methylation were analyzed using pyrosequencing to quantify methylation levels. Immunohistochemistry (IHC) was performed on formalin-fixed paraffin-embedded (FFPE) tumor tissue samples from these patients to assess BRCA1 expression. In 47 patients with the highest BRCA1 methylation and decreased BRCA1 expression, Sanger sequencing was performed encompassing 643 bp of BRCA1 promoter to identify potential variants associated with methylation and/or breast cancer. A variant was identified and genotyped in multiple patient groups, including 336 BRCA1 methylation-positive women, 1898 unselected breast cancer cases, 2234 healthy controls, and 309 BRCA1 pathogenic variant (PV) carriers. Statistical analyses were performed using Fisher’s exact test and Chi-square test in Stata/IC version 16.1. Results The study identified BRCA1 c.20 + 101 C/G (rs799905) in the promoter region of the gene. However, no significant association was found between rs799905 and BRCA1 methylation or breast cancer risk. Nevertheless, a borderline association was observed between rs799905 and the occurrence of triple-negative breast cancer (TNBC) (p = 0.048) as well as lymph node (LN) metastases (p = 0.046). Among BRCA1 PV carriers, the GG genotype was significantly more frequent, while the CC genotype was 10 times less common compared to non-carriers (p = 0.003). Conclusion Rs799905 variant is not associated with BRCA1 methylation breast cancer risk. However, it may be linked to the occurrence of TNBC and LN metastases. Additionally, rs799905 may be associated to some extent with BRCA1 PVs, though further research is needed to clarify the nature of this potential correlation.https://doi.org/10.1186/s13053-025-00317-8BRCA1 geneMethylationBreast cancer |
| spellingShingle | Karolina Prajzendanc Paweł Domagała Jolanta Hybiak Wojciech Kluźniak Cezary Cybulski Katarzyna Białkowska Alicja Ogrodniczak Janusz Ryś Aleksandra Sejda Marek Szwiec Joanna Tomiczek-Szwiec Tomasz Kluz Roksana Dwornik Dagmara Cylwik Jacek Gronwald Jan Lubiński Anna Jakubowska BRCA1 promoter hypermethylation is not associated with germline variants in Polish breast cancer patients Hereditary Cancer in Clinical Practice BRCA1 gene Methylation Breast cancer |
| title | BRCA1 promoter hypermethylation is not associated with germline variants in Polish breast cancer patients |
| title_full | BRCA1 promoter hypermethylation is not associated with germline variants in Polish breast cancer patients |
| title_fullStr | BRCA1 promoter hypermethylation is not associated with germline variants in Polish breast cancer patients |
| title_full_unstemmed | BRCA1 promoter hypermethylation is not associated with germline variants in Polish breast cancer patients |
| title_short | BRCA1 promoter hypermethylation is not associated with germline variants in Polish breast cancer patients |
| title_sort | brca1 promoter hypermethylation is not associated with germline variants in polish breast cancer patients |
| topic | BRCA1 gene Methylation Breast cancer |
| url | https://doi.org/10.1186/s13053-025-00317-8 |
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