Evidence for a pre-malignant cell line in a skin biopsy from a patient with Nijmegen breakage syndrome
Abstract Background Nijmegen breakage syndrome is an autosomal recessive disorder characterized by microcephaly, immunodeficiency, hypersensitivity to X-irradiation, and a high predisposition to cancer. Nibrin, the product of the NBN gene, is part of the MRE11/RAD50 (MRN) complex that is involved in...
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| Format: | Article |
| Language: | English |
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BMC
2018-02-01
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| Series: | Molecular Cytogenetics |
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| Online Access: | http://link.springer.com/article/10.1186/s13039-018-0364-6 |
| _version_ | 1818195897464389632 |
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| author | Raneem Habib Heidemarie Neitzel Aurelie Ernst John K. L. Wong Bozenna Goryluk-Kozakiewicz Antje Gerlach Ilja Demuth Karl Sperling Krystyna Chrzanowska |
| author_facet | Raneem Habib Heidemarie Neitzel Aurelie Ernst John K. L. Wong Bozenna Goryluk-Kozakiewicz Antje Gerlach Ilja Demuth Karl Sperling Krystyna Chrzanowska |
| author_sort | Raneem Habib |
| collection | DOAJ |
| description | Abstract Background Nijmegen breakage syndrome is an autosomal recessive disorder characterized by microcephaly, immunodeficiency, hypersensitivity to X-irradiation, and a high predisposition to cancer. Nibrin, the product of the NBN gene, is part of the MRE11/RAD50 (MRN) complex that is involved in the repair of DNA double strand breaks (DSBs), and plays a critical role in the processing of DSBs in immune gene rearrangements, telomere maintenance, and meiotic recombination. NBS skin fibroblasts grow slowly in culture and enter early into senescence. Case presentation Here we present an incidental finding. Skin fibroblasts, derived from a 9 year old NBS patient, showed a mosaic of normal diploid cells (46,XY) and those with a complex, unbalanced translocation. The aberrant karyotype was analysed by G-banding, comparative genomic hybridization, and whole chromosome painting. The exact breakpoints of the derivative chromosome were mapped by whole genome sequencing: 45,XY,der(6)(6pter → 6q11.1::13q11 → 13q21.33::20q11.22 → 20qter),-13. The deleted region of chromosomes 6 harbors almost 1.400 and that of chromosome 13 more than 500 genes, the duplicated region of chromosome 20 contains about 700 genes. Such unbalanced translocations are regularly incompatible with cellular survival, except in malignant cells. The aberrant cells, however, showed a high proliferation potential and could even be clonally expanded. Telomere length was significantly reduced, hTERT was not expressed. The cells underwent about 50 population doublings until they entered into senescence. The chromosomal preparation performed shortly before senescence showed telomere fusions, premature centromere divisions, endoreduplications and tetraploid cells, isochromatid breaks and a variety of marker chromosomes. Inspection of the site of skin biopsy 18 years later, presented no evidence for abnormal growth. Conclusions The aberrant cells had a significant selective advantage in vitro. It is therefore tempting to speculate that this highly unbalanced translocation could be a primary driver of cancer cell growth. |
| first_indexed | 2024-12-12T01:25:29Z |
| format | Article |
| id | doaj.art-ea6b73b7893847ec9d22ae687d41b9a8 |
| institution | Directory Open Access Journal |
| issn | 1755-8166 |
| language | English |
| last_indexed | 2024-12-12T01:25:29Z |
| publishDate | 2018-02-01 |
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| series | Molecular Cytogenetics |
| spelling | doaj.art-ea6b73b7893847ec9d22ae687d41b9a82022-12-22T00:43:06ZengBMCMolecular Cytogenetics1755-81662018-02-011111910.1186/s13039-018-0364-6Evidence for a pre-malignant cell line in a skin biopsy from a patient with Nijmegen breakage syndromeRaneem Habib0Heidemarie Neitzel1Aurelie Ernst2John K. L. Wong3Bozenna Goryluk-Kozakiewicz4Antje Gerlach5Ilja Demuth6Karl Sperling7Krystyna Chrzanowska8Department of Human Genetics, Ruhr-University BochumInstitute of Medical and Human Genetics, Charité - Universitaetsmedizin BerlinDivision of Molecular Genetics, German Cancer Research Center (DKFZ)Division of Molecular Genetics, German Cancer Research Center (DKFZ)Department of Medical Genetics, The Children’s Memorial Health InstituteInstitute of Medical and Human Genetics, Charité - Universitaetsmedizin BerlinLipid Clinic at the Interdisciplinary Metabolism Center, Charité - Universitaetsmedizin BerlinInstitute of Medical and Human Genetics, Charité - Universitaetsmedizin BerlinDepartment of Medical Genetics, The Children’s Memorial Health InstituteAbstract Background Nijmegen breakage syndrome is an autosomal recessive disorder characterized by microcephaly, immunodeficiency, hypersensitivity to X-irradiation, and a high predisposition to cancer. Nibrin, the product of the NBN gene, is part of the MRE11/RAD50 (MRN) complex that is involved in the repair of DNA double strand breaks (DSBs), and plays a critical role in the processing of DSBs in immune gene rearrangements, telomere maintenance, and meiotic recombination. NBS skin fibroblasts grow slowly in culture and enter early into senescence. Case presentation Here we present an incidental finding. Skin fibroblasts, derived from a 9 year old NBS patient, showed a mosaic of normal diploid cells (46,XY) and those with a complex, unbalanced translocation. The aberrant karyotype was analysed by G-banding, comparative genomic hybridization, and whole chromosome painting. The exact breakpoints of the derivative chromosome were mapped by whole genome sequencing: 45,XY,der(6)(6pter → 6q11.1::13q11 → 13q21.33::20q11.22 → 20qter),-13. The deleted region of chromosomes 6 harbors almost 1.400 and that of chromosome 13 more than 500 genes, the duplicated region of chromosome 20 contains about 700 genes. Such unbalanced translocations are regularly incompatible with cellular survival, except in malignant cells. The aberrant cells, however, showed a high proliferation potential and could even be clonally expanded. Telomere length was significantly reduced, hTERT was not expressed. The cells underwent about 50 population doublings until they entered into senescence. The chromosomal preparation performed shortly before senescence showed telomere fusions, premature centromere divisions, endoreduplications and tetraploid cells, isochromatid breaks and a variety of marker chromosomes. Inspection of the site of skin biopsy 18 years later, presented no evidence for abnormal growth. Conclusions The aberrant cells had a significant selective advantage in vitro. It is therefore tempting to speculate that this highly unbalanced translocation could be a primary driver of cancer cell growth.http://link.springer.com/article/10.1186/s13039-018-0364-6Nijmegen breakage syndromeCell lineUnbalanced translocationProliferative advantage |
| spellingShingle | Raneem Habib Heidemarie Neitzel Aurelie Ernst John K. L. Wong Bozenna Goryluk-Kozakiewicz Antje Gerlach Ilja Demuth Karl Sperling Krystyna Chrzanowska Evidence for a pre-malignant cell line in a skin biopsy from a patient with Nijmegen breakage syndrome Molecular Cytogenetics Nijmegen breakage syndrome Cell line Unbalanced translocation Proliferative advantage |
| title | Evidence for a pre-malignant cell line in a skin biopsy from a patient with Nijmegen breakage syndrome |
| title_full | Evidence for a pre-malignant cell line in a skin biopsy from a patient with Nijmegen breakage syndrome |
| title_fullStr | Evidence for a pre-malignant cell line in a skin biopsy from a patient with Nijmegen breakage syndrome |
| title_full_unstemmed | Evidence for a pre-malignant cell line in a skin biopsy from a patient with Nijmegen breakage syndrome |
| title_short | Evidence for a pre-malignant cell line in a skin biopsy from a patient with Nijmegen breakage syndrome |
| title_sort | evidence for a pre malignant cell line in a skin biopsy from a patient with nijmegen breakage syndrome |
| topic | Nijmegen breakage syndrome Cell line Unbalanced translocation Proliferative advantage |
| url | http://link.springer.com/article/10.1186/s13039-018-0364-6 |
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