A Multifocal Pediatric Papillary Thyroid Carcinoma (PTC) Harboring the <i>AGK-BRAF</i> and <i>RET/PTC3</i> Fusion in a Mutually Exclusive Pattern Reveals Distinct Levels of Genomic Instability and Nuclear Organization
The spectrum and incidence of gene fusions in papillary thyroid carcinoma (PTC) can differ significantly depending on the age of onset, histological subtype or radiation exposure history. In sporadic pediatric PTC, <i>RET/PTC1-3</i> and <i>AGK-BRAF</i> fusions are common gene...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-02-01
|
| Series: | Biology |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2079-7737/10/2/125 |
| _version_ | 1827603174461014016 |
|---|---|
| author | Luiza Sisdelli Maria Isabel V. Cordioli Fernanda Vaisman Osmar Monte Carlos A. Longui Adriano N. Cury Monique O. Freitas Aline Rangel-Pozzo Sabine Mai Janete M. Cerutti |
| author_facet | Luiza Sisdelli Maria Isabel V. Cordioli Fernanda Vaisman Osmar Monte Carlos A. Longui Adriano N. Cury Monique O. Freitas Aline Rangel-Pozzo Sabine Mai Janete M. Cerutti |
| author_sort | Luiza Sisdelli |
| collection | DOAJ |
| description | The spectrum and incidence of gene fusions in papillary thyroid carcinoma (PTC) can differ significantly depending on the age of onset, histological subtype or radiation exposure history. In sporadic pediatric PTC, <i>RET/PTC1-3</i> and <i>AGK-BRAF</i> fusions are common genetic alterations. The role of <i>RET/PTC</i> as a prognostic marker in pediatric PTC is still under investigation. We recently showed that <i>AGK-BRAF</i> fusion is prevalent in young patients (mean 10 years) and associated with specific and aggressive pathological features such as multifocality and lung metastasis. In this pilot study, we report a unique patient harboring three different foci: the first was positive for <i>AGK-BRAF</i> fusion, the second was positive for just <i>RET/PTC3</i> fusion and the third was negative for both rearrangements. To investigate whether <i>AGK-BRAF</i> and <i>RET/PTC3</i> are associated with genomic instability and chromatin modifications, we performed quantitative fluorescence in situ hybridization (Q-FISH) of telomere repeats followed by 3D imaging analysis and 3D super-resolution Structured Illumination Microscopy (3D-SIM) to analyze the DNA structure from the foci. We demonstrated in this preliminary study that <i>AGK-BRAF</i> is likely associated with higher levels of telomere-related genomic instability and chromatin remodeling in comparison with <i>RET/PTC3</i> foci. Our results suggest a progressive disruption in chromatin structure in <i>AGK-BRAF</i>-positive cells, which might explain a more aggressive disease outcome in patients harboring this rearrangement. |
| first_indexed | 2024-03-09T05:34:15Z |
| format | Article |
| id | doaj.art-350775c7c9a04ea1bdcbf16051c54167 |
| institution | Directory Open Access Journal |
| issn | 2079-7737 |
| language | English |
| last_indexed | 2024-03-09T05:34:15Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biology |
| spelling | doaj.art-350775c7c9a04ea1bdcbf16051c541672023-12-03T12:29:50ZengMDPI AGBiology2079-77372021-02-0110212510.3390/biology10020125A Multifocal Pediatric Papillary Thyroid Carcinoma (PTC) Harboring the <i>AGK-BRAF</i> and <i>RET/PTC3</i> Fusion in a Mutually Exclusive Pattern Reveals Distinct Levels of Genomic Instability and Nuclear OrganizationLuiza Sisdelli0Maria Isabel V. Cordioli1Fernanda Vaisman2Osmar Monte3Carlos A. Longui4Adriano N. Cury5Monique O. Freitas6Aline Rangel-Pozzo7Sabine Mai8Janete M. Cerutti9The Genetic Basis of Thyroid Tumors Lab, Division of Genetics, Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo 04039-032, BrazilThe Genetic Basis of Thyroid Tumors Lab, Division of Genetics, Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo 04039-032, BrazilInstituto Nacional do Câncer, Rio de Janeiro 22451-000, BrazilDepartment of Pediatrics, Irmandade da Santa Casa de Misericórdia de São Paulo, São Paulo 01221-010, BrazilDepartment of Pediatrics, Irmandade da Santa Casa de Misericórdia de São Paulo, São Paulo 01221-010, BrazilDepartment of Medicine, Irmandade da Santa Casa de Misericórdia de São Paulo, São Paulo 01221-010, BrazilMedical Genetics Service of the Martagão Gesteira Childcare and Pediatrics Institute (IPPMG), Medical School, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-912, BrazilCell Biology, Research Institute of Oncology and Hematology, University of Manitoba, CancerCare Manitoba, Winnipeg, MB R3E 0V9, CanadaCell Biology, Research Institute of Oncology and Hematology, University of Manitoba, CancerCare Manitoba, Winnipeg, MB R3E 0V9, CanadaThe Genetic Basis of Thyroid Tumors Lab, Division of Genetics, Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo 04039-032, BrazilThe spectrum and incidence of gene fusions in papillary thyroid carcinoma (PTC) can differ significantly depending on the age of onset, histological subtype or radiation exposure history. In sporadic pediatric PTC, <i>RET/PTC1-3</i> and <i>AGK-BRAF</i> fusions are common genetic alterations. The role of <i>RET/PTC</i> as a prognostic marker in pediatric PTC is still under investigation. We recently showed that <i>AGK-BRAF</i> fusion is prevalent in young patients (mean 10 years) and associated with specific and aggressive pathological features such as multifocality and lung metastasis. In this pilot study, we report a unique patient harboring three different foci: the first was positive for <i>AGK-BRAF</i> fusion, the second was positive for just <i>RET/PTC3</i> fusion and the third was negative for both rearrangements. To investigate whether <i>AGK-BRAF</i> and <i>RET/PTC3</i> are associated with genomic instability and chromatin modifications, we performed quantitative fluorescence in situ hybridization (Q-FISH) of telomere repeats followed by 3D imaging analysis and 3D super-resolution Structured Illumination Microscopy (3D-SIM) to analyze the DNA structure from the foci. We demonstrated in this preliminary study that <i>AGK-BRAF</i> is likely associated with higher levels of telomere-related genomic instability and chromatin remodeling in comparison with <i>RET/PTC3</i> foci. Our results suggest a progressive disruption in chromatin structure in <i>AGK-BRAF</i>-positive cells, which might explain a more aggressive disease outcome in patients harboring this rearrangement.https://www.mdpi.com/2079-7737/10/2/125papillary thyroid carcinomapediatric thyroid cancernuclear architecturesuper-resolution microscopeAGK-BRAFRET/PTC |
| spellingShingle | Luiza Sisdelli Maria Isabel V. Cordioli Fernanda Vaisman Osmar Monte Carlos A. Longui Adriano N. Cury Monique O. Freitas Aline Rangel-Pozzo Sabine Mai Janete M. Cerutti A Multifocal Pediatric Papillary Thyroid Carcinoma (PTC) Harboring the <i>AGK-BRAF</i> and <i>RET/PTC3</i> Fusion in a Mutually Exclusive Pattern Reveals Distinct Levels of Genomic Instability and Nuclear Organization Biology papillary thyroid carcinoma pediatric thyroid cancer nuclear architecture super-resolution microscope AGK-BRAF RET/PTC |
| title | A Multifocal Pediatric Papillary Thyroid Carcinoma (PTC) Harboring the <i>AGK-BRAF</i> and <i>RET/PTC3</i> Fusion in a Mutually Exclusive Pattern Reveals Distinct Levels of Genomic Instability and Nuclear Organization |
| title_full | A Multifocal Pediatric Papillary Thyroid Carcinoma (PTC) Harboring the <i>AGK-BRAF</i> and <i>RET/PTC3</i> Fusion in a Mutually Exclusive Pattern Reveals Distinct Levels of Genomic Instability and Nuclear Organization |
| title_fullStr | A Multifocal Pediatric Papillary Thyroid Carcinoma (PTC) Harboring the <i>AGK-BRAF</i> and <i>RET/PTC3</i> Fusion in a Mutually Exclusive Pattern Reveals Distinct Levels of Genomic Instability and Nuclear Organization |
| title_full_unstemmed | A Multifocal Pediatric Papillary Thyroid Carcinoma (PTC) Harboring the <i>AGK-BRAF</i> and <i>RET/PTC3</i> Fusion in a Mutually Exclusive Pattern Reveals Distinct Levels of Genomic Instability and Nuclear Organization |
| title_short | A Multifocal Pediatric Papillary Thyroid Carcinoma (PTC) Harboring the <i>AGK-BRAF</i> and <i>RET/PTC3</i> Fusion in a Mutually Exclusive Pattern Reveals Distinct Levels of Genomic Instability and Nuclear Organization |
| title_sort | multifocal pediatric papillary thyroid carcinoma ptc harboring the i agk braf i and i ret ptc3 i fusion in a mutually exclusive pattern reveals distinct levels of genomic instability and nuclear organization |
| topic | papillary thyroid carcinoma pediatric thyroid cancer nuclear architecture super-resolution microscope AGK-BRAF RET/PTC |
| url | https://www.mdpi.com/2079-7737/10/2/125 |
| work_keys_str_mv | AT luizasisdelli amultifocalpediatricpapillarythyroidcarcinomaptcharboringtheiagkbrafiandiretptc3ifusioninamutuallyexclusivepatternrevealsdistinctlevelsofgenomicinstabilityandnuclearorganization AT mariaisabelvcordioli amultifocalpediatricpapillarythyroidcarcinomaptcharboringtheiagkbrafiandiretptc3ifusioninamutuallyexclusivepatternrevealsdistinctlevelsofgenomicinstabilityandnuclearorganization AT fernandavaisman amultifocalpediatricpapillarythyroidcarcinomaptcharboringtheiagkbrafiandiretptc3ifusioninamutuallyexclusivepatternrevealsdistinctlevelsofgenomicinstabilityandnuclearorganization AT osmarmonte amultifocalpediatricpapillarythyroidcarcinomaptcharboringtheiagkbrafiandiretptc3ifusioninamutuallyexclusivepatternrevealsdistinctlevelsofgenomicinstabilityandnuclearorganization AT carlosalongui amultifocalpediatricpapillarythyroidcarcinomaptcharboringtheiagkbrafiandiretptc3ifusioninamutuallyexclusivepatternrevealsdistinctlevelsofgenomicinstabilityandnuclearorganization AT adrianoncury amultifocalpediatricpapillarythyroidcarcinomaptcharboringtheiagkbrafiandiretptc3ifusioninamutuallyexclusivepatternrevealsdistinctlevelsofgenomicinstabilityandnuclearorganization AT moniqueofreitas amultifocalpediatricpapillarythyroidcarcinomaptcharboringtheiagkbrafiandiretptc3ifusioninamutuallyexclusivepatternrevealsdistinctlevelsofgenomicinstabilityandnuclearorganization AT alinerangelpozzo amultifocalpediatricpapillarythyroidcarcinomaptcharboringtheiagkbrafiandiretptc3ifusioninamutuallyexclusivepatternrevealsdistinctlevelsofgenomicinstabilityandnuclearorganization AT sabinemai amultifocalpediatricpapillarythyroidcarcinomaptcharboringtheiagkbrafiandiretptc3ifusioninamutuallyexclusivepatternrevealsdistinctlevelsofgenomicinstabilityandnuclearorganization AT janetemcerutti amultifocalpediatricpapillarythyroidcarcinomaptcharboringtheiagkbrafiandiretptc3ifusioninamutuallyexclusivepatternrevealsdistinctlevelsofgenomicinstabilityandnuclearorganization AT luizasisdelli multifocalpediatricpapillarythyroidcarcinomaptcharboringtheiagkbrafiandiretptc3ifusioninamutuallyexclusivepatternrevealsdistinctlevelsofgenomicinstabilityandnuclearorganization AT mariaisabelvcordioli multifocalpediatricpapillarythyroidcarcinomaptcharboringtheiagkbrafiandiretptc3ifusioninamutuallyexclusivepatternrevealsdistinctlevelsofgenomicinstabilityandnuclearorganization AT fernandavaisman multifocalpediatricpapillarythyroidcarcinomaptcharboringtheiagkbrafiandiretptc3ifusioninamutuallyexclusivepatternrevealsdistinctlevelsofgenomicinstabilityandnuclearorganization AT osmarmonte multifocalpediatricpapillarythyroidcarcinomaptcharboringtheiagkbrafiandiretptc3ifusioninamutuallyexclusivepatternrevealsdistinctlevelsofgenomicinstabilityandnuclearorganization AT carlosalongui multifocalpediatricpapillarythyroidcarcinomaptcharboringtheiagkbrafiandiretptc3ifusioninamutuallyexclusivepatternrevealsdistinctlevelsofgenomicinstabilityandnuclearorganization AT adrianoncury multifocalpediatricpapillarythyroidcarcinomaptcharboringtheiagkbrafiandiretptc3ifusioninamutuallyexclusivepatternrevealsdistinctlevelsofgenomicinstabilityandnuclearorganization AT moniqueofreitas multifocalpediatricpapillarythyroidcarcinomaptcharboringtheiagkbrafiandiretptc3ifusioninamutuallyexclusivepatternrevealsdistinctlevelsofgenomicinstabilityandnuclearorganization AT alinerangelpozzo multifocalpediatricpapillarythyroidcarcinomaptcharboringtheiagkbrafiandiretptc3ifusioninamutuallyexclusivepatternrevealsdistinctlevelsofgenomicinstabilityandnuclearorganization AT sabinemai multifocalpediatricpapillarythyroidcarcinomaptcharboringtheiagkbrafiandiretptc3ifusioninamutuallyexclusivepatternrevealsdistinctlevelsofgenomicinstabilityandnuclearorganization AT janetemcerutti multifocalpediatricpapillarythyroidcarcinomaptcharboringtheiagkbrafiandiretptc3ifusioninamutuallyexclusivepatternrevealsdistinctlevelsofgenomicinstabilityandnuclearorganization |