Chromosome instability in neuroblastoma: A pathway to aggressive disease
For over 100-years, genomic instability has been investigated as a central player in the pathogenesis of human cancer. Conceptually, genomic instability includes an array of alterations from small deletions/insertions to whole chromosome alterations, referred to as chromosome instability. Chromosome...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-10-01
|
| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.988972/full |
| _version_ | 1798027647730581504 |
|---|---|
| author | Lucia Paolini Lucia Paolini Sajjad Hussain Paul J. Galardy Paul J. Galardy |
| author_facet | Lucia Paolini Lucia Paolini Sajjad Hussain Paul J. Galardy Paul J. Galardy |
| author_sort | Lucia Paolini |
| collection | DOAJ |
| description | For over 100-years, genomic instability has been investigated as a central player in the pathogenesis of human cancer. Conceptually, genomic instability includes an array of alterations from small deletions/insertions to whole chromosome alterations, referred to as chromosome instability. Chromosome instability has a paradoxical impact in cancer. In most instances, the introduction of chromosome instability has a negative impact on cellular fitness whereas in cancer it is usually associated with a worse prognosis. One exception is the case of neuroblastoma, the most common solid tumor outside of the brain in children. Neuroblastoma tumors have two distinct patterns of genome instability: whole-chromosome aneuploidy, which is associated with a better prognosis, or segmental chromosomal alterations, which is a potent negative prognostic factor. Through a computational screen, we found that low levels of the de- ubiquitinating enzyme USP24 have a highly significant negative impact on survival in neuroblastoma. At the molecular level, USP24 loss leads to destabilization of the microtubule assembly factor CRMP2 - producing mitotic errors and leading to chromosome missegregation and whole-chromosome aneuploidy. This apparent paradox may be reconciled through a model in which whole chromosome aneuploidy leads to the subsequent development of segmental chromosome alterations. Here we review the mechanisms behind chromosome instability and the evidence for the progressive development of segmental alterations from existing numerical aneuploidy in support of a multi-step model of neuroblastoma progression. |
| first_indexed | 2024-04-11T18:56:03Z |
| format | Article |
| id | doaj.art-262af412051243bfb30305460957821a |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-11T18:56:03Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-262af412051243bfb30305460957821a2022-12-22T04:08:11ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-10-011210.3389/fonc.2022.988972988972Chromosome instability in neuroblastoma: A pathway to aggressive diseaseLucia Paolini0Lucia Paolini1Sajjad Hussain2Paul J. Galardy3Paul J. Galardy4Department of Pediatrics, University of Milano-Bicocca, San Gerardo Hospital, Monza, MI, ItalyDepartment of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, United StatesDepartment of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, United StatesDepartment of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, United StatesDivision of Pediatric Hematology-Oncology, Mayo Clinic, Rochester, MN, United StatesFor over 100-years, genomic instability has been investigated as a central player in the pathogenesis of human cancer. Conceptually, genomic instability includes an array of alterations from small deletions/insertions to whole chromosome alterations, referred to as chromosome instability. Chromosome instability has a paradoxical impact in cancer. In most instances, the introduction of chromosome instability has a negative impact on cellular fitness whereas in cancer it is usually associated with a worse prognosis. One exception is the case of neuroblastoma, the most common solid tumor outside of the brain in children. Neuroblastoma tumors have two distinct patterns of genome instability: whole-chromosome aneuploidy, which is associated with a better prognosis, or segmental chromosomal alterations, which is a potent negative prognostic factor. Through a computational screen, we found that low levels of the de- ubiquitinating enzyme USP24 have a highly significant negative impact on survival in neuroblastoma. At the molecular level, USP24 loss leads to destabilization of the microtubule assembly factor CRMP2 - producing mitotic errors and leading to chromosome missegregation and whole-chromosome aneuploidy. This apparent paradox may be reconciled through a model in which whole chromosome aneuploidy leads to the subsequent development of segmental chromosome alterations. Here we review the mechanisms behind chromosome instability and the evidence for the progressive development of segmental alterations from existing numerical aneuploidy in support of a multi-step model of neuroblastoma progression.https://www.frontiersin.org/articles/10.3389/fonc.2022.988972/fullneuroblastomachromosome instability (CIN)aneuploidydeubuquitylasesmitosischromosome missegregation |
| spellingShingle | Lucia Paolini Lucia Paolini Sajjad Hussain Paul J. Galardy Paul J. Galardy Chromosome instability in neuroblastoma: A pathway to aggressive disease Frontiers in Oncology neuroblastoma chromosome instability (CIN) aneuploidy deubuquitylases mitosis chromosome missegregation |
| title | Chromosome instability in neuroblastoma: A pathway to aggressive disease |
| title_full | Chromosome instability in neuroblastoma: A pathway to aggressive disease |
| title_fullStr | Chromosome instability in neuroblastoma: A pathway to aggressive disease |
| title_full_unstemmed | Chromosome instability in neuroblastoma: A pathway to aggressive disease |
| title_short | Chromosome instability in neuroblastoma: A pathway to aggressive disease |
| title_sort | chromosome instability in neuroblastoma a pathway to aggressive disease |
| topic | neuroblastoma chromosome instability (CIN) aneuploidy deubuquitylases mitosis chromosome missegregation |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.988972/full |
| work_keys_str_mv | AT luciapaolini chromosomeinstabilityinneuroblastomaapathwaytoaggressivedisease AT luciapaolini chromosomeinstabilityinneuroblastomaapathwaytoaggressivedisease AT sajjadhussain chromosomeinstabilityinneuroblastomaapathwaytoaggressivedisease AT pauljgalardy chromosomeinstabilityinneuroblastomaapathwaytoaggressivedisease AT pauljgalardy chromosomeinstabilityinneuroblastomaapathwaytoaggressivedisease |