Non-synonymous, synonymous, and non-coding nucleotide variants contribute to recurrently altered biological processes during retinoblastoma progression.
cancer progression
non-coding mutations
retinoblastoma
synonymous mutations
Journal
Genes, chromosomes & cancer
ISSN: 1098-2264
Titre abrégé: Genes Chromosomes Cancer
Pays: United States
ID NLM: 9007329
Informations de publication
Date de publication:
05 2023
05 2023
Historique:
revised:
15
12
2022
received:
12
10
2022
accepted:
20
12
2022
pmc-release:
01
05
2024
pubmed:
23
12
2022
medline:
11
3
2023
entrez:
22
12
2022
Statut:
ppublish
Résumé
Retinoblastomas form in response to biallelic RB1 mutations or MYCN amplification and progress to more aggressive and therapy-resistant phenotypes through accumulation of secondary genomic changes. Progression-related changes include recurrent somatic copy number alterations and typically non-recurrent nucleotide variants, including synonymous and non-coding variants, whose significance has been unclear. To determine if nucleotide variants recurrently affect specific biological processes, we identified altered genes and over-represented variant gene ontologies in 168 exome or whole-genome-sequenced retinoblastomas and 12 tumor-matched cell lines. In addition to RB1 mutations, MYCN amplification, and established retinoblastoma somatic copy number alterations, the analyses revealed enrichment of variant genes related to diverse biological processes including histone monoubiquitination, mRNA processing (P) body assembly, and mitotic sister chromatid segregation and cytokinesis. Importantly, non-coding and synonymous variants increased the enrichment significance of each over-represented biological process term. To assess the effects of such mutations, we examined the consequences of a 3' UTR variant of PCGF3 (a BCOR-binding component of Polycomb repressive complex I), dual 3' UTR variants of CDC14B (a regulator of sister chromatid segregation), and a synonymous variant of DYNC1H1 (a regulator of P-body assembly). One PCGF3 and one of two CDC14B 3' UTR variants impaired gene expression whereas a base-edited DYNC1H1 synonymous variant altered protease sensitivity and stability. Retinoblastoma cell lines retained only ~50% of variants detected in tumors and enriched for new variants affecting p53 signaling. These findings reveal potentially important differences in retinoblastoma cell lines and tumors and implicate synonymous and non-coding variants, along with non-synonymous variants, in retinoblastoma oncogenesis.
Identifiants
pubmed: 36550020
doi: 10.1002/gcc.23120
pmc: PMC10006380
mid: NIHMS1860595
doi:
Substances chimiques
Nucleotides
0
N-Myc Proto-Oncogene Protein
0
3' Untranslated Regions
0
CDC14B protein, human
EC 3.1.3.48
Dual-Specificity Phosphatases
EC 3.1.3.48
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
275-289Subventions
Organisme : NCI NIH HHS
ID : R01 CA137124
Pays : United States
Organisme : NCI NIH HHS
ID : K08 CA232344
Pays : United States
Organisme : NEI NIH HHS
ID : K08 EY030924
Pays : United States
Informations de copyright
© 2023 The Authors. Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.
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