11p15.5 epimutations in children with Wilms tumor and hepatoblastoma detected in peripheral blood.
Adolescent
Adult
Beckwith-Wiedemann Syndrome
/ blood
Child
Child, Preschool
Chromosomes, Human, Pair 11
/ genetics
DNA Methylation
/ genetics
Female
Genetic Predisposition to Disease
Genomic Imprinting
/ genetics
Germ-Line Mutation
/ genetics
Hepatoblastoma
/ blood
Humans
Infant
Male
Neoplasm Proteins
/ genetics
Wilms Tumor
/ blood
Young Adult
Beckwith-Wiedemann syndrome
Wilms tumor
genetic predisposition to disease
hepatoblastoma
methylation
Journal
Cancer
ISSN: 1097-0142
Titre abrégé: Cancer
Pays: United States
ID NLM: 0374236
Informations de publication
Date de publication:
01 07 2020
01 07 2020
Historique:
received:
17
07
2019
revised:
18
02
2020
accepted:
17
03
2020
pubmed:
23
4
2020
medline:
22
5
2021
entrez:
23
4
2020
Statut:
ppublish
Résumé
Constitutional or somatic mosaic epimutations are increasingly recognized as a mechanism of gene dysregulation resulting in cancer susceptibility. Beckwith-Wiedemann syndrome is the cancer predisposition syndrome most commonly associated with epimutation and is extremely variable in its phenotypic presentation, which can include isolated tumors. Because to the authors' knowledge large-scale germline DNA sequencing studies have not included methylation analysis, the percentage of pediatric cancer predisposition that is due to epimutations is unknown. Germline methylation testing at the 11p15.5 locus was performed in blood for 24 consecutive patients presenting with hepatoblastoma (3 patients) or Wilms tumor (21 patients). Six individuals with Wilms tumor and 1 patient with hepatoblastoma were found to have low-level gain of methylation at imprinting control 1, and a child with hepatoblastoma was found to have loss of methylation at imprinting control 2. The loss of methylation at imprinting control 2 was found to be maternally inherited, despite not being associated with any detectable genomic alteration. Overall, 33% of patients (8 of 24 patients) with Wilms tumor or hepatoblastoma were found to have an epigenetic susceptibility that was detectable in the blood. It is interesting to note that low-level gain of methylation at imprinting control 1 predominantly was detected in females with bilateral Wilms tumors. Further studies in larger cohorts are needed to determine the efficacy of testing all patients with Wilms tumor or hepatoblastoma for 11p15.5 epimutations in the blood as part of DNA analysis because this hallmark of predisposition will not be detected by sequencing-based approaches and detecting a cancer predisposition may modify treatment.
Sections du résumé
BACKGROUND
Constitutional or somatic mosaic epimutations are increasingly recognized as a mechanism of gene dysregulation resulting in cancer susceptibility. Beckwith-Wiedemann syndrome is the cancer predisposition syndrome most commonly associated with epimutation and is extremely variable in its phenotypic presentation, which can include isolated tumors. Because to the authors' knowledge large-scale germline DNA sequencing studies have not included methylation analysis, the percentage of pediatric cancer predisposition that is due to epimutations is unknown.
METHODS
Germline methylation testing at the 11p15.5 locus was performed in blood for 24 consecutive patients presenting with hepatoblastoma (3 patients) or Wilms tumor (21 patients).
RESULTS
Six individuals with Wilms tumor and 1 patient with hepatoblastoma were found to have low-level gain of methylation at imprinting control 1, and a child with hepatoblastoma was found to have loss of methylation at imprinting control 2. The loss of methylation at imprinting control 2 was found to be maternally inherited, despite not being associated with any detectable genomic alteration.
CONCLUSIONS
Overall, 33% of patients (8 of 24 patients) with Wilms tumor or hepatoblastoma were found to have an epigenetic susceptibility that was detectable in the blood. It is interesting to note that low-level gain of methylation at imprinting control 1 predominantly was detected in females with bilateral Wilms tumors. Further studies in larger cohorts are needed to determine the efficacy of testing all patients with Wilms tumor or hepatoblastoma for 11p15.5 epimutations in the blood as part of DNA analysis because this hallmark of predisposition will not be detected by sequencing-based approaches and detecting a cancer predisposition may modify treatment.
Identifiants
pubmed: 32320050
doi: 10.1002/cncr.32907
pmc: PMC7383476
doi:
Substances chimiques
Neoplasm Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
3114-3121Subventions
Organisme : NCI NIH HHS
ID : PO / CA008748
Pays : United States
Organisme : Cannonball Kids' Cancer
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : Corning Fund at MSK
Organisme : Crawford Fund
Organisme : St. Baldrick's Foundation
Organisme : Crawford Pediatric Cancer Genomics Fund at MSK
Organisme : V Foundation for Cancer Research
Organisme : Family and Friends of Caroline Bhatt
Organisme : NCI NIH HHS
ID : K08 / CA193915
Pays : United States
Organisme : Alex's Lemonade Stand Foundation for Childhood Cancer
Organisme : NCI NIH HHS
ID : K12 / CA18474
Pays : United States
Organisme : Robert and Kate Niehaus Center for Inherited Cancer Genomics at Memorial Sloan Kettering Cancer Center
Organisme : NCI NIH HHS
ID : K12 CA184746
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA214812
Pays : United States
Informations de copyright
© 2020 American Cancer Society.
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