11p15.5 epimutations in children with Wilms tumor and hepatoblastoma detected in peripheral blood
Open Access
- 22 April 2020
- Vol. 126 (13), 3114-3121
- https://doi.org/10.1002/cncr.32907
Abstract
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.Keywords
Funding Information
- St. Baldrick's Foundation
- National Cancer Institute (K08 / CA193915, K12 / CA18474, PO / CA008748)
- V Foundation for Cancer Research
- Alex's Lemonade Stand Foundation for Childhood Cancer
This publication has 44 references indexed in Scilit:
- Signatures of mutational processes in human cancerNature, 2013
- Constitutive promoter methylation of BRCA1 and RAD51C in patients with familial ovarian cancer and early-onset sporadic breast cancerHuman Molecular Genetics, 2012
- Targeting the Insulin Growth Factor Receptor 1Hematology/Oncology Clinics of North America, 2012
- The Pediatric Cancer Genome ProjectNature Genetics, 2012
- DNA methylation signatures for breast cancer classification and prognosisGenome Medicine, 2012
- Allele-specific methylated multiplex real-time quantitative PCR (ASMM RTQ-PCR), a powerful method for diagnosing loss of imprinting of the 11p15 region in Russell Silver and Beckwith Wiedemann syndromesHuman Mutation, 2010
- Imprinting Status of 11p15 Genes in Beckwith–Wiedemann Syndrome Patients with CDKN1C MutationsGenomics, 2001
- Low Frequency of p57KIP2 Mutation in Beckwith-Wiedemann SyndromeAmerican Journal of Human Genetics, 1997
- Mosaic uniparental disomy in Beckwith-Wiedemann syndrome.Journal of Medical Genetics, 1994
- Genetic mosaicism in normal tissues of Wilms' tumour patientsNature Genetics, 1993