Mosaic paternal haploidy in a patient with pancreatoblastoma and Beckwith–Wiedemann spectrum

Lee, Cheng-Ting; Tung, Yi‐Ching; Hwu, Wuh‐Liang; Shih, Jin-Yuan; Lin, Wen-Hsi; Wu, Mu-Zon; Kuo, Kuan‐Ting; Yang, Yung‐Li; Chen, Huey‐Ling; Chen, Ming; Su, Yi‐Ning; Jong, Yiin-Jeng; Liu, Shih-Yao; Tsai, Wen-Yu; Lee, Ni‐Chung

doi:10.1002/ajmg.a.61276

Cited by 7 publications

(5 citation statements)

References 29 publications

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“… 7 The most common cancers associated with BWSp are nephroblastoma and hepatoblastoma. 4 More rare cancers described in children with BWSp include acute lymphoblastic leukaemia, 8 , 9 adrenocortical carcinoma, 10 hemangiotheloma, 11 melanoma, 9 , 12 neuroblastoma and ganglioneuroblastoma, 9 pancreatoblastoma, 13 phaeochromocytoma, 14 rhabdomyosarcoma 15 and thyroid cancer. 16 The published overall childhood cancer risk in the various subgroups are the following: IC2-LOM 2.6%, IC1-GOM 28.1% (mainly Wilms tumour), UPDpat 16% (mainly Wilms tumour and hepatoblastoma), CDKN1C pathogenic variant 6.9% (mainly neuroblastoma) (reviewed in 1 ).…”

Section: Introductionmentioning

confidence: 99%

Cancer incidence and spectrum among children with genetically confirmed Beckwith-Wiedemann spectrum in Germany: a retrospective cohort study

et al. 2020

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Background Beckwith-Wiedemann syndrome (BWS) is a cancer predisposition syndrome caused by defects on chromosome 11p15.5. The quantitative cancer risks in BWS patients depend on the underlying (epi)genotype but have not yet been assessed in a population-based manner. Methods We identified a group of 321 individuals with a molecularly confirmed diagnosis of BWS and analysed the cancer incidence up to age 15 years and cancer spectrum by matching their data with the German Childhood Cancer Registry. Results We observed 13 cases of cancer in the entire BWS cohort vs 0.4 expected. This corresponds to a 33-fold increased risk (standardised incidence ratio (SIR) = 32.6; 95% confidence interval = 17.3-55.7). The specific cancers included hepatoblastoma (n = 6); nephroblastoma (n = 4); astrocytoma (n = 1); neuroblastoma (n = 1) and adrenocortical carcinoma (n = 1). The cancer SIR was highest in patients with a paternal uniparental disomy of 11p15.5 (UPDpat). A high cancer risk remained when cases of cancer diagnosed prior to the BWS diagnosis were excluded. Conclusions This study confirms an increased cancer risk in children with BWS. Our findings suggest that the highest cancer risk is associated with UPDpat. We were unable to confirm an excessive cancer risk in patients with IC1 gain of methylation (IC1-GOM) and this finding requires further investigation.

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Section: Introductionmentioning

confidence: 99%

Cancer incidence and spectrum among children with genetically confirmed Beckwith-Wiedemann spectrum in Germany: a retrospective cohort study

et al. 2020

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“…Conjugated hyperbilirubinemia is not established as a feature of imprinting disorders. However, this was documented in five girls with mosaic GWpUPD and a BWS-like phenotype with hyperinsulinism ( Kalish et al 2013 ; Lee et al 2019 ; Christesen et al 2020 ), in one case of UPD(6)pat (other methylation defects or UPDs were not ruled out in this patient) ( Kenny et al 2009 ), and in one case of UPD(7)pat ( Fares et al 2006 ).…”

Section: Introductionmentioning

confidence: 85%

Double paternal uniparental isodisomy 7 and 15 presenting with Beckwith–Wiedemann spectrum features

Berland

Rustad

Bentsen

et al. 2021

Cold Spring Harb Mol Case Stud

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Here we describe for the first time double paternal uniparental isodisomy (iUPD) 7 and 15 in a baby boy with features in the Beckwith-Wiedemann syndrome spectrum (BWSp) (placentomegaly, hyperinsulinism, enlarged viscera, hemangiomas, and earlobe creases) in addition to conjugated hyperbilirubinemia. His phenotype was also reminiscent of genome-wide paternal uniparental isodisomy. We discuss the most likely origin of the UPDs; a maternal double monosomy 7 and 15 rescued by duplication of the paternal chromosomes after fertilization. So far, paternal UPD7 is not associated with an abnormal phenotype, while paternal UPD15 causes Angelman syndrome. Methylation analysis for other clinically relevant imprinting disorders, including BWSp, was normal. Therefore, we hypothesized that the double UPD affected other imprinted genes. To look for such effects, patient fibroblast RNA was isolated and analyzed for differential expression compared to six controls. We did not find apparent transcription differences in imprinted genes outside chromosomes 7 and 15 in patient fibroblast. PEG10 (7q21.3) was the only paternally imprinted gene on these chromosomes upregulated beyond double-dose expectation (6-fold). We speculate that a high PEG10 level could have a growth-promoting effect as his phenotype was not related to aberrations in BWS-locus on 11p15.5 after DNA, RNA, and methylation testing. However, many genes in gene sets associated with growth were upregulated. This case broadens the phenotypic spectrum of UPDs but did not show evidence of involvement of an imprinted gene network.

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“…Other abnormalities include dysregulation of IGF2 (105,106). Pancreatoblastoma may be associated with Beckwith-Wiedemann syndrome and familial adenomatous polyposis (107,108). Gastroblastoma is a recently described tumor (109,110), arising in the stomach of children and young adults.…”

Section: Other Solid Tumorsmentioning

confidence: 99%

A Summary of the Inaugural WHO Classification of Pediatric Tumors: Transitioning from the Optical into the Molecular Era

et al. 2021

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Pediatric tumors are uncommon, yet are the leading cause of cancer-related death in childhood. Tumor types, molecular characteristics, and pathogenesis are unique, often originating from a single genetic driver event. The specific diagnostic challenges of childhood tumors led to the development of the first World Health Organization (WHO) Classification of Pediatric Tumors. The classification is rooted in a multilayered approach, incorporating morphology, IHC, and molecular characteristics. The volume is organized according to organ sites and provides a single, state-of-the-art compendium of pediatric tumor types. A special emphasis was placed on "blastomas, " which variably recapitulate the morphologic maturation of organs from which they originate.Significance: In this review, we briefly summarize the main features and updates of each chapter of the inaugural WHO Classification of Pediatric Tumors, including its rapid transition from a mostly microscopic into a molecularly driven classification systematically taking recent discoveries in pediatric tumor genomics into account.

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Mosaic paternal haploidy in a patient with pancreatoblastoma and Beckwith–Wiedemann spectrum

Cited by 7 publications

References 29 publications

Cancer incidence and spectrum among children with genetically confirmed Beckwith-Wiedemann spectrum in Germany: a retrospective cohort study

Cancer incidence and spectrum among children with genetically confirmed Beckwith-Wiedemann spectrum in Germany: a retrospective cohort study

Double paternal uniparental isodisomy 7 and 15 presenting with Beckwith–Wiedemann spectrum features

A Summary of the Inaugural WHO Classification of Pediatric Tumors: Transitioning from the Optical into the Molecular Era

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