Molecular Basis of Beckwith–Wiedemann Syndrome Spectrum with Associated Tumors and Consequences for Clinical Practice

Eggermann, Thomas; Maher, Eamonn R.; Kratz, Christian P.; Prawitt, Dirk

doi:10.3390/cancers14133083

Cited by 15 publications

(12 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…BWSp is a disorder predisposing to tumors of embryonic origin that arise during childhood, usually up to 10 years of age [ 4 , 5 , 27 ]. Data on tumor risk and histotype prevalence in adult BWSp patients are very limited because the clinical phenotype mitigates with age and a follow-up of large series of adults with BWSp has not been performed [ 1 , 11 ].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Co-Occurrence of Beckwith–Wiedemann Syndrome and Early-Onset Colorectal Cancer

Cecere

Pignata

Mele

et al. 2023

Cancers

View full text Add to dashboard Cite

CRC is an adult-onset carcinoma representing the third most common cancer and the second leading cause of cancer-related deaths in the world. EO-CRC (<45 years of age) accounts for 5% of the CRC cases and is associated with cancer-predisposing genetic factors in half of them. Here, we describe the case of a woman affected by BWSp who developed EO-CRC at age 27. To look for a possible molecular link between BWSp and EO-CRC, we analysed her whole-genome genetic and epigenetic profiles in blood, and peri-neoplastic and neoplastic colon tissues. The results revealed a general instability of the tumor genome, including copy number and methylation changes affecting genes of the WNT signaling pathway, CRC biomarkers and imprinted loci. At the germline level, two missense mutations predicted to be likely pathogenic were found in compound heterozygosity affecting the Cystic Fibrosis (CF) gene CFTR that has been recently classified as a tumor suppressor gene, whose dysregulation represents a severe risk factor for developing CRC. We also detected constitutional loss of methylation of the KCNQ1OT1:TSS-DMR that leads to bi-allelic expression of the lncRNA KCNQ1OT1 and BWSp. Our results support the hypothesis that the inherited CFTR mutations, together with constitutional loss of methylation of the KCNQ1OT1:TSS-DMR, initiate the tumorigenesis process. Further somatic genetic and epigenetic changes enhancing the activation of the WNT/beta-catenin pathway likely contributed to increase the growth advantage of cancer cells. Although this study does not provide any conclusive cause–effect relationship between BWSp and CRC, it is tempting to speculate that the imprinting defect of BWSp might accelerate tumorigenesis in adult cancer in the presence of predisposing genetic variants.

show abstract

Section: Discussionmentioning

confidence: 99%

“…The lowest risk (2.6%) is associated with IC2 LoM, and the related histotypes are hepatoblastoma (0.7%), rhabdomyosarcoma (0.5%) and neuroblastoma (0.5%). Furthermore, in the subset of BWSp patients with MLID, to date, no specific tumor-risk estimates have been defined [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Co-Occurrence of Beckwith–Wiedemann Syndrome and Early-Onset Colorectal Cancer

Cecere

Pignata

Mele

et al. 2023

Cancers

View full text Add to dashboard Cite

show abstract

“…BWS is a well-defined tumor predisposition syndrome, and 7.4–10% of patients develop embryonal tumors (WT, hepatoblastoma, neoblastoma, adrenal cell carcinoma) in childhood, usually before the age of 7 years [ 13 , 14 , 25 , 26 , 27 , 28 , 29 ]. Mussa et al [ 25 ] studied the characteristics of 318 BWS patients and reported a significant correlation between malignant neoplasms and lateralized overgrowth.…”

Section: Discussionmentioning

confidence: 99%

Investigation of 11p15.5 Methylation Defects Associated with Beckwith-Wiedemann Spectrum and Embryonic Tumor Risk in Lateralized Overgrowth Patients

Tüysüz

Bozlak

Alkaya

et al. 2023

Cancers

View full text Add to dashboard Cite

The Beckwith–Wiedemann spectrum (BWSp) ranges from isolated lateralized overgrowth (ILO) to classic phenotypes. In this broad clinical spectrum, an epigenetic alteration on chromosome 11p15.5 can be detected. The risk for embryonal tumors is high, especially in patients with lateralized overgrowth (LO). The aim of this study is to investigate epigenetic alterations in 11p15.5 and tumor risk in 87 children with LO. The methylation level of 11p15.5 was examined in the blood of all patients and in skin samples or buccal swabs from 40 patients with negative blood tests; 63.2% of patients were compatible with the ILO phenotype, 18.4% were atypical, and 18.4% were classic. The molecular diagnosis rate was 81.2% for the atypical and classic phenotypes, and 10.9% for the ILO phenotype. In patients with epigenetic alterations, LO was statistically significantly more severe than in test negatives. Tumors developed in six (6.9%) of the total 87 patients with LO; four belonged to the atypical or classical phenotype (12.5%) and two to ILO (3.5%). Three of the four patients with atypical/classical phenotypes had pUPD11, one had IC1-GOM alteration, and two ILO patients were negative. We conclude that LO patients should be monitored for tumor risk even if their epigenetic tests are negative.

show abstract

“…Certain syndromes, backed by robust clinical evidence, stand out for their well documented association with specific tumor predisposition. Beckwith–Wiedemann syndrome (BWS) is intricately linked to the heightened likelihood of developing Wilms tumor, hepatoblastoma, and adrenal cortical carcinoma, setting this syndrome apart from the others above as exhibiting a higher risk profile [32]. PTEN hamartoma tumor syndrome (thyroid, endometrial, and breast cancer) has guidelines [29–31,33].…”

Section: Comorbiditiesmentioning

confidence: 99%

Overgrowth syndromes, diagnosis and management

Klein,

Nisbet,

Kalish

2023

Current Opinion in Pediatrics

View full text Add to dashboard Cite

Purpose of review This review will focus on the current knowledge of the diagnosis and management of overgrowth syndromes with specific focus on mosaic conditions and treatment strategies. Recent findings With the implementation of massively parallel sequencing, the genetic etiology many classically described overgrowth syndromes has been identified. More recently, the role of mosaic genetic changes has been well described in numerous syndromes. Furthermore, the role of imprinting and methylation, especially of the 11p15 region, has been shown to be instrumental for growth. Perhaps most importantly, many overgrowth syndromes carry an increased risk of neoplasm formation especially in the first 10 years of life and possibly beyond. The systematic approach to the child with overgrowth will aide in timely diagnosis and efficient alignment them with appropriate screening strategies. In some cases, precision medical interventions are available to target the perturbed growth signaling pathways. Summary The systematic approach to the child with overgrowth aids in the standardization of the diagnostic pathway for these young patients, thereby expediting the diagnostic timeline, enabling rigorous monitoring, and delivering tailored therapeutic interventions.

show abstract

Molecular Basis of Beckwith–Wiedemann Syndrome Spectrum with Associated Tumors and Consequences for Clinical Practice

Cited by 15 publications

References 64 publications

Co-Occurrence of Beckwith–Wiedemann Syndrome and Early-Onset Colorectal Cancer

Co-Occurrence of Beckwith–Wiedemann Syndrome and Early-Onset Colorectal Cancer

Investigation of 11p15.5 Methylation Defects Associated with Beckwith-Wiedemann Spectrum and Embryonic Tumor Risk in Lateralized Overgrowth Patients

Overgrowth syndromes, diagnosis and management

Contact Info

Product

Resources

About