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

Abstract

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.

Understanding the Variability of 22q11.2 Deletion Syndrome: The Role of Epigenetic Factors

“…In some, the deletion may unmask recessive mutations in genes located in the intact 22q11.2 region, leading to atypical and more severe presentations of 22q11.2DS [ 21 ]. Furthermore, recent evidence demonstrates that 1% of patients with 22q11.2DS may be affected by a second genetic condition in the context of a dual diagnosis [ 90 , 91 , 92 ].…”

ICF1-Syndrome-Associated DNMT3B Mutations Prevent De Novo Methylation at a Subset of Imprinted Loci during iPSC Reprogramming

“…For the analysis of the iDMRs, we downloaded the coordinates from http://www.humanimprints.net/ (accessed on 18 September 2021) and calculated the average methylation level for each region with at least 3 probes. Pyrosequencing analysis was conducted as previously described and using primers reported in our previous manuscripts [28,29].…”

Introduction to the Beckwith–Wiedemann Syndrome and Cancer Special Issue

“…Cecere et al, in their paper "Co-Occurrence of Beckwith-Wiedemann Syndrome and Early-Onset Colorectal Cancer", described a case report of a BWS patient who developed colorectal cancer at age 27 [7]. The molecular lesions were investigated at the somatic and germline levels in this patient.…”