LAUSR

Simple Summary Beckwith–Wiedemann Spectrum (BWSp) is a disorder predisposing to tumors of embryonic origin arising during childhood. Little is known concerning tumor risk and histotype prevalence in adult BWSp patients. However, some reports of co-occurrence of BWSp and tumors in early adulthood suggest that the cancer risk in this syndrome may also be relevant later than childhood. Here, we report for the first time a case of co-occurrence of BWSp and early-onset colorectal cancer (EO-CRC). The results demonstrate genetic and epigenetic molecular lesions at both somatic and germline levels, providing support to the hypothesis that epigenetic changes contribute to cancer initiation in tissues where a genetic insult is already present, thus acting in a cooperative manner to stimulate tumorigenesis. This study adds further evidence to the need for tumor surveillance beyond childhood in patients with BWSp. 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.