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

Author:

Cecere Francesco1ORCID,Pignata Laura1ORCID,Hay Mele Bruno2ORCID,Saadat Abu1,D’Angelo Emilia1,Palumbo Orazio3ORCID,Palumbo Pietro3ORCID,Carella Massimo3ORCID,Scarano Gioacchino4ORCID,Rossi Giovanni Battista5,Angelini Claudia6ORCID,Sparago Angela1ORCID,Cerrato Flavia1ORCID,Riccio Andrea17ORCID

Affiliation:

1. Department of Environmental Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), Università degli Studi della Campania “Luigi Vanvitelli”, 81100 Caserta, Italy

2. Department of Biology, Università degli Studi di Napoli “Federico II”, 80126 Napoli, Italy

3. Division of Medical Genetics, Fondazione IRCCS “Casa Sollievo della Sofferenza”, 71013 San Giovanni Rotondo, Italy

4. Medical Genetics Unit, Azienda Ospedaliera “San Pio” P.”Gaetano Rummo”, 82100 Benevento, Italy

5. Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, 80131 Napoli, Italy

6. Istituto per le Applicazioni del Calcolo (IAC) “Mauro Picone”, Consiglio Nazionale delle Ricerche (CNR), 80131 Napoli, Italy

7. Institute of Genetics and e Biophysics (IGB) “Adriano Buzzati-Traverso”, Consiglio Nazionale delle Ricerche (CNR), 80131 Napoli, Italy

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.

Publisher

MDPI AG

Subject

Cancer Research,Oncology

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