Abstract 5220: The consequences of 11p15 mosaicism in Beckwith-Wiedemann syndrome/spectrum: Epigenotypes associated with cancer development and necessity for universal tumor screening

Abstract

Abstract Beckwith-Wiedemann Spectrum (BWSp) is the most common (epi)genetic cancer predisposition disorder. BWSp has a heterogeneous clinical presentation and is caused by epigenetic changes at two regions on chromosome 11p15. These epigenetic changes occur post-zygotically leading to a mosaic distribution among tissues. Clinical molecular testing usually starts with blood; however, we and others have demonstrated that positive molecular testing rates are increased if testing is performed on affected tissues. Clinical and molecular diagnosis is important because patients with BWS are at risk for development of embryonal tumors (Wilms tumor (WT), hepatoblastoma (HB), and neuroendocrine tumors). Formal surveillance guidelines were published in 2017 as part of a United States-based cancer predisposition effort that recommended alpha fetoprotein and complete abdominal ultrasound screening for all patients with BWSp until 4 years of age for HB and renal ultrasound screening until 7 years of age for WT. In contrast, the European-based BWS international consensus group (BWS-ICG) applied stratified cancer screening recommendations based on (epi)genotype. In the present study, we investigated cancer development rates and epigenotype profiles associated with cancer in patients diagnosed with BWSp. We present a series of patients with history of WT, HB, and/or neuroendocrine tumors to highlight that there can be differing BWSp epigenotype profiles in tumor and adjacent normal tissue compared to blood, demonstrating the presence of multiple cell populations with distinct epigenetic changes within patients. These distinct changes show that more than one epigenetic alteration in the chromosome 11p15 region can be present in a single tissue type. These findings suggest that the epigenetic classification in blood alone should not be used to stratify cancer risk in BWSp. Additionally, the mild BWSp clinical phenotype and low BWS-ICG clinical scores for these patients highlight that some patients present with few external features. Therefore, neither blood epigenotype nor external phenotype can help inform an individual’s unique tumor risk. This work further suggests that the BWS-ICG tumor risk stratification system cannot be applied to the full Beckwith-Wiedemann Spectrum due to the emerging epigenetic and phenotypic landscape of patients diagnosed with BWSp. These results support a recommendation of universal tumor screening for all patients diagnosed with even mild BWSp phenotypes and/or a 11p15 epigenetic abnormality. Citation Format: Kelly A. Duffy, Evan R. Hathaway, Mallory E. Byrne, Andrew M. George, Timothy Mcelroy, Suzanne P. MacFarland, Garrett M. Brodeur, Jennifer M. Kalish. The consequences of 11p15 mosaicism in Beckwith-Wiedemann syndrome/spectrum: Epigenotypes associated with cancer development and necessity for universal tumor screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5220.