Abstract
Epigenetics has achieved a profound impact in the biomedical field, providing new experimental opportunities and innovative therapeutic strategies to face a plethora of diseases. In the rare diseases scenario, Beckwith-Wiedemann syndrome (BWS) is a pediatric pathological condition characterized by a complex molecular basis, showing alterations in the expression of different growth-regulating genes. The molecular origin of BWS is associated with impairments in the genomic imprinting of two domains at the 11p15.5 chromosomal region. The first domain contains three different regions: insulin growth like factor gene (IGF2), H19, and abnormally methylated DMR1 region. The second domain consists of cell proliferation and regulating-genes such as CDKN1C gene encoding for cyclin kinase inhibitor its role is to block cell proliferation. Although most cases are sporadic, about 5–10% of BWS patients have inheritance characteristics. In the 11p15.5 region, some of the patients have maternal chromosomal rearrangements while others have Uniparental Paternal Disomy UPD(11)pat. Defects in DNA methylation cause alteration of genes and the genomic structure equilibrium leading uncontrolled cell proliferation, which is a typical tumorigenesis event. Indeed, in BWS patients an increased childhood tumor predisposition is observed. Here, we summarize the latest knowledge on BWS and focus on the impact of epigenetic alterations to an increased cancer risk development and to metabolic disorders. Moreover, we highlight the correlation between assisted reproductive technologies and this rare disease. We also discuss intriguing aspects of BWS in twinning. Epigenetic therapies in clinical trials have already demonstrated effectiveness in oncological and non-oncological diseases. In this review, we propose a potential “epigenetic-based” approaches may unveil new therapeutic options for BWS patients. Although the complexity of the syndrome is high, patients can be able to lead a normal life but tumor predispositions might impair life expectancy. In this sense epigenetic therapies should have a supporting role in order to guarantee a good prognosis.
Highlights
Epigenetic alterations play a crucial role in both cancer and non-oncological diseases (Mau and Yung, 2014) regulating DNA methylation, histone modifications (Nowacka-Zawisza and Wisnik, 2017) and micro-RNA expression that determines gene expression (Abi Khalil, 2014).Some rare congenital diseases present alterations in epigenetically regulated genes (Niculescu and Lupu, 2011), providing the rationale to interfere via an epigenetic rebalance to mitigate/overcome these conditions (Nguyen, 2019)
The generally low number of patients is a bottleneck and a hindrance to the development of dedicated therapeutic approaches nor the causal identification of “druggable” targets proven beneficial for the restoration of the health status or, at least, for symptoms defeat
The lesson learned from Beckwith-Wiedemann syndrome (BWS) homozygotic twins suggests the existence of a phenotypic link between epigenome deregulation and the complexity of BWS disease, but it indicates the potential of targeting the epigenome pharmacologically in BWS to at least obtain beneficial effects ameliorating the quality of life
Summary
Epigenetic alterations play a crucial role in both cancer and non-oncological diseases (Mau and Yung, 2014) regulating DNA methylation, histone modifications (Nowacka-Zawisza and Wisnik, 2017) and micro-RNA expression that determines gene expression (Abi Khalil, 2014). The majority of IDs such as BWS present the same four classes of molecular alterations lead to imbalanced gene expression: uniparental disomy (UPD), epimutation (aberrant methylation marks), copy number variations (CNVs) and point mutations in imprinted genes. The major limitation for it to be carried on is due to the low patients’ number (Nguyen, 2019) For this reason, multi-institutional collaborations are required in order to reach a statistically significant number of patients for the constitution of an observational cohort or a clinical trial (Griggs et al, 2009). In order to overcome this limitation and trying to boost patient care, the Coordination of Rare Diseases at Sanford (CoRDS) started in 2013 a program (NCT01793168) providing a centralizedinternational patients registry for all rare diseases This program helps in the identification, advance treatments, and therapies on a large cohort of patients
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