Papulino Chiara, Chianese Ugo, Nicoletti Maria Maddalena, Benedetti Rosaria, Altucci Lucia
Department of Precision Medicine, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy.
Front Genet. 2020 Sep 15;11:563718. doi: 10.3389/fgene.2020.563718. eCollection 2020.
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 , 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 (), , and abnormally methylated DMR1 region. The second domain consists of cell proliferation and regulating-genes such as 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.
表观遗传学在生物医学领域产生了深远影响，为应对众多疾病提供了新的实验机会和创新治疗策略。在罕见病中，贝克威思-维德曼综合征（BWS）是一种儿科病理状况，其特征是分子基础复杂，表现为不同生长调节基因表达的改变。BWS的分子起源与11p15.5染色体区域两个结构域的基因组印记受损有关。第一个结构域包含三个不同区域：胰岛素样生长因子基因（）、和异常甲基化的DMR1区域。第二个结构域由细胞增殖和调节基因组成，如编码细胞周期蛋白激酶抑制剂的基因，其作用是阻止细胞增殖。虽然大多数病例是散发性的，但约5-10%的BWS患者具有遗传特征。在11p15.5区域，一些患者有母系染色体重排，而另一些患者有单亲父源二体性（UPD(11)pat）。DNA甲基化缺陷会导致基因和基因组结构平衡的改变，导致细胞增殖失控，这是典型的肿瘤发生事件。事实上，在BWS患者中观察到儿童期肿瘤易感性增加。在这里，我们总结了关于BWS的最新知识，并关注表观遗传改变对癌症风险增加和代谢紊乱的影响。此外，我们强调了辅助生殖技术与这种罕见疾病之间的相关性。我们还讨论了BWS在双胞胎中的有趣方面。临床试验中的表观遗传疗法已经在肿瘤和非肿瘤疾病中证明了有效性。在这篇综述中，我们提出一种潜在的“基于表观遗传学”的方法可能为BWS患者揭示新的治疗选择。尽管该综合征的复杂性很高，但患者能够过上正常生活，但肿瘤易感性可能会影响预期寿命。从这个意义上说，表观遗传疗法应该发挥支持作用，以保证良好的预后。
