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Cancers Mar 2023CRC 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)...
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 :TSS-DMR that leads to bi-allelic expression of the lncRNA and BWSp. Our results support the hypothesis that the inherited CFTR mutations, together with constitutional loss of methylation of the :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.
PubMed: 37046605
DOI: 10.3390/cancers15071944 -
Molecular Syndromology Jul 2016Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS) are 2 clinically opposite growth-affecting disorders belonging to the group of congenital imprinting... (Review)
Review
Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS) are 2 clinically opposite growth-affecting disorders belonging to the group of congenital imprinting disorders. The expression of both syndromes usually depends on the parental origin of the chromosome in which the imprinted genes reside. SRS is characterized by severe intrauterine and postnatal growth retardation with various additional clinical features such as hemihypertrophy, relative macrocephaly, fifth finger clinodactyly, and triangular facies. BWS is an overgrowth syndrome with many additional clinical features such as macroglossia, organomegaly, and an increased risk of childhood tumors. Both SRS and BWS are clinically and genetically heterogeneous, and for clinical diagnosis, different diagnostic scoring systems have been developed. Six diagnostic scoring systems for SRS and 4 for BWS have been previously published. However, neither syndrome has common consensus diagnostic criteria yet. Most cases of SRS and BWS are associated with opposite epigenetic or genetic abnormalities in the 11p15 chromosomal region leading to opposite imbalances in the expression of imprinted genes. SRS is also caused by maternal uniparental disomy 7, which is usually identified in 5-10% of the cases, and is therefore the first imprinting disorder that affects 2 different chromosomes. In this review, we describe in detail the clinical diagnostic criteria and scoring systems as well as molecular causes in both SRS and BWS.
PubMed: 27587987
DOI: 10.1159/000447413 -
Frontiers in Genetics 2020Epigenetics has achieved a profound impact in the biomedical field, providing new experimental opportunities and innovative therapeutic strategies to face a plethora of... (Review)
Review
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.
PubMed: 33101381
DOI: 10.3389/fgene.2020.563718 -
European Journal of Human Genetics :... Jan 2010Beckwith-Wiedemann syndrome (BWS) is a model disorder for the study of imprinting, growth dysregulation, and tumorigenesis. Unique observations in this disorder point to... (Review)
Review
Beckwith-Wiedemann syndrome (BWS) is a model disorder for the study of imprinting, growth dysregulation, and tumorigenesis. Unique observations in this disorder point to an important embryonic developmental window relevant to the observations of increased monozygotic twinning and an increased rate of epigenetic errors after subfertility/assisted reproduction.
Topics: Beckwith-Wiedemann Syndrome; Diagnosis, Differential; Genetic Counseling; Genetic Testing; Humans
PubMed: 19550435
DOI: 10.1038/ejhg.2009.106 -
International Journal of Molecular... Mar 2021Beckwith-Wiedemann syndrome (BWS) is a clinically and genetically heterogeneous overgrowth disease. BWS is caused by (epi)genetic defects at the 11p15 chromosomal... (Review)
Review
Beckwith-Wiedemann syndrome (BWS) is a clinically and genetically heterogeneous overgrowth disease. BWS is caused by (epi)genetic defects at the 11p15 chromosomal region, which harbors two clusters of imprinted genes, / and /, regulated by differential methylation of imprinting control regions, :IG DMR and :TSS DMR, respectively. A subset of BWS patients show multi-locus imprinting disturbances (MLID), with methylation defects extended to other imprinted genes in addition to the disease-specific locus. Specific (epi)genotype-phenotype correlations have been defined in order to help clinicians in the classification of patients and referring them to a timely diagnosis and a tailored follow-up. However, specific phenotypic correlations have not been identified among MLID patients, thus causing a debate on the usefulness of multi-locus testing in clinical diagnosis. Finally, the high incidence of BWS monozygotic twins with discordant phenotypes, the high frequency of BWS among babies conceived by assisted reproductive technologies, and the female prevalence among BWS-MLID cases provide new insights into the timing of imprint establishment during embryo development. In this review, we provide an overview on the clinical and molecular diagnosis of single- and multi-locus BWS in pre- and post-natal settings, and a comprehensive analysis of the literature in order to define possible (epi)genotype-phenotype correlations in MLID patients.
Topics: Beckwith-Wiedemann Syndrome; Cluster Analysis; Cyclin-Dependent Kinase Inhibitor p57; DNA Methylation; Epigenesis, Genetic; Female; Gene Silencing; Genetic Association Studies; Genomic Imprinting; Humans; Insulin-Like Growth Factor II; Male; Phenotype; Potassium Channels, Voltage-Gated; Prenatal Diagnosis; Reproductive Techniques, Assisted; Twins, Monozygotic; X Chromosome Inactivation
PubMed: 33810554
DOI: 10.3390/ijms22073445 -
Sao Paulo Medical Journal = Revista... May 2003Beckwith-Wiedemann syndrome is a complex and heterogeneous overgrowth syndrome with genetic and epigenetic alterations, involving genomic imprinting and cancer... (Review)
Review
CONTEXT
Beckwith-Wiedemann syndrome is a complex and heterogeneous overgrowth syndrome with genetic and epigenetic alterations, involving genomic imprinting and cancer predisposition. Isolated hemihyperplasia is of unknown cause, and it may represent a partial or incomplete expression of Beckwith-Wiedemann syndrome.
OBJECTIVES
A clinical and molecular review and proposal of the use of an experimental protocol to provide a practical approach for the physician.
DATA SYNTHESIS
This review demonstrates the genetic and epigenetic mechanisms involved in the Beckwith-Wiedemann syndrome and isolated hemihyperplasia, and the candidate genes. To our knowledge, this is the first Brazilian protocol for research into these disorders. The results have been used at the Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, to elucidate the basis of Beckwith-Wiedemann syndrome and isolated hemihyperplasia, and have been applied at the Hospital Universitário of the Faculdade de Medicina.
CONCLUSIONS
Elucidation of the etiological mechanisms and use of a laboratory protocol to detect alterations in these disorders may be useful for guiding the management of such patients and genetic counseling of the families.
Topics: Beckwith-Wiedemann Syndrome; Humans; Hypertrophy
PubMed: 12920477
DOI: 10.1590/s1516-31802003000300010 -
Archives of Disease in Childhood. Fetal... Jan 2001
Review
Topics: Beckwith-Wiedemann Syndrome; Child, Preschool; Chromosome Aberrations; Developmental Disabilities; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypoglycemia; Infant; Infant, Newborn; Male
PubMed: 11124932
DOI: 10.1136/fn.84.1.f67 -
Disease Models & Mechanisms May 2020Genomic imprinting, a phenomenon in which the two parental alleles are regulated differently, is observed in mammals, marsupials and a few other species, including... (Review)
Review
Genomic imprinting, a phenomenon in which the two parental alleles are regulated differently, is observed in mammals, marsupials and a few other species, including seed-bearing plants. Dysregulation of genomic imprinting can cause developmental disorders such as Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS). In this Review, we discuss (1) how various (epi)genetic lesions lead to the dysregulation of clinically relevant imprinted loci, and (2) how such perturbations may contribute to the developmental defects in BWS and SRS. Given that the regulatory mechanisms of most imprinted clusters are well conserved between mice and humans, numerous mouse models of BWS and SRS have been generated. These mouse models are key to understanding how mutations at imprinted loci result in pathological phenotypes in humans, although there are some limitations. This Review focuses on how the biological findings obtained from innovative mouse models explain the clinical features of BWS and SRS.
Topics: Animals; Beckwith-Wiedemann Syndrome; DNA Methylation; Disease Models, Animal; Epigenesis, Genetic; Genomic Imprinting; Humans; Mice; Silver-Russell Syndrome
PubMed: 32424032
DOI: 10.1242/dmm.044123 -
Hepatology Communications Aug 2022Beckwith-Wiedemann Syndrome (BWS) is the most common human overgrowth disorder caused by structural and epigenetic changes to chromosome 11p15. Patients with BWS are...
Beckwith-Wiedemann Syndrome (BWS) is the most common human overgrowth disorder caused by structural and epigenetic changes to chromosome 11p15. Patients with BWS are predisposed to developing hepatoblastoma (HB). To better understand the mechanism of HB oncogenesis in this cancer predisposition background, we performed the first multi-dimensional study of HB samples collected from patients diagnosed with BWS. This multi-omic investigation of seven BWS HB and five matched nontumor BWS liver samples from 7 unique patients included examination of whole exome sequences, messenger RNA/microRNA expression, and methylation levels to elucidate the genomic, transcriptomic, and epigenomic landscape of BWS-associated HB. We compared the transcriptional profiles of the BWS samples, both HB and nontumor, to that of control livers. Genes differentially expressed across BWS tissues were identified as BWS HB predisposition factors; this gene group included cell cycle regulators, chromatin organizers, and WNT, mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K)/AKT members. We also compared transcriptional changes associated with non-syndromic HB carrying BWS-like 11p15 alterations compared to those without, as well as to BWS HB. Through this analysis, we identified factors specific to 11p15-altered HB oncogenesis, termed the BWS oncogenesis network. We propose that 11p15 alterations drive HB oncogenesis by initially dysregulating cell-cycle regulators and chromatin organizers, including histone deacetylase 1 (HDAC1), ATP-dependent helicase X, and F-Box and WD repeat domain containing 7. Furthermore, we found oncogenic factors such as dickkopf WNT signaling pathway inhibitor 1 and 4, WNT16, forkhead box O3 (FOXO3), and MAPK10 are differentially expressed in 11p15-altered HB in both the BWS and non-syndromic backgrounds. These genes warrant further investigation as diagnostic or therapeutic targets.
Topics: Beckwith-Wiedemann Syndrome; Carcinogenesis; Chromatin; DNA Methylation; Genomic Imprinting; Hepatoblastoma; Humans; Liver Neoplasms; Phosphatidylinositol 3-Kinases
PubMed: 35507738
DOI: 10.1002/hep4.1972 -
Cancers Jun 2022Beckwith-Wiedemann syndrome (BWS, OMIM 130650) is a congenital imprinting condition with a heterogenous clinical presentation of overgrowth and an increased childhood... (Review)
Review
Beckwith-Wiedemann syndrome (BWS, OMIM 130650) is a congenital imprinting condition with a heterogenous clinical presentation of overgrowth and an increased childhood cancer risk (mainly nephroblastoma, hepatoblastoma or neuroblastoma). Due to the varying clinical presentation encompassing classical, clinical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly, the syndromic entity was extended to the Beckwith-Wiedemann spectrum (BWSp). The tumor risk of up to 30% depends on the molecular subtype of BWSp with causative genetic or epigenetic alterations in the chromosomal region 11p15.5. The molecular diagnosis of BWSp can be challenging for several reasons, including the range of causative molecular mechanisms which are frequently mosaic. The molecular basis of tumor formation appears to relate to stalled cellular differentiation in certain organs that predisposes persisting embryonic cells to accumulate additional molecular defects, which then results in a range of embryonal tumors. The molecular subtype of BWSp not only influences the overall risk of neoplasia, but also the likelihood of specific embryonal tumors.
PubMed: 35804856
DOI: 10.3390/cancers14133083