Bilateral Wilms Tumor and Early Presentation in Pediatric Patients Is Associated with the Truncation of the Wilms Tumor 1 Protein
Center for Transplant and Renal Research, Westmead Millennium Institute, The University of Sydney, New South Wales, Australia. The Journal of pediatrics
(Impact Factor: 3.79).
02/2013; 163(1). DOI: 10.1016/j.jpeds.2012.12.080
To investigate the frequency of constitutional Wilms tumor 1 gene (WT1) abnormalities in children with bilateral Wilms tumor (WT) and the age of tumor onset in patients with a mutation.
Eight patients with bilateral WT were studied. High-resolution melting and direct sequencing were used to screen for the WT1 gene. Western blotting was performed to determine whether the identified mutations were associated with expressed truncated WT1 protein.
The median age of tumor onset in patients with a mutation in the WT1 was lower (10 months) than in those without a mutation (39 months). Three novel heterozygous nonsense mutations were identified in exon 8 in peripheral blood from 3 individuals, whereas all 3 tumor tissues lacked the wild-type allele. All mutations led to a premature stop codon with truncation of the WT1 protein. In 1 patient, a truncated form of WT1 protein was identified, suggesting that development of the WT may have resulted from expression of an abnormal protein. Four distinct silent single-nucleotide polymorphisms (SNPs) were detected. All 3 patients with a pathogenic WT1 mutation had 2 synonymous SNPs, whereas only 1 of the remaining 5 patients had a single synonymous SNP (P < .05).
Bilateral WT are associated with early presentation in pediatric patients and a high frequency of WT1 nonsense mutations in exon 8. Silent SNPs may also be involved in the development of WT.
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ABSTRACT: In this sequel article on Amlexanox I investigate the multi-tasking potential for this drug, a recently discovered readthrough agent with immune-modulatory properties, for management of a wide range of human diseases including ageing modeled as a disease. The focus is not only on correction or disease rescue, but also on early prevention through use of Amlexanox prophylaxis. The concept of readthrough of nonsense mutations is further explored and correlation of nonsense mutation with cancer spread and stage is examined. Many other prevalent disease processes are examined in the light of nonsense-mediated causation, for example, intellectual disability and ageing. A primary aim of my current investigation is to show that both communicable diseases (related to infections from viral and bacterial agents) as well as non-communicable diseases (such as cancer, diabetes and inherited malformations/dysfunctions) may all form suited targets for Amlexanox therapy. As such, ex vivo and in vitro studies and animal models are discussed with the overall theme being to translate positive findings into the clinic. Clearly, this would have a major benefit with management in many inherited disease states and for infectious diseases. Further, a major benefit can be predicted for acquired chronic conditions too. The long understood property of Amlexanox in immune-modulation is exploited in this analysis. By acting through part-control of the NF-kappaB transcriptional factor-inflammatory axis, Amlexanox is capable of modulating the pathophysiology of such processes as cancer, vascular disease and diabetes with obesity. Moderating the response to pathogen challenge is a focus of attention in this present investigation. This is important insofar as Amlexanox mediates inflammatory-axis regulation and host-pathogen interactions, strongly suggesting that it must be explored in this context. As a result of this, interference with this arm of the innate immune system may well have consequences in terms of exposure to certain infectious agents. Detailed animal model systems as well as formal clinical trials are definitely called for to clarify the longer-term adverse reaction this may produce in the face of pathogen exposure. Amlexanox has been clinically approved for many years and, along with other drugs with similar immune-modulating capacity, appears satisfactory for long-term usage. Therefore, in practical terms, pathogen challenge in such a context may not pose significant threat. Overall, clinical trials are universally called for in order to ascertain the full potential for this old drug presenting with some exciting 'new tricks'. I aim to be able to purposefully 'repurpose' Amlexanox and add this drug into the 'Doctor's bag' as a highly valuable medical adjunct to manage a wide plethora of medical conditions.
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Bilateral Wilms tumours (BWTs) occur by germline mutation of various predisposing genes; one of which is WT1 whose abnormality was reported in 17-38% of BWTs in Caucasians, whereas no such studies have been conducted in East-Asians. Carriers with WT1 mutations are increasing because of improved survival.
Statuses of WT1 and IGF2 were examined in 45 BWTs from 31 patients with WT1 sequencing and SNP array-based genomic analyses. The penetrance rates were estimated in WT1-mutant familial Wilms tumours collected from the present and previous studies.
We detected WT1 abnormalities in 25 (81%) of 31 patients and two families, which were included in the penetrance rate analysis of familial Wilms tumour. Of 35 BWTs from the 25 patients, 31 had small homozygous WT1 mutations and uniparental disomy of IGF2, while 4 had large 11p13 deletions with the retention of 11p heterozygosity. The penetrance rate was 100% if children inherited small WT1 mutations from their fathers, and 67% if inherited the mutations from their mothers, or inherited or had de novo 11p13 deletions irrespective of parental origin (P=0.057).
The high incidence of WT1 abnormalities in Japanese BWTs sharply contrasts with the lower incidence in Caucasian counterparts, and the penetrance rates should be clarified for genetic counselling of survivors with WT1 mutations.
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