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Hotspots mutational analysis of Wilms tumor 1 gene in acute myeloid leukaemia; prevalence and clinical correlation in North Indian population.

ABSTRACT: BACKGROUND:The pathogenic role of Wilms tumor 1 gene (WT1) is well known in renal cancer. However, recently, its over expression is been documented in cases of acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL) and myelodysplastic syndrome (MDS). WT1 mutations is found in about 6%-15% of cases of AML affecting mainly hotspot exon 7 and 9, and less frequently in other exon such as 1, 2, 3, and 8. Different studies have shown equivocal findings with few of them depicting poorer prognosis, while others suggesting lack of any significant clinical impact. OBJECTIVE:This study was planned to evaluate prevalence of WT1 gene mutation on exon 7 & 9 in de novo cases of AML and its correlation with their clinical features and disease course. METHODOLOGY:A total of newly diagnosed and treatment naive 100 cases of AML, having blast count of ?20% in peripheral blood or bone marrow were enrolled. Genomic DNA of all participants was extracted from blood/bone marrow sample using Qiagen® DNA extraction kit. Haematological workup for counts and flow cytometry based immunophenotypes was done. Mutation on exon 7 & 9 were detected with the help of Sanger sequencing. RESULTS:WT1 mutations were detected in both types of cases having normal vs. abnormal cytogenetics. The overall prevalence of WT1 mutation of 2% was found. We have reported one novel mutation on exon 9 of WT1 gene. Twelve cases (12%) among all analyzed AMLs were found to have synonymous single nucleotide polymorphism (SNPs) on exon 7 which has been previously reported in SNP database (rs16754). CONCLUSION:In our study, presence of synonymous SNP was not associated with any change at protein level. We also evaluated mutational status with deaths during induction remission and concluded that presence of WT1 gene mutation was associated with death during induction therapy.

SUBMITTER: Haider I

PROVIDER: S-EPMC7675118 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Hotspots mutational analysis of Wilms tumor 1 gene in acute myeloid leukaemia; prevalence and clinical correlation in North Indian population.

Haider Imran I Kumar Chandan C Jain Garima G Bakhshi Sameer S Kumar Lalit L Chopra Anita A Ranjan Amar A Tanwar Pranay P

American journal of blood research 20201015 5

<h4>Background</h4>The pathogenic role of <i>Wilms tumor 1</i> gene (WT1) is well known in renal cancer. However, recently, its over expression is been documented in cases of acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL) and myelodysplastic syndrome (MDS). WT1 mutations is found in about 6%-15% of cases of AML affecting mainly hotspot exon 7 and 9, and less frequently in other exon such as 1, 2, 3, and 8. Different studies have shown equivocal findings with few of them depic ...[more]

PMID: 33224562

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Project description:Background/purposeDespite high long-term survival rates in patients with Wilms tumor, there is a need to develop better prognostic biomarkers in order to maximize cure while avoiding treatment-associated morbidities. Tumor-associated macrophages have been recently associated with poorer prognosis and increased disease progression in a number of adult cancers. We investigated the relationship between macrophages and clinicopathological fators in this pediatric solid tumor.MethodsTissue microarray sections of 124 Wilms tumor cases obtained from the Cooperative Human Tissue Network were stained with CD68, a macrophage marker using standard immunohistochemical techniques and quantified using digital image processing techniques. Macrophage densities were correlated by tumor stage, and survival analyses were conducted with available clinical data. Immunohistochemistry was performed on 25 additional Wilms tumor cases obtained from the tumor bank at Columbia University Medical Center and correlated with presence of tumor microvascular invasion.ResultsMean macrophage count densities in stage IV tumors were significantly greater than densities in stage I and III tumors (p=.021, .036). Although the overall and disease-free survival did not differ between high and low macrophage presence groups across all stages, increased macrophage presence was associated with decreased disease-free survival in patients with stage II tumors (p=0.035). Increased macrophage presence may have also correlated with decreased disease-free survival in stage IV patients, but the sample size was too small to allow detection of this difference with significance (p=0.575). Increased macrophage presence was associated with tumor microvascular invasion (p=0.0004).ConclusionOur results suggest that macrophage recruitment may be associated with disease progression in Wilms tumor. Quantitation of macrophage presence may therefore be a useful adjunct in refining staging algorithms for patients with stage II Wilms tumor. Such data might be useful in the effort to reduce the risk of adverse effects associated with under- or overtreatment of this neoplasm.

Project description:PURPOSE: To screen a cohort of corneal dystrophy patients from North India for mutations in the transforming growth factor beta induced (TGFBI) gene, to correlate genotypes to phenotypes, to describe structural implications of various mutations on protein function, and to discuss the implications for diagnosis. METHODS: Eighty affected individuals from 61 unrelated families, who were diagnosed with autosomal dominant granular and/or lattice corneal dystrophy, were recruited for the study. Detailed clinical evaluation was undertaken for these patients to establish their corneal phenotypes. Genomic DNA was isolated from peripheral blood samples and all exons of TGFBI were screened for mutations by polymerase chain reaction (PCR) and direct DNA sequencing. Protein molecular dynamics (MD) simulations were performed for the mutations detected to assess the changes in protein structure. RESULTS: The most common mutations seen were Arg555Trp and Arg124Cys. Two novel mutations, Ser516Arg (c.DNA1548C>G), with a phenotype similar to granular corneal dystrophy I (GCDI), and Leu559Val (c.DNA1675T>G), with an atypical phenotype closely resembling epithelial basement membrane dystrophy/map dot fingerprint dystrophy, were identified. Protein modeling studies involving wild type and mutant protein indicated that the Leu559Val is a destabilizing mutation and that Ser516Arg could adversely affect the specific binding of Fas1 domain 4 with other proteins. In addition, two single-nucleotide polymorphisms, rs4669 and rs11331170, were also identified. Mutations were not identified in 8 affected individuals, 6 of whom were diagnosed with bowman layer dystrophy and 2 with lattice corneal dystrophy. CONCLUSIONS: This is the first comprehensive report of TGFBI mutations covering a large part of North India. Identification of novel mutations, the presence of phenotypic variability, and the genetic heterogeneity seen in our cases stress the need for mandatory screening of TGFBI for precise diagnosis and classification of corneal dystrophies.

Dataset Information

Hotspots mutational analysis of Wilms tumor 1 gene in acute myeloid leukaemia; prevalence and clinical correlation in North Indian population.

Publications

Hotspots mutational analysis of Wilms tumor 1 gene in acute myeloid leukaemia; prevalence and clinical correlation in North Indian population.

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