The prognostic effect of high diagnostic <i>WT1</i> gene expression in pediatric AML depends on <i>WT1</i> SNP rs16754 status: Report from the Children's Oncology Group

Ho, Phoenix A.; Alonzo, Todd A.; Gerbing, Robert B.; Kühn, Julia; Pollard, Jessica A.; Hirsch, Betsy A.; Raimondi, Susana C.; Gamis, Alan S.; Meshinchi, Soheil

doi:10.1002/pbc.24700

Cited by 18 publications

(12 citation statements)

References 29 publications

(52 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our finding of WT1 overexpression in CRC tissue was consistent with previous reports (11,16). Although differences in WT1 expression in blood leukocytes among rs16754 genotypes have been reported in a previous study (18), a recent study on pediatric leukemia failed to detect any significant association between expression and genotype (28). Consistent with the latter study, our findings suggest that the expression level of WT1 in colonic tissue is independent of the rs16754 genotype.…”

supporting

confidence: 83%

Association of Wilms' tumor 1 gene single-nucleotide polymorphism rs16754 with colorectal cancer

Sangkhathat

Maneechay

Chaiyapan

et al. 2015

Molecular and Clinical Oncology

View full text Add to dashboard Cite

Abstract. Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. Our recent study demonstrated that the expression of Wilms' tumor 1 gene (WT1) is associated with surgical outcome in CRC patients. The present study aimed to investigate the genetic association of the single-nucleotide polymorphism rs16754 in the WT1 gene with the occurrence of CRC, using an age-matched case-control study design. In addition, the correlation between genotype and WT1 expression was investigated. Genomic DNA samples from 104 CRC cases, aged 15-65 years, and 208 healthy controls, were genotyped for rs16754 using the TaqMan genotyping method. The genotype distribution conformed to the Hardy-Weinberg equilibrium (P=0.80). The overall minor allele frequency (MAF) of rs16754 (allele A) was 0.33. The MAF among CRC cases was significantly higher compared with that in controls (0.39 vs. 0.31, respectively; P=0.03). The AA genotype was significantly associated with the disease (odds ratio = 2.51, 95% confidence interval: 1.24-5.07, P=0.01). Cases with the AA genotype exhibited a significantly poorer 3-year overall survival (60%), compared with those with the GG or GA genotypes (80%) (log-rank test, P<0.01). Reverse transcription quantitative polymerase chain reaction analysis demonstrated that the expression of WT1 in tumor tissues was higher compared with that in normal tissue; however, there were no significant differences in its expression among different genotypes. Therefore, rs16754 was found to be associated with the occurrence and prognosis of CRC in our subjects.

show abstract

supporting

confidence: 83%

Association of Wilms' tumor 1 gene single-nucleotide polymorphism rs16754 with colorectal cancer

Sangkhathat

Maneechay

Chaiyapan

et al. 2015

Molecular and Clinical Oncology

View full text Add to dashboard Cite

show abstract

“…Selected molecular features (e.g. KIT , RAS , NPM , WT1 , CEBPA, IDH1 mutations and FLT3/ITD ) were clinically available (4,8,9). …”

Section: Methodsmentioning

confidence: 99%

Genomic Profiling of Pediatric Acute Myeloid Leukemia Reveals a Changing Mutational Landscape from Disease Diagnosis to Relapse

et al. 2016

Self Cite

View full text Add to dashboard Cite

The genomic and clinical information used to develop and implement therapeutic approaches for AML originated primarily from adult patients and has been generalized to patients with pediatric AML. However, age-specific molecular alterations are becoming more evident and may signify the need to age-stratify treatment regimens. The NCI/COG TARGET-AML initiative employed whole exome capture sequencing (WXS) to interrogate the genomic landscape of matched trios representing specimens collected upon diagnosis, remission, and relapse from 20 cases of de novo childhood AML. One hundred forty-five somatic variants at diagnosis (median 6 mutations per patient) and 149 variants at relapse (median 6.5 mutations) were identified and verified by orthogonal methodologies. Recurrent somatic variants (in {greater than or equal to}2 patients) were identified for 10 genes (FLT3, NRAS, PTPN11, WT1, TET2, DHX15, DHX30, KIT, ETV6, KRAS), with variable persistence at relapse. The variant allele fraction (VAF), used to measure the prevalence of somatic mutations, varied widely at diagnosis. Mutations that persisted from diagnosis to relapse had a significantly higher diagnostic VAF compared to those that resolved at relapse (median VAF 0.43 vs. 0.24, P<0.001). Further analysis revealed that 90% of the diagnostic variants with VAF >0.4 persisted to relapse compared to 28% with VAF <0.2 (P<0.001). This study demonstrates significant variability in the mutational profile and clonal evolution of pediatric AML from diagnosis to relapse. Furthermore, mutations with high VAF at diagnosis, representing variants shared across a leukemic clonal structure, may constrain the genomic landscape at relapse and help to define key pathways for therapeutic targeting.

show abstract

“…Aberrant expression of WT1 therefore contributes to the development of tumors arising in organs that ordinarily express WT1 under tight developmental control. Although the prognostic significance of WT1 expression in AML remains controversial [ 5 – 7 ], its importance as a tumor antigen and marker of minimal residual disease is growing [ 8 – 11 ]. In fact, a pilot project of the US National Cancer Institute to prioritize potential cancer vaccine antigens based on therapeutic function, immunogenicity, role in oncogenicity, specificity, expression level, number of epitopes and cellular localization listed WT1 as the top priority [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-Sensitive Epigenetic Regulation of an Antisense-Oriented lncRNA Controls WT1 Expression in Myeloid Leukemia Cells

McCarty

Loeb

2015

PLoS ONE

View full text Add to dashboard Cite

WT1 is a transcription factor expressed in hematopoietic stem cells and in most cases of myeloid leukemia. We investigated the roles of hypoxia and epigenetics in the regulation of WT1 expression in myeloid leukemia cells. WT1 expression correlates with hypomethylation of the CpG island in Intron 1, and pharmacologic demethylation of this CpG island induces WT1 mRNA expression. Hypoxia causes decreases in DNMT expression and activity and increased expression and activity of TET2 and TET3, resulting in demethylation of this CpG island and expression of WT1 mRNA. Demethylation of the CpG island, either from pharmacologic treatment or induction of hypoxia, results in transcription of an antisense-oriented lncRNA, and inhibiting lncRNA expression with shRNA blocks WT1 mRNA expression. These results reveal a novel model of hypoxia-mediated epigenetic gene regulation. In addition, this is the first report that TET2 and TET3, increasingly recognized as important epigenetic regulators of gene expression in stem cells and in cancer cells, can be regulated by hypoxia, providing a solid mechanistic link between hypoxia and epigenetic regulation of gene expression with important implications for the role of hypoxia in stem cell function.

show abstract

The prognostic effect of high diagnostic WT1 gene expression in pediatric AML depends on WT1 SNP rs16754 status: Report from the Children's Oncology Group

Cited by 18 publications

References 29 publications

Association of Wilms' tumor 1 gene single-nucleotide polymorphism rs16754 with colorectal cancer

Association of Wilms' tumor 1 gene single-nucleotide polymorphism rs16754 with colorectal cancer

Genomic Profiling of Pediatric Acute Myeloid Leukemia Reveals a Changing Mutational Landscape from Disease Diagnosis to Relapse

Hypoxia-Sensitive Epigenetic Regulation of an Antisense-Oriented lncRNA Controls WT1 Expression in Myeloid Leukemia Cells

Contact Info

Product

Resources

About