Gene Summary

Gene:WT1; WT1 transcription factor
Aliases: GUD, AWT1, WAGR, WT33, NPHS4, WIT-2
Summary:This gene encodes a transcription factor that contains four zinc-finger motifs at the C-terminus and a proline/glutamine-rich DNA-binding domain at the N-terminus. It has an essential role in the normal development of the urogenital system, and it is mutated in a small subset of patients with Wilms tumor. This gene exhibits complex tissue-specific and polymorphic imprinting pattern, with biallelic, and monoallelic expression from the maternal and paternal alleles in different tissues. Multiple transcript variants have been described. In several variants, there is evidence for the use of a non-AUG (CUG) translation initiation codon upstream of, and in-frame with the first AUG. Authors of PMID:7926762 also provide evidence that WT1 mRNA undergoes RNA editing in human and rat, and that this process is tissue-restricted and developmentally regulated. [provided by RefSeq, Mar 2015]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:Wilms tumor protein
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

The Wilms' tumour suppressor gene (WT1) gene was first cloned in 1989. The protein it produces is thought to have an important role in normal kidney and gonad development. Mutations in this gene are found in children with familial (inherited) Wilms' tumour and in children with WAGR genitourinary malformations. However, only about 10% of sporadic (non-familial) Wilms' tumours contain a WT1 mutation.

WT1 is overexpressed in a wide range of hematological and solid malignancies, including acute leukaemias where WT1 expression has prosgnostic significance.

Therapeutic use: WT1 is proving to be a promising tumor antigen for the development of a new class of universal cancer vaccines. There are a number of cancer vaccine trials using WT1-targeted immunotherapy in a range of cancers.

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (14)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Wilms TumourWT1 mutation in Wilms Tumour
Mutations of the WT1 gene are found in children with familial (inherited) Wilms' tumour and in children with WAGR genitourinary malformations. However, only about 10% of sporadic (non-familial) Wilms' tumours contain a WT1 mutation.
View Publications560
Acute Myeloid Leukaemia (AML)WT1 and Acute Myeloid Leukaemia
WT1 is aberrantly over-expressed in AML.
View Publications297
-WT1 use in Cancer Immunotherapy Therapy
In a National Cancer Institute prioritization project, WT1 was ranked first in a list of 75 cancer antigens (Cheever et al, 2009) promoting clinical trials of WT1-targeted therapies. There are a number of cancer vaccine trials using WT1-targeted immunotherapy in a range of cancers.Several features of WT1 make it a promising target for immunotherapy (Van Driessche et al, 2012). It is highly expressed in several types of hematological malignancies and solid tumors. Studies using WT1 antisense oligonucleotides have indicated growth inhibition in leukemic and solid tumour cells using treatment with WT1 antisense oligonucleotides. Moreover, WT1 has been shown to have a negative influence on differentiation, but promotes proliferation of progenitor cells. The WT1 protein exhibits high T-cell antigenicity, and loss of WT1 expression can lead to cessation of proliferation or death of cancer cells.
View Publications155
Childhood LeukaemiaWT1 expression in Childhood Leukemia View Publications104
MesotheliomaWT1 expression in MesotheliomaPrognostic View Publications110
Myelodysplastic SyndromesWT1 expression in Myelodysplastic Syndromes View Publications100
Denys-Drash SyndromeWT1 abnormalities in Denys-Drash Syndrome
Denys-Drash Syndrome is a rare condition characterised by renal failure, pseudohermaphroditism, and Wilms' tumor. It is associated with abnormalities of the WT1 gene.
View Publications87
-WT1 and Residual Disease View Publications88
Ovarian CancerWT1 expression in Ovarian Cancer View Publications50
WAGR SyndromeWT1 deletions in WAGR Syndrome
Wilms tumor, aniridia, genitourinary anomalies and mental retardation syndrome (WAGR) is a contiguous gene syndrome caused by deletions at chromosome 11p13 in a region containing the WT1 and PAX6 genes.
View Publications34
Lung Cancer, Non-Small CellWT1 expression in Non-Small Cell Lung CancerPrognostic Epigenetics
A number of studies have shown that WT1 expression is relevant in NSCLC. For exampple Nikolaidis et al (2012) identified hypermethylation at p16, TERT, WT1, and RASSF1 as having diagnostic significance in a case-control study of NSCLC. Hayashi et al. (2012) found that low WT1 expression predicted poor prognosis in patients with NSCLC.
View Publications33
Desmoplastic Small Round Cell Tumourt(11;22)(p13;q12): EWSR1-WT1 in Desmoplastic Small Round Cell Tumour
DSRCT is a rare and an aggressive malignancy characterised by a translocation of the EWSR1 and WT1 genes, resulting in a EWSR1-WT1 fusion protein.
View Publications28
-WT1 Polymorphism rs16754 in AML
Ho wr al (2014) reported a relationship between prognosis in childhood AML, WT1 expression and WT1 SNP rs16754. In SNP- patients, high WT1 expression predicted decreased survival in univariate, but not multivariate, analysis, due to a preponderance of high-risk cyto/molecular abnormalities in the highest expression group.
View Publications24

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: WT1 (cancer-related)

Liu Z, He F, OuYang S, et al.
miR-140-5p could suppress tumor proliferation and progression by targeting TGFBRI/SMAD2/3 and IGF-1R/AKT signaling pathways in Wilms' tumor.
BMC Cancer. 2019; 19(1):405 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Wilms' tumor is also called nephroblastoma and is the most common pediatric renal cancer. Several genetic and epigenetic factors have been found to account for the development of Wilms' tumor. MiRNAs play important roles in this tumorigenic process. In the present study, we aimed to investigate the role of miR-140-5p in nephroblastoma by identifying its targets, as well as its underlying molecular mechanism of action.
METHODS: The miRNA expression profile of nephroblastoma samples was investigated and the targets of miR-140-5p were predicted and validated using the miRNA luciferase reporter method. Moreover, the roles of miR-140-5p in regulating nephroblastoma cell proliferation, migration and cell cycle were analyzed by the CCK8, migration and flow cytometry assays, respectively. The downstream protein of the direct target of miR-140-5p was also identified.
RESULTS: miR-140-5p was downregulated in Wilms' tumor tissues, whereas in the nephroblastoma cell lines G401 and WT-CLS1 that exhibited high levels of miRNA-140-5p, inhibition of cellular proliferation and metastasis were noted as well as cell cycle arrest at the G1/S phase. TGFBRI and IGF1R were identified as direct target genes for miRNA-140-5p. In addition, SMAD2/3 and p-AKT were regulated by TGFBRI and IGF1R separately and participated in the miRNA-140-5p regulatory network. Ectopic expression of TGFBR1 and IGF-1R could abrogate the inhibitory effect of miR-140-5p.
CONCLUSION: We demonstrated that miRNA-140-5p participates in the progression of Wilms' tumor by targeting the TGFBRI/SMAD2/3 and the IGF-1R/AKT signaling pathways.

Singh V, Singh AP, Sharma I, et al.
Epigenetic deregulations of Wnt/β-catenin and transforming growth factor beta-Smad pathways in esophageal cancer: Outcome of DNA methylation.
J Cancer Res Ther. 2019 Jan-Mar; 15(1):192-203 [PubMed] Related Publications
Background: Promoter methylation of tumor suppressor genes (TSGs) is a well-reported portent in carcinogenesis; hence, it is worthy to investigate this in high-risk Northeast population of India. The study was designed to investigate methylation status of 94 TSGs in esophageal squamous cell carcinoma (ESCC). Further, the effect of OPCML promoter methylation on gene expression was analyzed by immunohistochemistry. Moreover, in silico protein-protein interactions were examined among 8 TSGs identified in the present study and 23 epigenetically regulated genes reported previously by our group in ESCC.
Materials and Methods: Methylation profiling was carried out by polymerase chain reaction array and OPCML protein expression was examined by tissue microarray-based immunohistochemistry.
Results: OPCML, NEUROG1, TERT, and WT1 genes were found hypermethylated and SCGB3A1, CDH1, THBS1, and VEGFA were hypomethylated in Grade 2 tumor. No significant change in OPCML expression was observed among control, Grade 1, and Grade 2 tumor. Conclusively, hypermethylation of the studied OPCML promoter in Grade 2 tumor produced no effect on expression. Unexpectedly, OPCML expression was downregulated in Grade 3 tumor in comparison to other groups signifying that downregulation of OPCML expression may lead to higher grade of tumor formation at the time of diagnosis of ESCC in patients. Significant interactions at protein level were found as VEGFA:PTK2, CTNNB1:CDH1, CTNNB1:VEGFA, CTNNB1:NEUROG1, CTNND2:CDH1, and CTNNB1:TERT. These interactions are pertinent to Wnt/β-catenin and TGF-β-Smad pathways.
Conclusions: Deranged OPCML expression may lead to high-grade ESCC as well as epigenetically regulated genes, that is, CDH1, CTNNB1, CTNND2, THBS1, PTK2, WT1, OPCML, TGFB1, and SMAD4 may alter the Wnt/β-catenin and TGF-β-Smad pathways in ESCC. Further study of these genes could be useful to understand the molecular pathology of ESCC with respect to epithelial-mesenchymal transition (EMT) mediated by Wnt/β-catenin and TGF-β signaling pathways.

Sapio MR, Iadarola MJ, LaPaglia DM, et al.
Haploinsufficiency of the brain-derived neurotrophic factor gene is associated with reduced pain sensitivity.
Pain. 2019; 160(5):1070-1081 [PubMed] Free Access to Full Article Related Publications
Rare pain-insensitive individuals offer unique insights into how pain circuits function and have led to the development of new strategies for pain control. We investigated pain sensitivity in humans with WAGR (Wilms tumor, aniridia, genitourinary anomaly, and range of intellectual disabilities) syndrome, who have variably sized heterozygous deletion of the 11p13 region. The deletion region can be inclusive or exclusive of the brain-derived neurotrophic factor (BDNF) gene, a crucial trophic factor for nociceptive afferents. Nociceptive responses assessed by quantitative sensory testing demonstrated reduced pain sensitivity only in the WAGR subjects whose deletion boundaries included the BDNF gene. Corresponding behavioral assessments were made in heterozygous Bdnf knockout rats to examine the specific role of Bdnf. These analogous experiments revealed impairment of Aδ- and C-fiber-mediated heat nociception, determined by acute nociceptive thermal stimuli, and in aversive behaviors evoked when the rats were placed on a hot plate. Similar results were obtained for C-fiber-mediated cold responses and cold avoidance on a cold-plate device. Together, these results suggested a blunted responsiveness to aversive stimuli. Our parallel observations in humans and rats show that hemizygous deletion of the BDNF gene reduces pain sensitivity and establishes BDNF as a determinant of nociceptive sensitivity.

Zidanloo SG, Colagar AH, Ayatollahi H, Bagheryan Z
G-quadruplex forming region within WT1 promoter is selectively targeted by daunorubicin and mitoxantrone: A possible mechanism for anti-leukemic effect of drugs.
J Biosci. 2019; 44(1) [PubMed] Related Publications
Wilms tumor 1

Ni D, Liu J, Hu Y, et al.
A1CF-Axin2 signal axis regulates apoptosis and migration in Wilms tumor-derived cells through Wnt/β-catenin pathway.
In Vitro Cell Dev Biol Anim. 2019; 55(4):252-259 [PubMed] Related Publications
A1CF, a complementary factor of APOBEC-1, is involved in many cellular processes for its mRNA editing role, such as cell proliferation, apoptosis, and migration. Here, we explored the regulatory function of A1CF in Wilms tumor-derived cells. Quantitative real-time PCR was performed to detect the mRNA level of A1CF, Axin2, β-Catenin, CCND1 or NKD1 in A1CF-depleted or A1CF-overexpression G401 cells. Western bolt was used to analyze the expression of A1CF, Axin2, and β-catenin protein. The cell apoptosis and migration ability were determined using flow cytometry assay or wound healing, respectively. Our study demonstrated that overexpression of A1CF, Axin2 was upregulated and knockdown of A1CF decreased Axin2 expression at mRNA and protein levels in G401 cells. Besides, knockdown of A1CF further upregulated β-catenin, the classical regulator of Wnt signal pathway, and increased CCND1 and NKD1, the target genes of Wnt/β-catenin. Furthermore, overexpression of Axin2 partly rescued the expression of β-catenin in A1CF-deficiency stable G401 cells. In Wnt agonist BML-284 treated G401 cells, A1CF was increased like other classical regulator of Wnt signal pathway, such as Axin2 and β-catenin. Meanwhile, knockdown of Axin2 rescued β-catenin expression which was decreased in A1CF overexpression condition with BML-284. Further, overexpression of A1CF reduced cell apoptosis but promoted cell migration, and overexpression of Axin2 got similar results. In A1CF-decreased stable G401 cells, overexpression of Axin2 partly rescued the cell apoptosis and migration. We find that A1CF is a positive regulator of Axin2, a Wnt/β-catenin pathway inhibitor, and A1CF-Axin2 signal axis regulates Wilms tumor-derived cells' apoptosis and migration through Axin2.

Wang X, Song P, Huang C, et al.
Weighted gene co‑expression network analysis for identifying hub genes in association with prognosis in Wilms tumor.
Mol Med Rep. 2019; 19(3):2041-2050 [PubMed] Free Access to Full Article Related Publications
Wilms tumor (WT) is the most common type of renal malignancy in children. Survival rates are low and high‑risk WT generally still carries a poor prognosis. To better elucidate the pathogenesis and tumorigenic pathways of high‑risk WT, the present study presents an integrated analysis of RNA expression profiles of high‑risk WT to identify predictive molecular biomarkers, for the improvement of therapeutic decision‑making. mRNA sequence data from high‑risk WT and adjacent normal samples were downloaded from The Cancer Genome Atlas to screen for differentially expressed genes (DEGs) using R software. From 132 Wilms tumor samples and six normal samples, 2,089 downregulated and 941 upregulated DEGs were identified. In order to identify hub DEGs that regulate target genes, weighted gene co‑expression network analysis (WGCNA) was used to identify 11 free‑scale gene co‑expressed clusters. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were annotated using KEGG Orthology Based Annotation System annotation of different module genes. The Search Tool for the Retrieval of Interacting Genes was used to construct a protein‑protein interaction network for the identified DEGs, and the hub genes of WGCNA modules were identified using the Cytohubb plugin with Cytoscape software. Survival analysis was subsequently performed to highlight hub genes with a clinical signature. The present results suggest that epidermal growth factor, cyclin dependent kinase 1, endothelin receptor type A, nerve growth factor receptor, opa‑interacting protein 5, NDC80 kinetochore complex component and cell division cycle associated 8 are essential to high‑risk WT pathogenesis, and they are closely associated with clinical prognosis.

Hatano Y, Tamada M, Asano N, et al.
High-grade serous ovarian carcinoma with mucinous differentiation: report of a rare and unique case suggesting transition from the "SET" feature of high-grade serous carcinoma to the "STEM" feature.
Diagn Pathol. 2019; 14(1):4 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: High-grade serous carcinoma, a representative high-grade ovarian carcinoma, is believed to be closely associated with a TP53 mutation. Recently, this category of ovarian carcinoma has gained increasing attention owing to the recognition of morphological varieties of TP53-mutated high-grade ovarian carcinoma. Herein, we report the case of a patient with high-grade serous carcinoma with mucinous differentiation.
CASE PRESENTATION: A 59-year-old postmenopausal woman was referred to the gynecologist because of abnormal vaginal bleeding. The radiological assessment revealed an intrapelvic multicystic mass, which was interpreted as an early right ovarian cancer and then removed by radical surgery. Histologically, the cancer cells were found in the bilateral ovaries and para-aortic lymph nodes. The cancer cells showed high-grade nuclear atypia and various morphologies, including the solid, pseudo-endometrioid, transitional cell-like (SET) pattern, and mucin-producing patterns. Benign and/or borderline mucin-producing epithelium, serous tubal intraepithelial carcinoma, and endometriosis-related lesions were not observed. In immunohistochemistry analyses, the cancer cells were diffuse positive for p53; block positive for p16; partial positive for WT1, ER, PgR, CDX2 and PAX8; and negative for p40, p63, GATA3, Napsin A, and vimentin. The Ki-67 labeling index of the cancer cells was 60-80%. Direct sequencing revealed that the cancer cells contained a missense mutation (c.730G>A) in the TP53 gene.
CONCLUSION: Mucinous differentiation in high-grade serous carcinoma is a rare and unique ovarian tumor phenotype and it mimics the phenotypes of mucinous or seromucinous carcinoma. To avoid the misdiagnosis, extensive histological and immunohistochemical analyses should be performed when pathologists encounter high-grade mucin-producing ovarian carcinoma. The present case shows that the unusual histological characteristic of high-grade serous carcinoma, the "SET" feature, could be extended to the solid, transitional, endometrioid and mucinous-like (STEM) feature.

Cottin L, Riou J, Boyer F, et al.
WT1 gene is overexpressed in myeloproliferative neoplasms, especially in myelofibrosis.
Blood Cells Mol Dis. 2019; 75:35-40 [PubMed] Related Publications
Classical Philadelphia-negative myeloproliferative neoplasms include Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). They are characterized by the presence of driver mutations of JAK2, CALR or MPL genes. Overexpression of WT1 is used as a marker of minimal residual disease in acute myeloid leukemia, especially after allogeneic stem cell transplantation (SCT). We investigated WT1 expression at diagnosis in 152 MPN patients and showed that the WT1 transcript was overexpressed in PMFs and PVs compared to controls. In particular, WT1 transcript levels were higher in PMF than in ET and PV. WT1 transcript levels were significantly increased during myelofibrotic transformation of ET or PV. Using multivariate linear regression, high WT1 transcript levels in PMF were associated with age over 65, splenomegaly and thrombocytopenia. The ROC curve analysis showed that a level of WT1 transcript >10 WT1 copies/10

Potter N, Miraki-Moud F, Ermini L, et al.
Single cell analysis of clonal architecture in acute myeloid leukaemia.
Leukemia. 2019; 33(5):1113-1123 [PubMed] Free Access to Full Article Related Publications
We used single cell Q-PCR on a micro-fluidic platform (Fluidigm) to analyse clonal, genetic architecture and phylogeny in acute myeloid leukaemia (AML) using selected mutations. Ten cases of NPM1c mutant AML were screened for 111 mutations that are recurrent in AML and cancer. Clonal architectures were relatively simple with one to six sub-clones and were branching in some, but not all, patients. NPM1 mutations were secondary or sub-clonal to other driver mutations (DNM3TA, TET2, WT1 and IDH2) in all cases. In three of the ten cases, single cell analysis of enriched CD34

Armstrong AE, Gadd S, Huff V, et al.
A unique subset of low-risk Wilms tumors is characterized by loss of function of TRIM28 (KAP1), a gene critical in early renal development: A Children's Oncology Group study.
PLoS One. 2018; 13(12):e0208936 [PubMed] Free Access to Full Article Related Publications
This study explores the genomic alterations that contribute to the formation of a unique subset of low-risk, epithelial differentiated, favorable histology Wilms tumors (WT), tumors that have been characterized by their expression of post-induction renal developmental genes (Subset 1 WT). We demonstrate copy neutral loss of heterozygosity involving 19q13.32-q13.43, unaccompanied by evidence for imprinting by DNA methylation. We further identified loss-of-function somatic mutations in TRIM28 (also known as KAP1), located at 19q13, in 8/9 Subset 1 tumors analyzed. An additional germline TRIM28 mutation was identified in one patient. Retrospective evaluation of previously analyzed WT outside of Subset 1 identified an additional tumor with anaplasia and both TRIM28 and TP53 mutations. A major function of TRIM28 is the repression of endogenous retroviruses early in development. We depleted TRIM28 in HEK293 cells, which resulted in increased expression of endogenous retroviruses, a finding also demonstrated in TRIM28-mutant WT. TRIM28 has been shown by others to be active during early renal development, and to interact with WTX, another gene recurrently mutated in WT. Our findings suggest that inactivation of TRIM28 early in renal development contributes to the formation of this unique subset of FHWTs, although the precise manner in which TRIM28 impacts both normal renal development and oncogenesis remains elusive.

Su H, Wang X, Song J, et al.
MicroRNA-539 inhibits the progression of Wilms' Tumor through downregulation of JAG1 and Notch1/3.
Cancer Biomark. 2019; 24(1):125-133 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Previous studies demonstrated that miR-539 play an important role in the carcinogenesis of some cancers. The aim of the present study was to determine the role of miR-539 in the pathogenesis of Wilms' Tumor (WT).
METHODS: The expression level of miR-539 was measured by qRT-PCR in 42 WT tissues and SK-NEP-1 cell line. Protein expression of genes (E-cadherin, N-cadherin, Vimentin, Notch 1, Notch 3 and JAG1) was assessed by Western blot. The function of miR-539 was investigated in SK-NEP-1 cells by MTT and Transwell assays. The relationship between miR-539 and JAG1 was verified by a dual luciferase assay in SK-NEP-1 cells.
RESULTS: The expression level of miR-539 was significantly decreased in WT tissues. Downregulation of miR-539 was closely related to NWTS-5 stage, lymph node metastasis and histological type of WT patients. Furthermore, low miR-539 expression was associated with a shorter overall survival rate in WT patients. In vitro, overexpression of miR-539 suppressed proliferation, migration and invasion of SK-NEP-1 cells. In addition, JAG1 was a direct target of miR-539. MiR-539 inhibited the development of WT by inhibiting JAG1-Notch1/3 expressing and blocking EMT.
CONCLUSION: MiR-539 inhibited the progression of WT through downregulation of JAG1 and Notch1/3.

Haruta M, Arai Y, Okita H, et al.
Combined Genetic and Chromosomal Characterization of Wilms Tumors Identifies Chromosome 12 Gain as a Potential New Marker Predicting a Favorable Outcome.
Neoplasia. 2019; 21(1):117-131 [PubMed] Free Access to Full Article Related Publications
To identify prognostic factors, array CGH (aCGH) patterns and mutations in WT1 and 9 other genes were analyzed in 128 unilateral Wilms tumors (WTs). Twenty patients had no aCGH aberrations, and 31 had WT1 alterations [silent and WT1 types: relapse-free survival (RFS), 95% and 83%, respectively]. Seventy-seven patients had aCGH changes without WT1 alterations (nonsilent/non-WT1 type) and were subtyped into those with or without +12, 11q-, 16q-, or HACE1 loss. RFS was better for those with than those without +12 (P = .010) and worse for those with than those without 11q-, 16q-, or HACE1 loss (P = .001, .025, or 1.2E-04, respectively). Silent and WT1 type and 8 subtype tumors were integrated and classified into 3 risk groups: low risk for the silent type and +12 subgroup; high risk for the no +12 plus 11q-, 16q-, or HACE1 loss subgroup; intermediate risk for the WT1 type and no +12 plus no 11q-, 16q-, or HACE1 loss subgroup. Among the 27 WTs examined, the expression of 146 genes on chromosome 12 was stronger in +12 tumors than in no +12 tumors, while that of 10 genes on 16q was weaker in 16q- tumors than in no 16q- tumors. Overexpression in 75 out of 146 upregulated genes and underexpression in 7 out of 10 downregulated genes correlated with better and worse overall survival, respectively, based on the public database. +12 was identified as a potential new marker predicting a favorable outcome, and chromosome abnormalities may be related to altered gene expression associated with these abnormalities.

Yang Z, Qi W, Sun L, et al.
DNA methylation analysis of selected genes for the detection of early-stage lung cancer using circulating cell-free DNA.
Adv Clin Exp Med. 2019; 28(3):361-366 [PubMed] Related Publications
BACKGROUND: Lung cancer is still the deadliest cancer in the world, but early diagnosis cannot be achieved because of the limitations of diagnostic methods. DNA methylation has been proven to be a potentially powerful tool for cancer detection and diagnosis over the past decade.
OBJECTIVES: We explored whether free DNA methylation in plasma can be a reliable biomarker for noninvasive lung cancer detection.
MATERIAL AND METHODS: We detected the methylation of 8 genes in plasma-free DNA of patients with pulmonary space-occupying lesions using real-time quantitative methylation-specific polymerase chain reaction (QMSP). Among the 50 selected patients, 39 were confirmed using pathological analysis as having early lung cancer and 11 had an inflammatory pseudotumor.
RESULTS: The QMSP detection showed that the methylation levels of 8 genes in the patients were significantly higher than in the non-lung cancer group. The methylation level of CALCA was the highest and the methylation level of HOXA9 was the lowest. Methylation of RASSF1A, CDKN2A and DLEC1 occured only in lung cancer patients, while methylation of CALCA, CDH13, PITX2, HOXA9, and WT1 occured not only in lung cancer patients, but also in non-lung cancers. The specificity reached 95~100%, whether for a single gene or overall, but the sensitivity was relatively low for each gene. The sensitivity can reach 72% if the methylation of any of the 8 genes is positive and the overall specificity was 91%. The positive and negative predictive values were 96% and 60%, respectively.
CONCLUSIONS: Quantitative detection of DNA methylation in plasma is a potential method for early diagnosis of lung cancer.

Devecchi A, De Cecco L, Dugo M, et al.
The genomics of desmoplastic small round cell tumor reveals the deregulation of genes related to DNA damage response, epithelial-mesenchymal transition, and immune response.
Cancer Commun (Lond). 2018; 38(1):70 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive, and poorly investigated simple sarcoma with a low frequency of genetic deregulation other than an Ewing sarcoma RNA binding protein 1 (EWSR1)-Wilm's tumor suppressor (WT1) translocation. We used whole-exome sequencing to interrogate six consecutive pre-treated DSRCTs whose gene expression was previously investigated.
METHODS: DNA libraries were prepared from formalin-fixed, paraffin-embedded archival tissue specimens following the Agilent SureSelectXT2 target enrichment protocol and sequenced on Illumina NextSeq 500. Raw sequence data were aligned to the reference genome with Burrows-Wheeler Aligner algorithm. Somatic mutations and copy number alterations (CNAs) were identified using MuTect2 and EXCAVATOR2, respectively. Biological functions associated with altered genes were investigated through Ingenuity Pathway Analysis (IPA) software.
RESULTS: A total of 137 unique somatic mutations were identified: 133 mutated genes were case-specific, and 2 were mutated in two cases but in different positions. Among the 135 mutated genes, 27% were related to two biological categories: DNA damage-response (DDR) network that was also identified through IPA and mesenchymal-epithelial reverse transition (MErT)/epithelial-mesenchymal transition (EMT) already demonstrated to be relevant in DSRCT. The mutated genes in the DDR network were involved in various steps of transcription and particularly affected pre-mRNA. Half of these genes encoded RNA-binding proteins or DNA/RNA-binding proteins, which were recently recognized as a new class of DDR players. CNAs in genes/gene families, involved in MErT/EMT and DDR, were recurrent across patients and mostly segregated in the MErT/EMT category. In addition, recurrent gains of regions in chromosome 1 involving many MErT/EMT gene families and loss of one arm or the entire chromosome 6 affecting relevant immune-regulatory genes were recorded.
CONCLUSIONS: The emerging picture is an extreme inter-tumor heterogeneity, characterized by the concurrent deregulation of the DDR and MErT/EMT dynamic and plastic programs that could favour genomic instability and explain the refractory DSRCT profile.

Krueger K, Catanese L, Sciesielski LK, et al.
Deletion of an intronic HIF-2α binding site suppresses hypoxia-induced WT1 expression.
Biochim Biophys Acta Gene Regul Mech. 2019; 1862(1):71-83 [PubMed] Related Publications
Hypoxia-inducible factors (HIFs) play a key role in the adaptation to low oxygen by interacting with hypoxia response elements (HREs) in the genome. Cellular levels of the HIF-2α transcription factor subunit influence the histopathology and clinical outcome of neuroblastoma, a malignant childhood tumor of the sympathetic ganglia. Expression of the Wilms tumor gene, WT1, marks a group of high-risk neuroblastoma. Here, we identify WT1 as a downstream target of HIF-2α in Kelly neuroblastoma cells. In chromatin immunoprecipitation assays, HIF-2α bound to a HRE in intron 3 of the WT1 gene, but not to another predicted HIF binding site (HBS) in the first intron. The identified element conferred oxygen sensitivity to otherwise hypoxia-resistant WT1 and SV40 promoter constructs. Deletion of the HBS in the intronic HRE by genome editing abolished WT1 expression in hypoxic neuroblastoma cells. Physical interaction between the HRE and the WT1 promoter in normoxic and hypoxic Kelly cells was shown by chromosome conformation capture assays. These findings demonstrate that binding of HIF-2α to an oxygen-sensitive enhancer in intron 3 stimulates transcription of the WT1 gene in neuroblastoma cells by hypoxia-independent chromatin looping. This novel regulatory mechanism may have implications for the biology and prognosis of neuroblastoma.

Bejar R
What biologic factors predict for transformation to AML?
Best Pract Res Clin Haematol. 2018; 31(4):341-345 [PubMed] Related Publications
Transformation of myelodysplastic syndromes (MDS) into secondary acute myeloid leukemia (sAML) is defined by an arbitrary boundary of ≥20% bone marrow blasts but does not necessarily reflect a defined biological transition. The more obvious distinction lies between MDS patients that have an isolated bone marrow failure phenotype and those with excess blasts. Subtyping of MDS might be more accurately stratified into clonal cytopenias and oligoblastic leukemias, using the degree of dysplasia and blast percentage as risk features, respectively, rather than as diagnostic criteria. Transformation from MDS to sAML often involves clonal evolution or expansion of existing subclones that can be assessed by changes in variant allele frequencies of the somatic mutations that define them. There are a number of predictors for transformation that have been identified: these include mutations of genes in growth signaling pathways (NRAS, KRAS, PTPN11, FLT3), mutations in genes more commonly observed in AML (NPM1, WT1, IDH2), certain cytogenetic abnormalities (monosomy 7, complex karyotype, loss of 17p). Gene expression profiles that divide MDS into two major categories identify a progenitor gene signature subtype associated with a high risk of AML transformation. Assessing for these genetic abnormalities may better identify MDS patients at greatest risk of transformation.

Yang K, Lu XF, Luo PC, Zhang J
Identification of Six Potentially Long Noncoding RNAs as Biomarkers Involved Competitive Endogenous RNA in Clear Cell Renal Cell Carcinoma.
Biomed Res Int. 2018; 2018:9303486 [PubMed] Free Access to Full Article Related Publications

Anderson WJ, Hornick JL
Immunohistochemical correlates of recurrent genetic alterations in sarcomas.
Genes Chromosomes Cancer. 2019; 58(2):111-123 [PubMed] Related Publications
Accurate diagnosis of sarcomas relies on the integration of clinical, histopathological and molecular features. Our understanding of the latter has increased dramatically in recent years with the application of high-throughput sequencing. Concomitantly, the role of immunohistochemistry has expanded as genomic alterations have been exploited by the development of diagnostic markers that serve as surrogates for their detection. Herein, we review selected immunohistochemical markers that can infer the presence of diverse molecular events. These include gene fusions in vascular neoplasms (FOSB, CAMTA1 and TFE3), round cell sarcomas (BCOR, DUX4 and WT1), and fibroblastic/myofibroblastic tumors (STAT6, ALK and Pan-TRK); amplifications in well-differentiated and dedifferentiated liposarcomas (MDM2 and CDK4); and deletions in several aggressive neoplasms (SMARCB1 and SMARCA4). Protein correlates of single nucleotide variants (beta-catenin in desmoid fibromatosis) and epigenetic alterations (histone H3K27me3 in malignant peripheral nerve sheath tumor) and markers discovered through gene expression profiling (NKX2.2 and MUC4) are also discussed.

Kruber P, Angay O, Winkler A, et al.
Loss or oncogenic mutation of DROSHA impairs kidney development and function, but is not sufficient for Wilms tumor formation.
Int J Cancer. 2019; 144(6):1391-1400 [PubMed] Related Publications
Wilms tumor (WT) is the most common kidney cancer in childhood. Mutations in the microprocessor genes DROSHA and DGCR8 have been identified as putative oncogenic drivers, indicating a critical role of aberrant miRNA processing in WT formation. To characterize the in vivo role of DROSHA mutations during kidney development and their oncogenic potential, we analyzed mouse lines with either a targeted deletion of Drosha or an inducible expression of human DROSHA carrying a tumor-specific E1147K mutation that acts in a dominant negative manner. Both types of mutation induce striking changes in miRNA patterns. Six2-cre mediated deletion of Drosha in nephron progenitors led to perinatal lethality with apoptotic loss of progenitor cells and early termination of nephrogenesis. Mosaic deletions via Wt1-cre

Gu X, Coates PJ, Boldrup L, et al.
Copy number variation: A prognostic marker for young patients with squamous cell carcinoma of the oral tongue.
J Oral Pathol Med. 2019; 48(1):24-30 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The incidence of squamous cell carcinoma of the oral tongue (SCCOT) is increasing in people under age 40. There is an urgent need to identify prognostic markers that help identify young SCCOT patients with poor prognosis in order to select these for individualized treatment.
MATERIALS AND METHODS: To identify genetic markers that can serve as prognostic markers for young SCCOT patients, we first investigated four young (≤40 years) and five elderly patients (≥50 years) using global RNA sequencing and whole-exome sequencing. Next, we combined our data with data on SCCOT from the cancer genome atlas (TCGA), giving a total of 16 young and 104 elderly, to explore the correlations between genomic variations and clinical outcomes.
RESULTS: In agreement with previous studies, we found that SCCOT from young and elderly patients was transcriptomically and also genomically similar with no significant differences regarding cancer driver genes, germline predisposition genes, or the burden of somatic single nucleotide variations (SNVs). However, a disparate copy number variation (CNV) was found in young patients with distinct clinical outcome. Combined with data from TCGA, we found that the overall survival was significantly better in young patients with low-CNV (n = 5) compared to high-CNV (n = 11) burden (P = 0.044).
CONCLUSIONS: Copy number variation burden is a useful single prognostic marker for SCCOT from young, but not elderly, patients. CNV burden thus holds promise to form an important contribution when selecting suitable treatment protocols for young patients with SCCOT.

Tang S, Dodd LG
CIC-DUX4 sarcoma diagnosed by fine-needle aspiration cytology: A case report.
Diagn Cytopathol. 2018; 46(11):958-963 [PubMed] Related Publications
The CIC-DUX4 sarcoma is a small round blue cell sarcoma which presents like extraskeletal Ewing sarcoma, but is negative for the EWSR1 gene translocation. The recognition of CIC-DUX4 sarcomas as an aggressive sarcoma may be challenging in fine needle aspirates or small needle core biopsies. We present a case of a 13-year-old female with a fine needle aspiration (FNA) and core needle biopsy (CNB) of a thigh mass showing CIC-DUX4 sarcoma. Cytologic findings include tumor cells with high nuclear to cytoplasmic (N:C) ratio, eccentric nuclei and small nucleoli. The tumor cells were arranged in sheets and singly dispersed with background necrosis. Mitotic figures and apoptosis were present. These findings are similar to cases previously reported. Other reported findings of spindled nuclei, clear cell change and lobular growth pattern were not seen in our case. Immunohistochemical stains showed tumor cells positive for CD99, WT1, vimentin and negative for pancytokeratin, desmin and myogenin, which is the pattern similar to cases previously reported. However, our case was also positive for BCL-2. Fluorescence in situ hybridization (FISH) was negative for EWSR1 and SS18 (SYT) rearrangements and positive for CIC gene rearrangement. On balance, if the following features are seen: (1) a small round blue cell tumor with histomorphology more atypical than that of Ewing sarcoma, (2) cytoplasmic CD99 staining, nuclear WT1 positivity, negative keratin, desmin and myogenin; and (3) EWSR1 rearrangement negative by FISH, then molecular testing for CIC-DUX4 sarcoma should be considered.

Välimäki N, Kuisma H, Pasanen A, et al.
Genetic predisposition to uterine leiomyoma is determined by loci for genitourinary development and genome stability.
Elife. 2018; 7 [PubMed] Free Access to Full Article Related Publications
Uterine leiomyomas (ULs) are benign tumors that are a major burden to women's health. A genome-wide association study on 15,453 UL cases and 392,628 controls was performed, followed by replication of the genomic risk in six cohorts. Effects of the risk alleles were evaluated in view of molecular and clinical characteristics. 22 loci displayed a genome-wide significant association. The likely predisposition genes could be grouped to two biological processes. Genes involved in genome stability were represented by

Phelps HM, Al-Jadiry MF, Corbitt NM, et al.
Molecular and epidemiologic characterization of Wilms tumor from Baghdad, Iraq.
World J Pediatr. 2018; 14(6):585-593 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: Wilms tumor (WT) is the most common childhood kidney cancer worldwide, yet its incidence and clinical behavior vary according to race and access to adequate healthcare resources. To guide and streamline therapy in the war-torn and resource-constrained city of Baghdad, Iraq, we conducted a first-ever molecular analysis of 20 WT specimens to characterize the biological features of this lethal disease within this challenged population.
METHODS: Next-generation sequencing of ten target genes associated with WT development and treatment resistance (WT1, CTNNB1, WTX, IGF2, CITED1, SIX2, p53, N-MYC, CRABP2, and TOP2A) was completed. Immunohistochemistry was performed for 6 marker proteins of WT (WT1, CTNNB1, NCAM, CITED1, SIX2, and p53). Patient outcomes were compiled.
RESULTS: Mutations were detected in previously described WT "hot spots" (e.g., WT1 and CTNNB1) as well as novel loci that may be unique to the Iraqi population. Immunohistochemistry showed expression domains most typical of blastemal-predominant WT. Remarkably, despite the challenges facing families and care providers, only one child, with combined WT1 and CTNNB1 mutations, was confirmed dead from disease. Median clinical follow-up was 40.5 months (range 6-78 months).
CONCLUSIONS: These data suggest that WT biology within a population of Iraqi children manifests features both similar to and unique from disease variants in other regions of the world. These observations will help to risk stratify WT patients living in this difficult environment to more or less intensive therapies and to focus treatment on cell-specific targets.

Ueno-Yokohata H, Okita H, Nakasato K, et al.
Preoperative diagnosis of clear cell sarcoma of the kidney by detection of BCOR internal tandem duplication in circulating tumor DNA.
Genes Chromosomes Cancer. 2018; 57(10):525-529 [PubMed] Related Publications
Clear cell sarcoma of the kidney (CCSK) is the second most common renal malignancy in children. The prognosis is poorer in CCSK than in Wilms' tumor, and multimodal treatment including surgery, intensive chemotherapy, and radiation is required to improve the outcome for children with CCSK. Histological evaluation is required for the diagnosis. However, biopsies of tumors to obtain diagnostic specimens are not routinely performed because of the risk of spreading tumor cells during the procedure. Recently, internal tandem duplication (ITD) of BCOR has been recognized as a genetic hallmark of CCSK. We herein established a novel BCOR-ITD-specific polymerase chain reaction method with well-designed primers, and then performed a liquid biopsy for cell-free DNA (cfDNA) obtained from plasma of three children with nonmetastatic renal tumors (stage II) and from one control. BCOR-ITD was positively detected in the cfDNA of two cases, both of which were later diagnosed as CCSK based on histological feature of the resected tumor specimen, while it was not detected for a normal control and a patient diagnosed with Wilms' tumor. Our study is the first one of preoperative circulating tumor DNA assay in pediatric renal tumors. The liquid biopsy method enables less invasive, preoperative diagnosis of CCSK with no risk of tumor spillage, which can avoid iatrogenic upstaging.

Zhang X, Li H, Yu X, et al.
Analysis of Circulating Tumor Cells in Ovarian Cancer and Their Clinical Value as a Biomarker.
Cell Physiol Biochem. 2018; 48(5):1983-1994 [PubMed] Related Publications
BACKGROUND/AIMS: Monitoring the appearance and progression of tumors are important for improving the survival rate of patients with ovarian cancer. This study aims to examine circulating tumor cells (CTCs) in epithelial ovarian cancer (EOC) patients to evaluate their clinical significance in comparison to the existing biomarker CA125.
METHODS: Immuomagnetic bead screening, targeting epithelial antigens on ovarian cancer cells, combined with multiplex reverse transcriptase-polymerase chain reaction (Multiplex RT-PCR) was used to detect CTCs in 211 samples of peripheral blood (5 ml) from 109 EOC patients. CTCs and CA125 were measured in serial from 153 blood and 153 serum samples from 51 patients and correlations with treatment were analyzed. Immunohistochemistry was used to detect the expression of tumor-associated proteins in tumor tissues and compared with gene expression in CTCs from patients.
RESULTS: CTCs were detected in 90% (98/109) of newly diagnosed patients. In newly diagnosed patients, the number of CTCs was correlated with stage (p=0.034). Patients with stage IA-IB disease had a CTC positive rate of 93% (13/14), much higher than the CA125 positive rate of only 64% (9/14) for the same patients. The numbers of CTCs changed with treatment, and the expression of EpCAM (p=0.003) and HER2 (p=0.035) in CTCs was correlated with resistance to chemotherapy. Expression of EpCAM in CTCs before treatment was also correlated with overall survival (OS) (p=0.041).
CONCLUSION: Detection of CTCs allows early diagnose and expression of EpCAM in CTC positive patients predicts prognosis and should be helpful for monitoring treatment.

Bharathavikru R, Hastie ND
Overgrowth syndromes and pediatric cancers: how many roads lead to
Genes Dev. 2018; 32(15-16):993-995 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Overgrowth syndromes such as Perlman syndrome and associated pediatric cancers, including Wilms tumor, arise through genetic and, in certain instances, also epigenetic changes. In the case of the Beckwith-Wiedemann overgrowth syndrome and in Wilms tumor, increased levels of

Carter JH, Deddens JA, Mueller G, et al.
Transcription factors WT1 and p53 combined: a prognostic biomarker in ovarian cancer.
Br J Cancer. 2018; 119(4):462-470 [PubMed] Related Publications
BACKGROUND: New approaches to ovarian cancer are needed to improve survival. Wilms' tumour 1 (WT1) is a tumour-associated antigen expressed in many ovarian cancers. P53 is also often altered. The clinical significance of the combined expression of these two transcription factors has not been studied.
METHODS: One hundred ninety-six ovarian tumours were classified histopathologically. Tumours were stained for WT1 and p53 immunohistochemically. Stains were analysed according to tumour type, grade and FIGO stage. Kaplan-Meier analyses on 96 invasive carcinomas determined whether categorical variables were related to survival.
RESULTS: WT1 and p53 were related to ovarian tumour type, grade, FIGO stage and patient survival. Uniform nuclear p53 expression was associated with invasion and WT1 expression was associated with advanced grade, FIGO stage and poor survival. When WT1 and p53 were both in the age-adjusted Cox model, WT1 was significant while p53 was not. When we combined tumours expressing WT1 and p53, then adjusted for age and tumour subtype, the hazard ratio compared to tumours without WT1 and with normal p53 was 2.70; when adjusted for age and FIGO stage, the hazard ratio was 2.40.
CONCLUSIONS: WT1, an antigen target, is a biomarker for poor prognosis, particularly when combined with altered p53.

Akahori Y, Wang L, Yoneyama M, et al.
Antitumor activity of CAR-T cells targeting the intracellular oncoprotein WT1 can be enhanced by vaccination.
Blood. 2018; 132(11):1134-1145 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
The recent success of chimeric antigen receptor (CAR)-T cell therapy for treatment of hematologic malignancies supports further development of treatments for both liquid and solid tumors. However, expansion of CAR-T cell therapy is limited by the availability of surface antigens specific for the tumor while sparing normal cells. There is a rich diversity of tumor antigens from intracellularly expressed proteins that current and conventional CAR-T cells are unable to target. Furthermore, adoptively transferred T cells often suffer from exhaustion and insufficient expansion, in part, because of the immunosuppressive mechanisms operating in tumor-bearing hosts. Therefore, it is necessary to develop means to further activate and expand those CAR-T cells in vivo. The Wilms tumor 1 (WT1) is an intracellular oncogenic transcription factor that is an attractive target for cancer immunotherapy because of its overexpression in a wide range of leukemias and solid tumors, and a low level of expression in normal adult tissues. In the present study, we developed CAR-T cells consisting of a single chain variable fragment (scFv) specific to the WT1

Trink A, Kanter I, Pode-Shakked N, et al.
Geometry of Gene Expression Space of Wilms' Tumors From Human Patients.
Neoplasia. 2018; 20(8):871-881 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Wilms' tumor is a pediatric malignancy that is thought to originate from faulty kidney development during the embryonic stage. However, there is a large variation between tumors from different patients in both histology and gene expression that is not well characterized. Here we use a meta-analysis of published microarray datasets to show that Favorable Histology Wilms' Tumors (FHWT's) fill a triangle-shaped continuum in gene expression space of which the vertices represent three idealized "archetypes". We show that these archetypes have predominantly renal blastemal, stromal, and epithelial characteristics and that they correlate well with the three major lineages of the developing embryonic kidney. Moreover, we show that advanced stage tumors shift towards the renal blastemal archetype. These results illustrate the potential of this methodology for characterizing the cellular composition of Wilms' tumors and for assessing disease progression.

Chen KS, Stroup EK, Budhipramono A, et al.
Mutations in microRNA processing genes in Wilms tumors derepress the
Genes Dev. 2018; 32(15-16):996-1007 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Many childhood Wilms tumors are driven by mutations in the microRNA biogenesis machinery, but the mechanism by which these mutations drive tumorigenesis is unknown. Here we show that the transcription factor

Further References

Van Driessche A, Berneman ZN, Van Tendeloo VF
Active specific immunotherapy targeting the Wilms' tumor protein 1 (WT1) for patients with hematological malignancies and solid tumors: lessons from early clinical trials.
Oncologist. 2012; 17(2):250-9 [PubMed] Free Access to Full Article Related Publications
There is a growing body of evidence that Wilms' tumor protein 1 (WT1) is a promising tumor antigen for the development of a novel class of universal cancer vaccines. Recently, in a National Cancer Institute prioritization project, WT1 was ranked first in a list of 75 cancer antigens. In this light, we exhaustively reviewed all published cancer vaccine trials reporting on WT1-targeted active specific immunotherapy in patients with hematological malignancies and solid tumors. In all clinical trials, vaccine-induced immunological responses could be detected. Importantly, objective clinical responses (including stable disease) were observed in 46% and 64% of evaluable vaccinated patients with solid tumors and hematological malignancies, respectively. Immunogenicity of WT1-based cancer vaccines was demonstrated by the detection of a specific immunological response in 35% and 68% of evaluable patients with solid tumors and hematological malignancies, respectively. In order to become part of the armamentarium of the modern oncologist, it will be important to design WT1-based immunotherapies applicable to a large patient population, to standardize vaccination protocols enabling systematic review, and to further optimize the immunostimulatory capacity of the vaccine components. Moreover, improved immunomonitoring tools that reveal clinically relevant T-cell responses will further shape the ideal WT1 immunotherapy strategy. In conclusion, the clinical results obtained so far in WT1-targeted cancer vaccine trials reveal an untapped potential for inducing cancer immunity with minimal side effects and hold promise for a new adjuvant treatment against residual disease and against cancer relapse.

Cheever MA, Allison JP, Ferris AS, et al.
The prioritization of cancer antigens: a national cancer institute pilot project for the acceleration of translational research.
Clin Cancer Res. 2009; 15(17):5323-37 [PubMed] Free Access to Full Article Related Publications
The purpose of the National Cancer Institute pilot project to prioritize cancer antigens was to develop a well-vetted, priority-ranked list of cancer vaccine target antigens based on predefined and preweighted objective criteria. An additional aim was for the National Cancer Institute to test a new approach for prioritizing translational research opportunities based on an analytic hierarchy process for dealing with complex decisions. Antigen prioritization involved developing a list of "ideal" cancer antigen criteria/characteristics, assigning relative weights to those criteria using pairwise comparisons, selecting 75 representative antigens for comparison and ranking, assembling information on the predefined criteria for the selected antigens, and ranking the antigens based on the predefined, preweighted criteria. Using the pairwise approach, the result of criteria weighting, in descending order, was as follows: (a) therapeutic function, (b) immunogenicity, (c) role of the antigen in oncogenicity, (d) specificity, (e) expression level and percent of antigen-positive cells, (f) stem cell expression, (g) number of patients with antigen-positive cancers, (h) number of antigenic epitopes, and (i) cellular location of antigen expression. None of the 75 antigens had all of the characteristics of the ideal cancer antigen. However, 46 were immunogenic in clinical trials and 20 of them had suggestive clinical efficacy in the "therapeutic function" category. These findings reflect the current status of the cancer vaccine field, highlight the possibility that additional organized efforts and funding would accelerate the development of therapeutically effective cancer vaccines, and accentuate the need for prioritization.

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