RECK Gene Polymorphism is Associated with Susceptibility and Prognosis of Wilms' Tumor in Chinese Children.

BACKGROUND: Wilms' tumor (WT) is the most common malignant renal tumor in children. Previous studies suggested the reversion-inducing, cysteine-rich protein with Kazal motifs (RECK) down-regulation might have a role in numerous human cancers. The current study was done to investigate the associations of RECK single-nucleotide polymorphisms (SNPs) with the WT susceptibility in Chinese children. MATERIAL AND METHODS: We analyzed 2 SNPs (rs10972727 and rs11788747) in a total of 97 WT children and 194 healthy matched controls (1:2 ratio) by real-time PCR and PCR-RFLP genotyping analysis. RESULTS: We found that the G allele of rs11788747 in the RECK gene was significantly associated with WT in Chinese children (OR=0.7, 95% CI: 0.45-0.99; P=0.042); as with another SNP rs10972727, however, no statistically significant difference was detected. Further analysis showed there was also a statistically significant difference in genotype frequencies between terminal tumor stage (P=0.026) and metastatic groups (P=0.002). CONCLUSIONS: The present data indicate that there is a significant association between mutant G of rs11788747 in RECK and WT risk. G carriers with advanced tumor stage or with metastasis might have an increased risk of WT.

Race disparities in peptide profiles of North American and Kenyan Wilms tumor specimens.

BACKGROUND: Wilms tumor (WT) is the most common childhood kidney cancer worldwide and arises in children of black African ancestry with greater frequency and severity than other race groups. A biologic basis for this pediatric cancer disparity has not been previously determined. We hypothesized that unique molecular fingerprints might underlie the variable incidence and distinct disease characteristics of WT observed between race groups. STUDY DESIGN: To evaluate molecular disparities between WTs of different race groups, the Children's Oncology Group provided 80 favorable histology specimens divided evenly between black and white patients and matched for disease characteristics. As a surrogate of black sub-Saharan African patients, we also analyzed 18 Kenyan WT specimens. Tissues were probed for peptide profiles using matrix-assisted laser desorption ionization time of flight imaging mass spectrometry. To control for histologic variability within and between specimens, cellular regions were analyzed separately as triphasic (containing blastema, epithelia, and stroma), blastema only, and stroma only. Data were queried using ClinProTools and statistically analyzed. RESULTS: Peptide profiles, detected in triphasic WT regions, recognized race with good accuracy, which increased for blastema- or stroma-only regions. Peptide profiles from North American WTs differed between black and white race groups but were far more similar in composition than Kenyan specimens. Individual peptides were identified that also associated with WT patient and disease characteristics (eg, treatment failure and stage). Statistically significant peptide fragments were used to sequence proteins, revealing specific cellular signaling pathways and candidate drug targets. CONCLUSIONS: Wilms tumor specimens arising among different race groups show unique molecular fingerprints that could explain disparate incidences and biologic behavior and that could reveal novel therapeutic targets.

The role of Hispanic ethnicity in pediatric Wilms' tumor survival.

Wilms' tumors (WT) constitute approximately 6-14% of all childhood cancers and about 95% of all pediatric renal malignancies. While prognostic factors for this malignancy are relatively well-defined, few studies have specifically examined the role of Hispanic ethnicity in pediatric WT survival. The purpose of this study was to compare WT survival among non-Hispanic white (NHW), non-Hispanic black (NHB), and Hispanic cases using data from the Surveillance, Epidemiology, and End Results (SEER) program. WT cases (ICD-O-3 histological code 8960) under age 20 were isolated from a recent subset of the SEER dataset (1990-2009). Demographics and tumor characteristics were compared by race/ethnicity, and 5- and 10-year survival probabilities were calculated. Multivariable Cox proportional hazards regression was used to assess the effects of race/ethnicity on WT survival, adjusting for relevant covariates. Hispanic ethnicity was significantly associated with WT-specific mortality hazard, controlling for age, sex, diagnosis/treatment era, laterality, SEER stage, cancer-directed surgery, and radiation therapy (HR: 1.52, 95% CI: 1.02-2.25). The results of this study suggest that Hispanic pediatric WT cases may have a higher risk of WT-related death, compared to NHW cases. Additional research on racial/ethnic disparities in WT survival is warranted.

Survivin gene promoter -31 G/C polymorphism is associated with Wilms tumor susceptibility in Serbian children.

Survivin, an apoptotic inhibitor, is overexpressed in various types of cancer. Mechanisms of survivin upregulation are still poorly understood, but single nucleotide polymorphisms in the survivin gene promoter have been shown to modulate survivin expression and consequently the risk for some types of cancer. The aim of the present study was to investigate whether survivin promoter -31 G/C and -241 C/T polymorphisms could represent susceptibility factors for Wilms tumor (WT) development in Serbian population. Genotype and allele frequencies for the 2 polymorphisms in survivin promoter have been analyzed by polymerase chain reaction/restriction fragment length polymorphism in 59 WT patients and 82 controls. The frequencies of alleles and genotypes were significantly different between patients and controls for the -31 G/C polymorphism. Individuals with CC and CG genotypes had significantly decreased risk of WT compared with GG individuals (odds ratio 0.26, 95% confidence interval, 0.07-0.96; odds ratio 0.30, 95% confidence interval, 0.15-0.60). There was also a statistically significant difference in genotype frequencies between intermediate and high-risk prognostic groups (P=0.015). The -241 C/T polymorphism did not show association with WT susceptibility. Our findings suggest that the G allele at -31 survivin gene promoter position is associated with a significantly higher cancer risk in Serbian children, with a gene dosage effect.

Different incidences of epigenetic but not genetic abnormalities between Wilms tumors in Japanese and Caucasian children.

Epidemiological studies show that the incidence of Wilms tumor (WT) in East-Asian children is half of that in Caucasian children. Abnormalities of WT1, CTNNB1, WTX, and IGF2 were reported to be involved in Wilms tumorigenesis in Caucasians, although none of the studies simultaneously evaluated the four genes. WTX forms the ß-catenin degradation complex; however, the relationship between WTX abnormality and CTNNB1 mutation was uncertain in WTs. We examined abnormalities of the four genes in 114 Japanese with WTs to clarify the relationship between genetic and epigenetic factors and the incidence of WTs. We found that abnormalities of WTX and CTNNB1 were mutually exclusive, and that although CTNNB1 mutation was frequent in WTs with WT1 abnormality, but rare in WTs without, the incidences of WTX abnormality were similar between WTs with or without WT1 abnormality. These findings were consistent with those reported in Caucasian populations, and indicate multiple roles of WTX abnormality. Abnormalities of WT1, WTX and CTNNB1, and loss of IGF2 imprinting (LOI) were detected in 31.6%, 22.8%, 26.3%, and 21.1% of the 114 WTs, respectively. When we selected 101 sporadic WTs, the incidences of WT1, CTNNB1, or WTX abnormality were generally comparable between the two populations, whereas the incidence of IGF2 LOI was lower in Japanese than that of IGF2 LOI reported in Caucasians (P = 0.04). This is the first comprehensive study of the four genes, and the results supported the hypothesis that the lower incidence of IGF2 LOI contributes to the lower incidence of WTs in Japanese children.

Race disparities in Wilms tumor incidence and biology.

BACKGROUND: Wilms tumor (WT) is thought to arise in children of Black African ancestry with greater frequency than in Whites. To clarify the biological basis for race disparities in WT, we first verified that Black children residing in Tennessee have an increased incidence of WT, and second, established molecular profiles in WT that are specific to race. MATERIALS AND METHODS: To assess race disparities in WT epidemiology, the Tennessee Cancer Registry (TCR) was queried for all in-state patients less than 20 y of age and registered between 1999 and 2008. To explore race disparities in WT biology, six Black and four White WT specimens acquired in Tennessee were analyzed using imaging mass spectrometry (IMS). RESULTS: TCR data show that Black children are over-represented among WT patients (29%) relative to all other childhood cancers (18.5%; P = 0.01). WT ranked the fifth most common cancer diagnosis among Blacks, but ninth among Whites. The diagnosis of WT occurred 79% more frequently among Blacks (n = 28) than Whites (n = 69; P = 0.01), and proportionally more Blacks tended to present with distant disease. Although overall survival from WT was not statistically different between Blacks (92.9%) and Whites (94.0%), Black males showed the lowest survival (85%; P = 0.21). IMS analysis identified peptide spectra from both WT blastema and stroma that independently classify specimens according to race with greater than 80% accuracy. CONCLUSIONS: In Tennessee, Black children appear more susceptible than Whites to develop WT. Race-specific molecular profiles can be determined that may help to clarify pathways of Wilms tumorigenesis and the biological basis for race disparities in WT incidence and biology.

Genotype/phenotype correlation in nephrotic syndrome caused by WT1 mutations.

BACKGROUND AND OBJECTIVES: The risk of developing Wilms tumor (WT) can be present or absent in patients with nephrotic syndrome (NS) caused by WT1 mutations. Here, the genotype/phenotype correlation regarding the outcome and risk for WT in 52 patients from 51 families with NS due to WT1 mutations is described. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study followed 19 patients with mutations in intron 9 splice donor site (KTS mutations), 27 patients with missense mutations, 4 patients with nonsense mutations, 1 patient with a splice site mutation in intron 8, and 1 patient with a deletion. RESULTS: Twenty-four different WT1 mutations were detected. Sixteen of the 19 patients with KTS mutations were females. These patients had isolated NS if karyotype was 46,XX and Frasier syndrome if karyotype was 46,XY. Patients with KTS mutations presented at a significantly older age and with a slower progression toward chronic kidney disease (CKD) stage 5, compared with missense mutations. Patients with nonsense mutations presented initially with WT. Six patients with missense mutations developed WT after the diagnosis of NS (interval-range from NS onset to WT of 0.1 to 1.4 years). CONCLUSIONS: (1) KTS mutations cause isolated NS with absence of WT in 46,XX females. (2) KTS mutations cause Frasier syndrome with gonadoblastoma risk in 46,XY phenotypic females. (3) KTS mutations cause NS with a slower progression when compared with missense mutations. (4) Missense mutations can occur with and without WT. (5) WT1 analysis is important in young patients with NS for early detection and tumor prophylaxis.

Cancer occurrence in Southeast Asian children in California.

OBJECTIVES: To estimate misclassification of ethnicity and cancer incidence in Southeast Asian children using the population-based California Cancer Registry. METHODS: Asian race/ethnicity was evaluated using lists of Asian surnames. Average annual incidence rates (per million) for 1988 to 1992 were calculated for non-Hispanic white, black, Hispanic, and Asian children (age <15 years). Proportional incidence ratios (PIRs) for 1988 to 1995 were used to compare Southeast Asian children to non-Hispanic white children. RESULTS: Of the Asian children, 4.2% (30/722) were misclassified by subgroup, predominantly Hmong listed as Laotian. The Asian cancer rate was 134.2 versus 159.2 for non-Hispanic whites. The germ cell tumor rate was higher in Asians (9.9) than in non-Hispanic whites (4.8), but the Wilms tumor rate was two-thirds lower (3.1 vs. 9.2). The rates of Hodgkin lymphoma and central nervous system tumors were lower (2.8 vs. 5.6 and 20.0 vs. 33.8) in Asians than non-Hispanic whites. Compared with non-Hispanic whites, the PIR for Wilms tumor in Southeast Asian children was reduced (PIR = 0.1). Southeast Asian children had increased PIRs for Burkitt lymphoma (PIR = 2.6) and leukemias not classified as acute lymphocytic leukemia or acute nonlymphocytic leukemia (PIR = 3.5). CONCLUSIONS: Accurate race/ethnicity classification of Southeast Asian children is a concern. Marked differences were found in the incidence and PIRs of specific cancers among Southeast Asian children, other Asian children, and other children in California.

Tumor de Wilms extra-renal: relato de caso / Extrarenal Wilms' tumor: a case report

Um caso de tumor de Wilms extra-renal de localização retroperitoneal em uma paciente do sexo feminino de dois anos de idade é apresentado, associado a revisão de literatura. Foram realizados exames de radiografia simples do abdome, urografia excretora, ultra-sonografia e tomografia computadorizada sem e com contraste, que evidenciaram a presença de massa retroperitoneal adjacente ao rim direito. A paciente foi submetida a intervenção cirúrgica, com ressecção de toda a massa, sendo o diagnóstico de tumor de Wilms confirmado com exame anatomopatológico. O tumor de Wilms extra-renal é uma entidade extremamente rara e maligna, descrito na literatura principalmente sob a forma de relato de caso. Pode ocorrer no retroperitônio, útero e ovários, canal inguinal, testículos, pele, e até mesmo no tórax. O mecanismo exato que poderia explicar a ocorrência deste tumor em tecido extra-renal não foi bem estabelecido ainda. O diagnóstico é feito através do estudo anatomopatológico da lesão, geralmente após intervenção cirúrgica.

The authors report a case of a two year-old girl with an extrarenal Wilms' tumor in the retroperitoneum. Abdominal plain films, intravenous urography, abdominal ultrasound and computed tomography examinations showed a retroperitoneal mass adjacent to the right kidney. The patient underwent surgery with complete resection of the mass. The diagnosis of Wilms' tumor was confirmed by histopathological study. Extrarenal Wilms' tumor is an extremely rare malignancy which is almost always presented in medical literature as a case report. The tumor may arise in the retroperitoneum, uterus and ovaries, inguinal groove, testes, skin, and even in the thorax. The exact mechanism of occurrence of this tumor in extrarenal tissues has not yet been established. The diagnosis relies on histopathological study, generally after surgical intervention.

Mutations/deletions of the WT1 gene, loss of heterozygosity on chromosome arms 11p and 11q, chromosome ploidy and histology in Wilms' tumors in Japan.

Incidence rates of Wilms' tumor (WT) markedly differ in East Asian and Caucasian children. In the present study, we examined WT1 deletions/mutations and loss of heterozygosity (LOH) on 11p and 11q in a large number of WTs and compared our findings with those from 4 series of Caucasian WTs. Incidence rates of the subtle WT1 mutation in 3 of the 5 series of sporadic and unilateral WTs including ours were 4.3-6.2% and similar. However, gross homozygous WT1 deletion was more frequent in our series than in some others. In addition, our series tended to show a higher incidence of LOH limited to 11p13 and a lower incidence of LOH including 11p15 than the Caucasian one. These findings indicate some genetic differences in WT between the 2 regions. One of the 4 Caucasian series reported a correlation of germinal WT1 mutation with the predominantly stromal histology. The present study not only confirms the correlation of germinal WT1 deletion/mutation with predominant stromal histology but also establishes a correlation with somatic WT1 deletion/mutations with predominant stromal histology. While WTs with WT1 abnormalities usually showed pseudodiploidy and predominant stromal histology, those without WT1 abnormalities showed various chromosome numbers and histologic subtypes.

International variations in the incidence of childhood renal tumours.

The International Agency for Research on Cancer has coordinated a worldwide study of childhood cancer incidence, with data from over 50 countries. We present here the results on renal tumours. Wilms' tumour was the most common malignant kidney tumour in all regions. It is sometimes considered to be an 'index cancer of childhood' but it is clear from the present study that there is at least a threefold difference in incidence between the age-standardised annual rates of over 10 per million in the Black populations in the United States and Nigeria and those of around three per million in several East Asian populations. In White Caucasian populations, Wilms' tumour had an annual incidence of 6-9 per million, accounting for 5-7% of all childhood cancer. It was almost everywhere equally common in boys and girls, but the sex ratio in East Asia was M/F = 1.4:1. Age distributions were similar among White Caucasian and Black populations, with the peak incidence in the second year of life. In East Asia, however, 25-40% of the total incidence occurred in infants aged under 1 year, compared with around 15% in many Western series. Other studies have shown that, in the United States, Wilms' tumour has a lower incidence among Asian children than among Whites or Blacks and tends to occur at a younger age. The variation in patterns of incidence of Wilms' tumour along ethnic rather than geographical lines suggests that genetic predisposition is important in its aetiology. Renal carcinoma in childhood is rare throughout the world, with little sign of international variation. It accounted for a higher proportion of childhood renal tumours in East Asia but this was attributable to the lower incidence of Wilms' tumour in that region.