Enrollment on upfront high-risk neuroblastoma trials by race, ethnicity, and poverty status: A report from the Children's Oncology Group.

It is not clear whether trial access disparities exist in the Children's Oncology Group (COG). Here, we leverage a cohort of children with high-risk neuroblastoma (HR-NBL) enrolled on the COG ANBL00B1 neuroblastoma biology study to examine subsequent enrollment to upfront COG therapeutic trials by race, ethnicity, and proxied poverty status. Among 1917 children with HR-NBL enrolled on ANBL00B1, 696 (36.3%) subsequently enrolled on an upfront therapeutic trial with no difference by race, ethnicity, or proxied poverty status. In neuroblastoma, trial access disparities are not comparable to adult oncology, and efforts to advance equity should prioritize other mechanisms of survival disparities.

lncRNA-uc003opf.1 rs11752942 A>G polymorphism decreases neuroblastoma risk in Chinese children.

Recent studies have revealed that long non-coding RNAs (lncRNAs) play critical roles in the tumorigenesis and proliferation of human cancer. Several polymorphisms of lncRNAs have been found to be involved in the risk of neuroblastoma (NB). However, studies on the relationship between polymorphisms in lncRNA exons and NB are infrequent. We evaluated the association between rs11752942 A > G polymorphism in lnc-RNA-uc003opf.1 exon and neuroblastoma susceptibility by performing a hospital-based study with 275 patients and 531 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) assessed by using logistic regression models were used to determine the strength of the association. We found that the rs11752942 G allele is significantly associated with decreased neuroblastoma risk (AG vs. AA: adjusted OR = 0.72, 95% CI = 0.53-0.98, P = 0.038; and AG/GG vs. AA: adjusted OR = 0.74, 95% CI = 0.55-0.99, P = 0.045) after adjusting for age and gender. This association was more prominent in females, subjects with tumor in the mediastinum or early-stage. Furthermore, the expression quantitative trait locus analysis indicated that rs11752942 G was associated with decreased expression of its neighboring gene LRFN2 mRNA. These results indicate that lncRNA-uc003opf.1 may be a novel potentially functional lncRNA that may be used as a predictive marker, for it might contribute to decreased neuroblastoma risk.

TP53 Arg72Pro polymorphism and neuroblastoma susceptibility in eastern Chinese children: a three-center case-control study.

TP53 is a tumor suppressor gene that regulates cell growth, apoptosis and DNA repair. Previous studies have reported the contribution of TP53 Arg72Pro (rs1042522 C>G) polymorphism to pathogenesis of multiple tumors. Hence, we evaluated the association between this polymorphism and neuroblastoma susceptibility in eastern Chinese children. The Taqman genotyping assay was performed in 373 patients and 762 controls. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of the association. No significant association was found between the TP53 gene rs1042522 C>G polymorphism and neuroblastoma susceptibility in the overall analysis (CG vs. CC: adjusted OR = 0.92, 95% CI = 0.70-1.22, P=0.567; GG vs. CC: adjusted OR = 0.99, 95% CI = 0.69-1.42, P=0.947; CG/GG vs. CC: adjusted OR = 0.94, 95% CI = 0.72-1.23, P=0.639; or GG vs. CC/CG: adjusted OR = 1.04, 95% CI = 0.75-1.43, P=0.814) and stratified analysis by age, gender, sites of origin, and clinical stages. The TP53 gene rs1042522 C>G polymorphism may not be a risk factor for neuroblastoma in eastern Chinese children. Future studies are needed to confirm this negative result and to reveal additional functional TP53 variants predisposing to neuroblastoma.

miR-34b/c rs4938723 T>C Decreases Neuroblastoma Risk: A Replication Study in the Hunan Children.

Neuroblastoma is the most common seen solid neural tumor in children less than age one. As mutation in the miR-34b/c gene is observed in several types of human malignancies, there likely to be similar events that contribute to the pathogenesis of neuroblastoma. We hypothesize that polymorphism in the miR-34b/c gene might predispose to neuroblastoma. Here, we conducted this replication study by genotyping rs4938723 T>C from miR-34b/c in Hunan children (162 subjects with neuroblastoma and 270 control subjects) and examined its effect on the risk of neuroblastoma. We determined such association using logistic regression, adjusted for age and gender. Relative to those with TT genotype, subjects with C allele had reduced neuroblastoma risk (TC vs. TT: adjusted OR = 0.46, 95%CI = 0.30-0.71; additive model: adjusted OR = 0.64, 95%CI = 0.47-0.88; TC/CC vs. TT: adjusted OR = 0.49, 95%CI = 0.33-0.73). Stratified analysis revealed that rs4938723 TC/CC carriers were less likely to develop neuroblastoma for patients in the subgroups of age ≤ 18 months, age > 18 months, females, males, tumors in retroperitoneal, tumors in other sites, and clinical stages II, III, IV, and III+IV. Our findings verified miR-34b/c rs4938723 C variant allele as a protective factor for the risk of neuroblastoma. Further investigation of how miR-34b/c rs4938723 T>C might modify neuroblastoma risk is warranted.

XRCC1 gene polymorphisms and risk of neuroblastoma in Chinese children.

Neuroblastoma is a common pediatric extra-cranial tumor of the sympathetic nervous system. XRCC1 is a scaffold protein that participates in DNA single-strand break repair by complexing with other proteins. XRCC1 gene polymorphisms are being increasingly explored in cancer epidemiology studies. However, the contribution of XRCC1 gene polymorphisms to neuroblastoma risk remains unclarified. Herein, we conducted a case-control study with 393 neuroblastoma patients and 812 controls to explore the association of XRCC1 gene polymorphisms (rs1799782 G>A, rs25487 C>T, rs25489 C>T and rs915927 T>C) with neuroblastoma risk. Results showed that none of the studied polymorphisms was associated with neuroblastoma risk. However, individuals with 2 risk genotypes seemed to be at significantly higher risk for neuroblastoma compared with those without risk genotype (adjusted odds ratio=1.69; 95% confidence interval=1.06-2.69). Stratified analysis revealed that the XRCC1 rs25489 CT/TT was strongly associated with reduced risk of neuroblastoma in the children ≤ 18 months of age and subgroup with clinical stage I+II+4s diseases, compared with CC genotypes. We also identified an increased neuroblastoma risk for carrier of 2-3 risk genotypes among children ≤ 18 months of age and subgroup with clinical stage I+II+4s. More evidence of the association between XRCC1 gene polymorphisms and neuroblastoma risk is needed.

Single nucleotide polymorphism rs11669203 in TGFBR3L is associated with the risk of neuroblastoma in a Chinese population.

With a primary mortality, neuroblastoma (NB) is the most common extracranial solid tumor in childhood. Amplification of the MYCN (v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog) oncogene is observed in 20-30 % of NB cases, a feature which also characterizes a highly aggressive subtype of the disease. However, the systematic study of association between single nucleotide polymorphisms (SNPs) in MYCN-regulated genes and the risk of NB has not been investigated. In the current study, we scanned a set of 16 SNPs located within known or predicted MYCN binding sites in a cohort of 247 patients of Chinese origin with neuroblastic family tumors, including neuroblastoma (NB), ganglioneuroma (GN), and ganglioneuroblastoma (GNB), and in 290 cancer-free controls to determine whether any of the tested SNPs are associated with neuroblastic family tumors. We found that the rs11669203 G>C polymorphism, located in TGFBR3L promoter, is significantly associated with the risk of NB. Further, we found that this association is site specific to adrenal NB compared to non-adrenal NB. In addition, transcriptome analysis indicated that increased expression of TGFBR3L is strongly correlated with poor survival. The SNP rs11669203 located at the MYCN binding site of TGFBR3L is significantly associated with elevated risk of NB, and abnormal MYCN-regulated TGFBR3L expression may contribute to NB oncogenesis.

Immunoglobulin GM allotypes as effect modifiers of cytomegalovirus-spurred neuroblastoma.

An uncommon immunoglobulin GM (γ marker) genotype has been reported to be strongly associated with susceptibility to neuroblastoma, but the mechanism(s) underlying this association is not known. Increasing evidence implicates human cytomegalovirus (HCMV) in the pathogenesis of neuroblastoma. HCMV has evolved a large repertoire of sophisticated strategies to evade host immunosurveillance. Particular GM alleles modulate an immunoevasion strategy of HCMV and contribute to humoral immunity to HCMV epitopes, attributes that provide possible mechanistic explanations for their involvement in the etiopathogenesis of neuroblastoma and explain, at least partially, why a common virus causes/spurs an uncommon cancer.

Copy number gain of MYCN gene is a recurrent genetic aberration and favorable prognostic factor in Chinese pediatric neuroblastoma patients.

BACKGROUND: Amplification of MYCN oncogene is an established marker indicating aggressive tumor progression of neuroblastoma (NBL). But copy number analyses of MYCN gene in ganglioneuroblastoma (GNBL) and ganglioneuroma(GN) is poorly described in the literature. In the study, we evaluated the copy number aberrations of MYCN gene in clinical samples of NBLs, GNBLs and GNs and analyzed their association with clinical outcome of the patients. METHODS: In this study, we analyzed MYCN gene and chromosome 2 aneusomy by using fluorescence in situ hybridization (FISH) method in a total of 220 patients with NBL, GNBL and GN cases. Kaplan-Meier curves were generated by using SPSS 12.0 software. RESULTS: Of 220 patients, 178 (81.0%) were NBLs, 32 (14.5%) were GNBLs and 10 (4.5%) were GNs. MYCN gain is a recurrent genetic aberration of neuroblastic tumors (71.8%, 158/220), which was found in 129 NBLs (58.6%, 129/220), 25 GNBLs (11.4%, 25/220) and 4 GN cases (1.8%, 4/220). However, MYCN amplification was only present in 24 NBL tumors (13.5%, 24/178) and 1 GNBL case (3.1%, 1/32). Kaplan-Meier survival analysis indicated that MYCN amplification is significantly correlated with decreased overall survival in NBLs (P=0.017). Furthermore, a better prognosis trend was observed in patients with MYCN gain tumors compared with those with MYCN gene normal copy number tumors and MYCN amplification tumors (P=0.012). CONCLUSIONS: In summary, the frequency of MYCN amplification in NBLs is high and is rarely observed in GNBLs and GNs, which suggest MYCN plays an important role in neuroblastic tumors differentiation. MYCN gain appeared to define a subgroup of NBLs with much better outcome and classification of MYCN gene copy number alteration as three groups (amplification, gain and normal) can provide a powerful prognostic indicator in NBLs. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/6417541528559124.

Replication of neuroblastoma SNP association at the BARD1 locus in African-Americans.

BACKGROUND: Neuroblastoma is an often fatal pediatric cancer more frequent in European-American than African-American children. African-American children, however, are at higher risk for the more severe form of neuroblastoma and have worse overall survival than European-American children. Genome-wide association studies (GWAS) have identified several single-nucleotide polymorphisms (SNP) associated to neuroblastoma in children of European descent. Knowledge of their association to neuroblastoma in African-American children is still lacking. METHODS: We genotyped and imputed SNPs located in three gene regions reported to be associated to neuroblastoma in children of European descent, and tested them for association in 390 African-American patients with neuroblastoma compared with 2,500 healthy, ethnically matched controls. RESULTS: SNPs in the BARD1 gene region show a similar pattern of association to neuroblastoma in African-American and European-American children. The more restricted extent of linkage disequilibrium in the African-American population suggests a smaller candidate region for the putative causal variants than previously reported. Limited association was observed at the other two gene regions tested, including LMO1 in 11p15 and FLJ22536 in 6p22. CONCLUSIONS: Common BARD1 SNPs affect risk of neuroblastoma in African-Americans. The role of other SNPs associated to neuroblastoma in children of European descent could not be confirmed, possibly due to different patterns of linkage disequilibrium or limited statistical power to detect association to variants with small effect on disease risk. Extension of GWAS to populations of African descent is important to confirm their results and validity beyond the European populations and can help to refine the location of the putative causal variants.

Disparities in cancer outcomes: lessons learned from children with cancer.

Disparities in cancer burden by race/ethnicity have been reported, primarily in adults with cancer. However, there appear to be gaps in the pediatric oncology literature with regards to a comprehensive overview on this topic. Extant literature is used to highlight the results of studies focusing on racial and ethnic disparities in outcome observed in selected childhood cancers. A comprehensive approach is utilized to understand possible underlying causes of disparities in cancer outcomes, and to highlight the gaps that currently exist. This review helps define areas of future research that could help develop targeted, disease-specific approaches to eliminate the disparities.

Racial and ethnic disparities in risk and survival in children with neuroblastoma: a Children's Oncology Group study.

PURPOSE: Although health disparities are well-described for many cancers, little is known about racial and ethnic disparities in neuroblastoma. To evaluate differences in disease presentation and survival by race and ethnicity, data from the Children's Oncology Group (COG) were analyzed. PATIENTS AND METHODS: The racial/ethnic differences in clinical and biologic risk factors, and outcome of patients with neuroblastoma enrolled on COG ANBL00B1 between 2001 and 2009 were investigated. RESULTS: A total of 3,539 patients (white, 72%; black, 12%; Hispanic, 12%; Asian, 4%; and Native American, < 1%) with neuroblastoma were included. The 5-year event-free survival (EFS) rates were 67% for whites (95% CI, 65% to 69%), 69% for Hispanics (95% CI, 63% to 74%), 62% for Asians (95% CI, 51% to 71%), 56% for blacks (95% CI, 50% to 62%), and 37% for Native American (95% CI, 17% to 58%). Blacks (P < .001) and Native Americans (P = .04) had a higher prevalence of high-risk disease than whites, and significantly worse EFS (P = .01 and P = .002, respectively). Adjustment for risk group abrogated these differences. However, closer examination of the EFS among high-risk patients who remained event free for 2 years or longer, revealed a higher prevalence of late-occurring events among blacks compared with whites (hazard ratio, 1.5; 95% CI, 1.0 to 2.3; P = .04). CONCLUSION: Black and Native American patients with neuroblastoma have a higher prevalence of high-risk disease, accounting for their worse EFS when compared with whites. The higher prevalence of late-occurring events among blacks with high-risk disease suggests that this population may be more resistant to chemotherapy. Studies focused on delineating the genetic basis for the racial disparities observed in this study are planned.

Birth characteristics and risk of neuroblastoma in young children.

The peak incidence of neuroblastoma during infancy suggests that certain prenatal or perinatal factors may be etiologically important. In this population-based study, California birth certificates were identified for 508 (86%) neuroblastoma cases diagnosed at less than 5 years of age between 1988 and 1997. For each case, two controls, matched on date of birth and gender, were randomly selected from the statewide birth registry. Results of multivariate analyses showed a reduced risk for children of Hispanic (odds ratio (OR) = 0.57, 95% confidence interval (CI): 0.43, 0.76) and "other" (OR = 0.56, 95% CI: 0.37, 0.85) race/ethnicity, compared with non-Hispanic Whites. Postterm/high birth weight delivery was associated with an increased risk of neuroblastoma compared with term/normal birth weight delivery among infants (OR = 6.99, 95% CI: 1.07, 45.55), while preterm birth appeared suggestive of a reduced risk among children 1-4 years of age. For children in this age group, the risk of neuroblastoma was elevated for cesarean delivery compared with vaginal delivery (OR = 1.72, 95% CI: 1.21, 2.47), and, for infants, the risk was reduced if the mother had had multiple previous pregnancies (OR = 0.39, 95% CI: 0.22, 0.69). These data suggest that etiologic factors associated with the prenatal and perinatal periods may be specific to age at neuroblastoma diagnosis.

Excess of congenital abnormalities in French-Canadian children with neuroblastoma: a case series study from Montréal.

Neuroblastoma is one of the most common cancers of childhood. Some studies have shown an excess of congenital abnormalities in children who have been diagnosed with neuroblastoma. In this study we examined the medical records of all children with neuroblastoma seen at St. Justine Children's Hospital between the years 1977 and 1993. A total of 141 children (131 of French-Canadian ancestry) were included in this study. Twelve children (8.5%) had 21 defined congenital abnormalities (1,490 per 10,000 children). This compared with a rate of 444.3 children with abnormalities per 10,000 live births (4.44%) for all congenital abnormalities in the British Columbia Health Surveillance Registry, 1979-1988 (relative risk = 1.91, P = 0.03). Six of the 12 children had cardiovascular malformations. These and previous results suggest that there may be a common developmental origin to neuroblastoma and to some congenital malformations. Genes that control development may be worthy of further study in these children.

[Malignant solid tumors in the first year of life].

The records of all children in Northern Israel under the age of 1 year in whom a malignant solid tumor was diagnosed were analyzed. Between 1973-1990 such tumors were found in 39 boys and 25 girls. The overall annual incidence was 137.1 per million, and the incidence was higher in boys (1.9/1.0), in Jews compared to non-Jews (1.3/1.0), and in Ashkenazic Jews compared to Sephardic Jews (1.2/1.0). Neuroblastoma was the most common (52% of all malignancies), followed by Wilms' tumor (13%), CNS neoplasm (11%), retinoblastoma (8%), soft tissue sarcoma (6%), lymphoma (5%) and all others (6%). The retinoblastomas were all in non-Jews, but Jews had a higher incidence of neuroblastomas. No differences in incidence were observed in other neoplasms.

International variations in the incidence of neuroblastoma.

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 for neuroblastoma. In predominantly white Caucasian populations the age-standardized rate was 7-12 per million, and 6-10% of all childhood cancers were neuroblastomas. Rates were highest in the first year of life (25-50 per million, 30% of total neuroblastoma incidence), and decreased with age to 15-20 per million (50% of the total) at age 1-4, 2-4 per million (15%) at 5-9 and 1-1.5 per million (5%) at 10-14. In the United States, black children had an incidence of 8.5 per million compared with 11.5 among Whites; Blacks tended to be older than Whites at diagnosis. The highest rate in Africa was in Bulawayo, Zimbabwe (8.0 per million) and the lowest in West Nile, Uganda, with no cases registered. Incidence in Israel was similar to that in many white populations, with Jews having a particularly high rate. In other parts of West Asia neuroblastoma had a low relative frequency, suggesting that incidence is low. Rates were also low throughout much of southern and eastern Asia, including India and China. Incidence in Japan was somewhat higher, though less than in Western countries, with the deficit most pronounced in the first year of life; these data relate to the period before mass screening of infants for neuroblastoma in the regions concerned. Incidence was generally higher in regions and among ethnic groups enjoying a higher standard of living, though previous studies within single countries had suggested that neuroblastoma is more common among less affluent groups. Blacks in Africa and the United States may have a weaker genetic predisposition to neuroblastoma, but some of the deficit in many developing countries is likely to be due to under-diagnosis.

The incidence and epidemiologic characteristics of neuroblastoma in the United States.

The incidence of neuroblastoma in the United States is described in relation to age, sex, race, and anatomic site, as well as population-derived indicators of socioeconomic levels, degree of urbanization, and farming activity. Incidence data were obtained for the years 1973-1978 from the Surveillance, Epidemiology and End Results Program of the National Cancer Institute. Based upon 265 cases, the overall incidence of neuroblastoma was 2.26 per million person-years. Approximately 60% of the cases were diagnosed under age two years, 75% under age five years and 84% under age 10 years. The incidence among males was 1.3 times that among females, but the male predominance was observed only among persons diagnosed under age five years. Although no difference in overall incidence was observed by race, the rate among whites was 1.6 times that among blacks and 1.5 times that among other nonwhites under age five years. Approximately 50% of all cases were diagnosed with tumors arising from the adrenals or soft tissues. No clear pattern of area-to-area variation in incidence was identified. Neuroblastoma incidence was inversely related to socioeconomic level as measured by per capita income (p = 0.05), as well as the proportion of county land devoted to farming (p = 0.034). No association was observed in relation to urbanization or population density.