A family-based study of gene variants and maternal folate and choline in neuroblastoma: a report from the Children’s Oncology Group

Mazul, Angela L.; Siega‐Riz, Anna Maria; Weinberg, Clarice R.; Engel, Stephanie M.; Zou, Fei; Carrier, Kathryn; Basta, Patricia V.; Vaksman, Zalman; Maris, John M.; Diskin, Sharon J.; Maxen, Charlene; Naranjo, Arlene; Olshan, Andrew F.

doi:10.1007/s10552-016-0799-1

Cited by 9 publications

(8 citation statements)

References 46 publications

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“…In fact, several investigators have successfully leveraged CCRN for etiologic studies of several childhood cancers. [6][7][8][9][10][11][12] Despite these accomplishments, however, questions remain about the overall representativeness of the resource.…”

Section: Introductionmentioning

confidence: 99%

“…Between 2008 and 2017, more than 50,000 children treated at COG member institutions were enrolled on CCRN, providing a rich resource for epidemiologic investigations. In fact, several investigators have successfully leveraged CCRN for etiologic studies of several childhood cancers 6‐12 . Despite these accomplishments, however, questions remain about the overall representativeness of the resource.…”

Section: Introductionmentioning

confidence: 99%

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An updated assessment of 43,110 patients enrolled in the Childhood Cancer Research Network: A Children's Oncology Group report

Brown

Sok

Scheurer

et al. 2022

Cancer

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Background The Childhood Cancer Research Network (CCRN) was established by the Children's Oncology Group (COG) as a resource for epidemiologic studies of childhood cancer. The objective of this study was to evaluate the representativeness of CCRN and identify factors associated with enrollment. Method The number of US childhood patients with cancer diagnosed <20 years of age enrolled in CCRN (2008‐2015) was compared to expected counts, calculated from Surveillance, Epidemiology, and End Results incidence rates and US Census population estimates. Observed‐to‐expected ratios and corresponding 95% confidence intervals (CI) were estimated across sex, race, diagnosis age, calendar year, and cancer diagnosis groups. Multivariable linear regression models were generated to evaluate the association between open COG phase 3 therapeutic trials and CCRN enrollment rates. Result The 43,110 cases enrolled in CCRN represented 36% of the expected childhood cancers diagnosed from 2008 to 2015 (N = 120,118). CCRN enrollment ratios [95% CI] were highest among males (0.38 [95% CI, 0.37‐0.38]), non‐Hispanics (0.35 [95% CI, 0.35‐0.36]), and those diagnosed from 1 to 4 years of age (0.50 [95% CI, 0.50‐51]). Enrollment ratios varied by diagnosis group, with leukemia, myeloproliferative diseases, myelodysplastic diseases (0.55 [95% CI, 0.54‐0.55]), and renal tumors (0.55 [95% CI, 0.53‐0.58]) having the highest enrollment. After adjusting for year of diagnosis and cancer diagnosis, there was a 3.1% [95% CI, 0.6‐5.6%] increase in CCRN enrollment during windows of open COG therapeutic trials. Conclusions Despite enrolling only 36% of newly diagnosed cases, CCRN remains a valuable resource for investigators conducting childhood cancer etiology and survivorship research. The results of this study may inform efforts to improve enrollment on current and future COG nontherapeutic registry protocols.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An updated assessment of 43,110 patients enrolled in the Childhood Cancer Research Network: A Children's Oncology Group report

Brown

Sok

Scheurer

et al. 2022

Cancer

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“…Lastly, to determine whether these 16p11.2 microdeletions arose de novo or were inherited, we considered four cases for which parental DNA had been collected through the Neuroblastoma Epidemiology in North America (NENA) study 52 and WGS had been performed through the GMKF Pediatric Research Program (Figure 3 and Table S7). By comparing relative coverage and low-frequency variants within the deleted region in the children to the same data from their parents, we concluded that the deletion arose de novo in three of four children; of these, two deletions arose on the maternal allele and one on the paternal allele.…”

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confidence: 99%

Germline 16p11.2 Microdeletion Predisposes to Neuroblastoma

Egolf

Vaksman

Lopez

et al. 2019

The American Journal of Human Genetics

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Neuroblastoma is a cancer of the developing sympathetic nervous system. It is diagnosed in 600-700 children per year in the United States and accounts for 12% of pediatric cancer deaths. Despite recent advances in our understanding of this malignancy's complex genetic architecture, the contribution of rare germline variants remains undefined. Here, we conducted a genome-wide analysis of large (>500 kb), rare (<1%) germline copy number variants (CNVs) in two independent, multi-ethnic cohorts totaling 5,585 children with neuroblastoma and 23,505 cancer-free control children. We identified a 550-kb deletion on chromosome 16p11.2 significantly enriched in neuroblastoma cases (0.39% of cases and 0.03% of controls; p ¼ 3.34 3 10 À9 ). Notably, this CNV corresponds to a known microdeletion syndrome that affects approximately one in 3,000 children and confers risk for diverse developmental phenotypes including autism spectrum disorder and other neurodevelopmental disorders. The CNV had a substantial impact on neuroblastoma risk, with an odds ratio of 13.9 (95% confidence interval ¼ 5.8-33.4). The association remained significant when we restricted our analysis to individuals of European ancestry in order to mitigate potential confounding by population stratification (0.42% of cases and 0.03% of controls; p ¼ 4.10 3 10 À8 ). We used whole-genome sequencing (WGS) to validate the deletion in paired germline and tumor DNA from 12 cases. Finally, WGS of four parent-child trios revealed that the deletion primarily arose de novo without maternal or paternal bias. This finding expands the clinical phenotypes associated with 16p11.2 microdeletion syndrome to include cancer, and it suggests that disruption of the 16p11.2 region may dysregulate neurodevelopmental pathways that influence both neurological phenotypes and neuroblastoma.

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“…Then, by determining a threshold for q -values to declare significant findings in multiple comparisons, we can control the expected proportion that declared associations are truly null. In this study, we used a threshold of 0.2, which was also adopted by recent studies 35 , 36 . Using such a less stringent threshold should enable us to find moderate associations, while controlling a reasonable FDR.…”

Section: Discussionmentioning

confidence: 99%

Genetic variation of SORBS1 gene is associated with glucose homeostasis and age at onset of diabetes: A SAPPHIRe Cohort Study

Chang

Wang

Hsiung

et al. 2018

Sci Rep

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The SORBS1 gene plays an important role in insulin signaling. We aimed to examine whether common single-nucleotide polymorphisms (SNPs) of SORBS1 are associated with prevalence and incidence of diabetes, age at onset of diabetes, and the related traits of glucose homeostasis. A total of 1135 siblings from 492 ethnic Chinese families were recruited at baseline, and 630 were followed up for 5.19 ± 0.96 years. Nine SNPs including rs7081076, rs2281939, rs3818540, rs2274490, rs61739184, rs726176, rs2296966, rs17849148, and rs3193970 were genotyped and examined. To deal with correlated data of subjects within the same families, the generalized estimating equations approach was applied throughout all association analyses. The GG genotype of rs2281939 was associated with a higher risk of diabetes at baseline, an earlier onset of diabetes, and higher steady-state plasma glucose levels in the modified insulin suppression test. The minor allele T of rs2296966 was associated with higher prevalence and incidence of diabetes, an earlier onset of diabetes, and higher 2-h glucose during oral glucose tolerance test. These two SNPs revealed independent associations with age of diabetes onset as well as risk of diabetes at baseline. These findings supported that SORBS1 gene participates in the pathogenesis of diabetes.

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A family-based study of gene variants and maternal folate and choline in neuroblastoma: a report from the Children’s Oncology Group

Cited by 9 publications

References 46 publications

An updated assessment of 43,110 patients enrolled in the Childhood Cancer Research Network: A Children's Oncology Group report

An updated assessment of 43,110 patients enrolled in the Childhood Cancer Research Network: A Children's Oncology Group report

Germline 16p11.2 Microdeletion Predisposes to Neuroblastoma

Genetic variation of SORBS1 gene is associated with glucose homeostasis and age at onset of diabetes: A SAPPHIRe Cohort Study

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