Multi-ancestry genome-wide association study of 4069 children with glioma identifies 9p21.3 risk locus.

BACKGROUND: Although recent sequencing studies have revealed that 10% of childhood gliomas are caused by rare germline mutations, the role of common variants is undetermined and no genome-wide significant risk loci for pediatric central nervous system tumors have been identified to date. METHODS: Meta-analysis of 3 population-based genome-wide association studies comprising 4069 children with glioma and 8778 controls of multiple genetic ancestries. Replication was performed in a separate case-control cohort. Quantitative trait loci analyses and a transcriptome-wide association study were conducted to assess possible links with brain tissue expression across 18 628 genes. RESULTS: Common variants in CDKN2B-AS1 at 9p21.3 were significantly associated with astrocytoma, the most common subtype of glioma in children (rs573687, P-value of 6.974e-10, OR 1.273, 95% CI 1.179-1.374). The association was driven by low-grade astrocytoma (P-value of 3.815e-9) and exhibited unidirectional effects across all 6 genetic ancestries. For glioma overall, the association approached genome-wide significance (rs3731239, P-value of 5.411e-8), while no significant association was observed for high-grade tumors. Predicted decreased brain tissue expression of CDKN2B was significantly associated with astrocytoma (P-value of 8.090e-8). CONCLUSIONS: In this population-based genome-wide association study meta-analysis, we identify and replicate 9p21.3 (CDKN2B-AS1) as a risk locus for childhood astrocytoma, thereby establishing the first genome-wide significant evidence of common variant predisposition in pediatric neuro-oncology. We furthermore provide a functional basis for the association by showing a possible link to decreased brain tissue CDKN2B expression and substantiate that genetic susceptibility differs between low- and high-grade astrocytoma.

A genome-wide association study on medulloblastoma.

INTRODUCTION: Medulloblastoma is a malignant embryonal tumor of the cerebellum that occurs predominantly in children. To find germline genetic variants associated with medulloblastoma risk, we conducted a genome-wide association study (GWAS) including 244 medulloblastoma cases and 247 control subjects from Sweden and Denmark. METHODS: Genotyping was performed using Illumina BeadChips, and untyped variants were imputed using IMPUTE2. RESULTS: Fifty-nine variants in 11 loci were associated with increased medulloblastoma risk (p < 1 × 10-5), but none were statistically significant after adjusting for multiple testing (p < 5 × 10-8). Thirteen of these variants were genotyped, whereas 46 were imputed. Genotyped variants were further investigated in a validation study comprising 249 medulloblastoma cases and 629 control subjects. In the validation study, rs78021424 (18p11.23, PTPRM) was associated with medulloblastoma risk with OR in the same direction as in the discovery cohort (ORT = 1.59, pvalidation = 0.02). We also selected seven medulloblastoma predisposition genes for investigation using a candidate gene approach: APC, BRCA2, PALB2, PTCH1, SUFU, TP53, and GPR161. The strongest evidence for association was found for rs201458864 (PALB2, ORT = 3.76, p = 3.2 × 10-4) and rs79036813 (PTCH1, ORA = 0.42, p = 2.6 × 10-3). CONCLUSION: The results of this study, including a novel potential medulloblastoma risk loci at 18p11.23, are suggestive but need further validation in independent cohorts.

Genetic Variants in the 9p21.3 Locus Associated with Glioma Risk in Children, Adolescents, and Young Adults: A Case-Control Study.

BACKGROUND: Genome-wide association studies have identified germline genetic variants in 25 genetic loci that increase the risk of developing glioma in adulthood. It is not known if these variants increase the risk of developing glioma in children and adolescents and young adults (AYA). To date, no studies have performed genome-wide analyses to find novel genetic variants associated with glioma risk in children and AYA. METHODS: We investigated the association between 8,831,628 genetic variants and risk of glioma in 854 patients diagnosed up to the age of 29 years and 3,689 controls from Sweden and Denmark. Recruitment of patients and controls was population based. Genotyping was performed using Illumina BeadChips, and untyped variants were imputed with IMPUTE2. We selected 41 established adult glioma risk variants for detailed investigation. RESULTS: Three adult glioma risk variants, rs634537, rs2157719, and rs145929329, all mapping to the 9p21.3 (CDKN2B-AS1) locus, were associated with glioma risk in children and AYA. The strongest association was seen for rs634537 (odds ratioG = 1.21; 95% confidence interval = 1.09-1.35; P = 5.8 × 10-4). In genome-wide analysis, an association with risk was suggested for 129 genetic variants (P <1 × 10-5). CONCLUSIONS: Carriers of risk alleles in the 9p21.3 locus have an increased risk of glioma throughout life. The results from genome-wide association analyses require validation in independent cohorts. IMPACT: Our findings line up with existing evidence that some, although not all, established adult glioma risk variants are associated with risk of glioma in children and AYA. Validation of results from genome-wide analyses may reveal novel susceptibility loci for glioma in children and AYA.

CCND2, CTNNB1, DDX3X, GLI2, SMARCA4, MYC, MYCN, PTCH1, TP53, and MLL2 gene variants and risk of childhood medulloblastoma.

Recent studies have described a number of genes that are frequently altered in medulloblastoma tumors and that have putative key roles in the development of the disease. We hypothesized that common germline genetic variations in these genes may be associated with medulloblastoma development. Based on recent publications, we selected 10 genes that were frequently altered in medulloblastoma: CCND2, CTNNB1, DDX3X, GLI2, SMARCA4, MYC, MYCN, PTCH1, TP53, and MLL2 (now renamed as KMT2D). Common genetic variants (single nucleotide polymorphisms) annotating these genes (n = 221) were genotyped in germline DNA (neonatal dried blood spot samples) from 243 childhood medulloblastoma cases and 247 control subjects from Sweden and Denmark. Eight genetic variants annotating three genes in the sonic hedgehog signaling pathway; CCND2, PTCH1, and GLI2, were found to be associated with the risk of medulloblastoma (P(combined) < 0.05). The findings were however not statistically significant following correction for multiple testing by the very stringent Bonferroni method. The results do not support our hypothesis that common germline genetic variants in the ten studied genes are associated with the risk of developing medulloblastoma.

Detection of IL-17A-producing peripheral blood monocytes in Langerhans cell histiocytosis patients.

Langerhans cell histiocytosis (LCH) is a rare disease of unknown cause with manifestations ranging from isolated granulomatous lesions to life-threatening multi-system organ involvement. This disorder is further characterized by infiltration of immune cells in affected tissues and an association with interleukin (IL)-17A has been reported. Here, we investigated the presence of IL-17A-producing cells among peripheral blood mononuclear cells isolated from LCH patients and observed a high percentage of IL-17A(+) monocytes in peripheral blood of LCH patients compared to controls. The IL-17A(+) monocytes were also positive for the transcription factor retinoic acid orphan receptor (ROR) γt and showed increased mRNA levels for both IL-17A and RORγt. Notably, IL-17A was produced by all monocyte subsets and the expression level was positively associated with LCH disease activity. These data support a role for monocytes in the pathogenesis of LCH. Future therapeutic approaches may consider identification of patients who may benefit from IL-17A-targeted interventions.

Human immunoglobulin G levels of viruses and associated glioma risk.

Few consistent etiological factors have been identified for primary brain tumors. Inverse associations to asthma and low levels of varicella-zoster virus, immunoglobulin (Ig) levels in prevalent cases have indicted a role for the immune system in the development of glioma. Because samples from prevalent cases of glioma could be influenced by treatments such as steroids and chemotherapy, we investigated pre-diagnostic samples from three large Scandinavian cohorts. To test the hypothesis that immune response levels to these viruses are associated etiologically with glioma risk, we investigated pre-diagnostic immunoglobulin levels for cytomegalovirus (CMV), varicella-zoster virus (VZV), adenovirus (Ad), and Epstein-Barr virus (EBV) including the nuclear antigen (EBNA1) using plasma samples from 197 cases of adult glioma and 394 controls collected from population-based cohorts in Sweden and Denmark. Low VZV IgG levels were marginally significantly more common in glioma cases than the controls (odds ratio (OR) = 0.68, 95% CI 0.41-1.13) for the fourth compared with the first quartile (p = 0.06 for trend). These results were more prominent when analyzing cases with blood sampling at least 2 years before diagnosis (OR = 0.63, 95% CI 0.37-1.08) (p = 0.03). No association with glioma risk was observed for CMV, EBV, and adenovirus.

Incidence and survival analyses in children with solid tumours diagnosed in Sweden between 1983 and 2007.

AIM: Solid tumours constitute 40% of childhood malignancies. The Swedish Childhood Cancer Registry is population based and includes all children with cancer reported from the six paediatric oncology centres in Sweden. The aim was to investigate incidence and survival. METHODS: We used the new WHO ICCC-3 for reclassification of the patients. Incidence and survival analyses were performed in the study population. RESULTS: Two thousand four hundred and eighty-seven children (<15 years) were diagnosed with solid tumours in Sweden between 1983 and 2007. The distribution of diagnoses was similar to that reported in other studies. The annual incidence was 65.3 per million children. The survival rates at 10 years of follow-up have improved significantly when comparing the two time periods, 1983-1995 and 1995-2007 (76 vs. 82%; p < 0.01). CONCLUSIONS: The mean annual incidence of solid tumours in children was 65.3/million and has been stable during the study period. Survival rates for solid tumours at 5, 10 and 20 years follow-up were 80, 79 and 76%, respectively.

Genetic variants in association studies--review of strengths and weaknesses in study design and current knowledge of impact on cancer risk.

Sequencing of the human genome has recently been completed and mapping of the complete genomic variation is ongoing. During the last decade there has been a huge expansion of studies of genetic variants, both with respect to association studies of disease risk and for studies of genetic factors of prognosis and treatments response, i.e., pharmacogenomics. The use of genetics to predict a patient's risk of disease or treatment response is one step toward an improved personalised prevention and screening modality for the prevention of cancer and treatment selection. The technology and statistical methods for completing whole genome tagging of variants and genome wide association studies has developed rapidly over the last decade. After identifying the genetic loci with the strongest, statistical associations with disease risk, future studies will need to further characterise the genotype-phenotype relationship to provide a biological basis for prevention and treatment decisions according to genetic profile. This review discusses some of the general issues and problems of study design; we also discuss challenges in conducting valid association studies in rare cancers such as paediatric brain tumours, where there is support for genetic susceptibility but difficulties in assembling large sample sizes. The clinical interpretation and implementation of genetic association studies with respect to disease risk and treatment is not yet well defined and remains an important area of future research.