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Open Access 01-10-2015 | Laboratory Investigation

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

Authors: Anna M. Dahlin, Mads V. Hollegaard, Carl Wibom, Ulrika Andersson, David M. Hougaard, Isabelle Deltour, Ulf Hjalmars, Beatrice Melin

Published in: Journal of Neuro-Oncology | Issue 1/2015

Abstract

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.

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Lannering B, Sandstrom PE, Holm S, Lundgren J, Pfeifer S, Samuelsson U, Stromberg B, Gustafsson G (2009) Classification, incidence and survival analyses of children with CNS tumours diagnosed in Sweden 1984-2005. Acta Paediatr 98:1620–1627. doi:10.1111/j.1651-2227.2009.01417.x CrossRefPubMed

Johnson KJ, Cullen J, Barnholtz-Sloan JS et al (2014) Childhood brain tumor epidemiology: a brain tumor epidemiology consortium review. Cancer Epidemiol Biomark Prev 23:2716–2736. doi:10.1158/1055-9965.EPI-14-0207 CrossRef

Hottinger AF, Khakoo Y (2009) Neurooncology of familial cancer syndromes. J Child Neurol 24:1526–1535. doi:10.1177/0883073809337539 CrossRefPubMed

Smith MJ, Beetz C, Williams SG et al (2014) Germline mutations in SUFU cause gorlin syndrome-associated childhood medulloblastoma and redefine the risk associated with PTCH1 mutations. J Clin Oncol. doi:10.1200/JCO.2014.58.2569

Parsons DW, Li M, Zhang X et al (2011) The genetic landscape of the childhood cancer medulloblastoma. Science 331:435–439. doi:10.1126/science.1198056 PubMedCentralCrossRefPubMed

Robinson G, Parker M, Kranenburg TA et al (2012) Novel mutations target distinct subgroups of medulloblastoma. Nature 488:43–48. doi:10.1038/nature11213 PubMedCentralCrossRefPubMed

Northcott PA, Shih DJ, Peacock J et al (2012) Subgroup-specific structural variation across 1000 medulloblastoma genomes. Nature 488:49–56. doi:10.1038/nature11327 PubMedCentralCrossRefPubMed

Northcott PA, Nakahara Y, Wu X et al (2009) Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma. Nat Genet 41:465–472. doi:10.1038/ng.336 PubMedCentralCrossRefPubMed

Pugh TJ, Weeraratne SD, Archer TC et al (2012) Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature 488:106–110. doi:10.1038/nature11329 PubMedCentralCrossRefPubMed

10.

Jones DT, Jager N, Kool M et al (2012) Dissecting the genomic complexity underlying medulloblastoma. Nature 488:100–105. doi:10.1038/nature11284 PubMedCentralCrossRefPubMed

11.

Hollegaard MV, Grauholm J, Borglum A et al (2009) Genome-wide scans using archived neonatal dried blood spot samples. BMC Genom 10:297. doi:10.1186/1471-2164-10-297 CrossRef

12.

Hollegaard MV, Grove J, Grauholm J et al (2011) Robustness of genome-wide scanning using archived dried blood spot samples as a DNA source. BMC Genet 12:58. doi:10.1186/1471-2156-12-58 PubMedCentralCrossRefPubMed

13.

Hollegaard MV, Thorsen P, Norgaard-Pedersen B, Hougaard DM (2009) Genotyping whole-genome-amplified DNA from 3- to 25-year-old neonatal dried blood spot samples with reference to fresh genomic DNA. Electrophoresis 30:2532–2535. doi:10.1002/elps.200800655 CrossRefPubMed

14.

Purcell S, Neale B, Todd-Brown K et al (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Human Genet 81:559–575. doi:10.1086/519795 CrossRef

15.

Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38:904–909. doi:10.1038/ng1847 CrossRefPubMed

16.

Patterson N, Price AL, Reich D (2006) Population structure and eigenanalysis. PLoS Genet 2:e190. doi:10.1371/journal.pgen.0020190 PubMedCentralCrossRefPubMed

17.

Evans DG, Ladusans EJ, Rimmer S, Burnell LD, Thakker N, Farndon PA (1993) Complications of the naevoid basal cell carcinoma syndrome: results of a population based study. J Med Genet 30:460–464PubMedCentralCrossRefPubMed

18.

Christensen JS, Mortensen LH, Roosli M et al (2012) Brain tumors in children and adolescents and exposure to animals and farm life: a multicenter case-control study (CEFALO). Cancer Causes Control 23:1463–1473. doi:10.1007/s10552-012-0020-0 CrossRefPubMed

19.

Searles Nielsen S, Mueller BA, Preston-Martin S, Farin FM, Holly EA, McKean-Cowdin R (2011) Childhood brain tumors and maternal cured meat consumption in pregnancy: differential effect by glutathione S-transferases. Cancer Epidemiol Biomark Prev 20:2413–2419. doi:10.1158/1055-9965.EPI-11-0196 CrossRef

20.

Peters S, Glass DC, Reid A, de Klerk N, Armstrong BK, Kellie S, Ashton LJ, Milne E, Fritschi L (2013) Parental occupational exposure to engine exhausts and childhood brain tumors. Int J Cancer 132:2975–2979. doi:10.1002/ijc.27972 CrossRefPubMed

21.

Northcott PA, Korshunov A, Pfister SM, Taylor MD (2012) The clinical implications of medulloblastoma subgroups. Nat Rev Neurol 8:340–351. doi:10.1038/nrneurol.2012.78 CrossRefPubMed

22.

Norgaard-Pedersen B, Hougaard DM (2007) Storage policies and use of the Danish Newborn Screening Biobank. J Inherit Metab Dis 30:530–536. doi:10.1007/s10545-007-0631-x CrossRefPubMed

Title: CCND2, CTNNB1, DDX3X, GLI2, SMARCA4, MYC, MYCN, PTCH1, TP53, and MLL2 gene variants and risk of childhood medulloblastoma
Authors: Anna M. Dahlin
Mads V. Hollegaard
Carl Wibom
Ulrika Andersson
David M. Hougaard
Isabelle Deltour
Ulf Hjalmars
Beatrice Melin
Publication date: 01-10-2015
Publisher: Springer US
Published in: Journal of Neuro-Oncology / Issue 1/2015
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI: https://doi.org/10.1007/s11060-015-1891-1

Keynote webinar | Spotlight on medication adherence

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

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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