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Common genetic variants associated with telomere length confer risk for neuroblastoma and other childhood cancers.

Publication ,  Journal Article
Walsh, KM; Whitehead, TP; de Smith, AJ; Smirnov, IV; Park, M; Endicott, AA; Francis, SS; Codd, V; ENGAGE Consortium Telomere Group, ; Samani, NJ ...
Published in: Carcinogenesis
June 2016

Aberrant telomere lengthening is an important feature of cancer cells in adults and children. In addition to somatic mutations, germline polymorphisms in telomere maintenance genes impact telomere length. Whether these telomere-associated polymorphisms affect risk of childhood malignancies remains largely unexplored. We collected genome-wide data from three groups with pediatric malignancies [neuroblastoma (N = 1516), acute lymphoblastic leukemia (ALL) (N = 958) and osteosarcoma (N = 660)] and three control populations (N = 6892). Using case-control comparisons, we analyzed eight single nucleotide polymorphisms (SNPs) in genes definitively associated with interindividual variation in leukocyte telomere length (LTL) in prior genome-wide association studies: ACYP2, TERC, NAF1, TERT, OBFC1, CTC1, ZNF208 and RTEL1 Six of these SNPs were associated (P < 0.05) with neuroblastoma risk, one with leukemia risk and one with osteosarcoma risk. The allele associated with longer LTL increased cancer risk for all these significantly associated SNPs. Using a weighted linear combination of the eight LTL-associated SNPs, we observed that neuroblastoma patients were predisposed to longer LTL than controls, with each standard deviation increase in genotypically estimated LTL associated with a 1.15-fold increased odds of neuroblastoma (95%CI = 1.09-1.22; P = 7.9×10(-7)). This effect was more pronounced in adolescent-onset neuroblastoma patients (OR = 1.46; 95%CI = 1.03-2.08). A one standard deviation increase in genotypically estimated LTL was more weakly associated with osteosarcoma risk (OR = 1.10; 95%CI = 1.01-1.19; P = 0.017) and leukemia risk (OR = 1.07; 95%CI = 1.00-1.14; P = 0.044), specifically for leukemia patients who relapsed (OR = 1.19; 95%CI = 1.01-1.40; P = 0.043). These results indicate that genetic predisposition to longer LTL is a newly identified risk factor for neuroblastoma and potentially for other cancers of childhood.

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Published In

Carcinogenesis

DOI

EISSN

1460-2180

Publication Date

June 2016

Volume

37

Issue

6

Start / End Page

576 / 582

Location

England

Related Subject Headings

  • Young Adult
  • Telomere Homeostasis
  • Proteins
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Polymorphism, Single Nucleotide
  • Osteosarcoma
  • Oncology & Carcinogenesis
  • Neuroblastoma
  • Leukocytes
  • Humans
 

Citation

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Chicago
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Walsh, K. M., Whitehead, T. P., de Smith, A. J., Smirnov, I. V., Park, M., Endicott, A. A., … Wiemels, J. L. (2016). Common genetic variants associated with telomere length confer risk for neuroblastoma and other childhood cancers. Carcinogenesis, 37(6), 576–582. https://doi.org/10.1093/carcin/bgw037
Walsh, Kyle M., Todd P. Whitehead, Adam J. de Smith, Ivan V. Smirnov, Minsun Park, Alyson A. Endicott, Stephen S. Francis, et al. “Common genetic variants associated with telomere length confer risk for neuroblastoma and other childhood cancers.Carcinogenesis 37, no. 6 (June 2016): 576–82. https://doi.org/10.1093/carcin/bgw037.
Walsh KM, Whitehead TP, de Smith AJ, Smirnov IV, Park M, Endicott AA, et al. Common genetic variants associated with telomere length confer risk for neuroblastoma and other childhood cancers. Carcinogenesis. 2016 Jun;37(6):576–82.
Walsh, Kyle M., et al. “Common genetic variants associated with telomere length confer risk for neuroblastoma and other childhood cancers.Carcinogenesis, vol. 37, no. 6, June 2016, pp. 576–82. Pubmed, doi:10.1093/carcin/bgw037.
Walsh KM, Whitehead TP, de Smith AJ, Smirnov IV, Park M, Endicott AA, Francis SS, Codd V, ENGAGE Consortium Telomere Group, Samani NJ, Metayer C, Wiemels JL. Common genetic variants associated with telomere length confer risk for neuroblastoma and other childhood cancers. Carcinogenesis. 2016 Jun;37(6):576–582.
Journal cover image

Published In

Carcinogenesis

DOI

EISSN

1460-2180

Publication Date

June 2016

Volume

37

Issue

6

Start / End Page

576 / 582

Location

England

Related Subject Headings

  • Young Adult
  • Telomere Homeostasis
  • Proteins
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Polymorphism, Single Nucleotide
  • Osteosarcoma
  • Oncology & Carcinogenesis
  • Neuroblastoma
  • Leukocytes
  • Humans