Common genetic variants associated with telomere length confer risk for neuroblastoma and other childhood cancers
Year: 2016
Type: article
Study design: Observational Study
Abstract: 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.
Source: Carcinogenesis
Institutions: University of California, San Francisco, Neurological Surgery, UCSF Helen Diller Family Comprehensive Cancer Center, University of California, Berkeley, University of Leicester, Glenfield Hospital, National Institute for Health and Care Research, NIHR Leicester Cardiovascular Biomedical Research Unit
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: Genetic Susceptibility to Pediatric Glioma inIndividuals and Diverse populations, Genome-Wide Association Study of Childhood Leukemia by Hispanic Status, Drug resistant pathways in relapsed acute lymphoblastic leukemia (ALL), PAAR4Kids-Pharmacogenomics of Anticancer Agents Research in Children, META-DAC - Managing Ethico-social and Technical issues and Administration of Data Access Committee, WTCCC2 core activities, Center for Integrative Research on Childhood Leukemia and the Environment, Glucocorticoids in Lymphoblastic Leukemia, Pharmacogenomics of Childhood Leukemia ALL, Support for Human Specimen Banking in NCI-Sponsored Clinical Trials-(CGB), Center for Integrative Research on Childhood Leukemia and the Environment, Telomere length measurement in UK Biobank: advancing understanding of biological ageing and age-related diseases, The Genetic Basis of Neuroblastoma Tumorigenesis, PDE4B and pharmacoethnicity of childhood leukemia, Pharmacogenomics of Racial Disparities in Childhood Leukemia Outcomes, Children's Oncology Group Chair's Grant, PHARMACOGENOMICS OF CHILDHOOD LEUKEMIA (ALL), The genetics of weight, BMI, adiposity and obesity, Training Program in Translational Brain Tumor Research, Cancer Center Support Grant (CCSG)
OpenAlex ID: W2323301362