Common genetic variants associated with telomere length confer risk for neuroblastoma and other childhood cancers
A partir de données portant sur des cas de cancers pédiatriques (1 516 neuroblastomes, 958 leucémies lymphoblastiques aiguës, 660 ostéosarcomes) et 6 892 témoins, cette étude identifie des polymorphismes à simple nucléotide de gènes associés à l’allongement des télomères leucocytaires et au risque de cancer
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 (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 inter-individual 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 8 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=7.9x10-7). 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.
http://carcin.oxfordjournals.org/content/early/2016/04/01/carcin.bgw037.abstract