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Savage S.A.,U.S. National Institutes of Health | Mirabello L.,U.S. National Institutes of Health | Wang Z.,U.S. National Cancer Institute | Gastier-Foster J.M.,Nationwide Childrens Hospital | And 51 more authors.
Nature Genetics | Year: 2013

Osteosarcoma is the most common primary bone malignancy of adolescents and young adults. To better understand the genetic etiology of osteosarcoma, we performed a multistage genome-wide association study consisting of 941 individuals with osteosarcoma (cases) and 3,291 cancer-free adult controls of European ancestry. Two loci achieved genome-wide significance: a locus in the GRM4 gene at 6p21.3 (encoding glutamate receptor metabotropic 4; rs1906953; P = 8.1 × 10 -9) and a locus in the gene desert at 2p25.2 (rs7591996 and rs10208273; P = 1.0 × 10 -8 and 2.9 × 10 -7, respectively). These two loci warrant further exploration to uncover the biological mechanisms underlying susceptibility to osteosarcoma. © 2013 Nature America, Inc. All rights reserved.

PubMed | Karolinska Institutet, Brown University, International Agency for Research on Cancer IARC WHO, Complex Traits Genetics Team and. and 130 more.
Type: Journal Article | Journal: Human molecular genetics | Year: 2014

Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 10(-39); Region 3: rs2853677, P = 3.30 10(-36) and PConditional = 2.36 10(-8); Region 4: rs2736098, P = 3.87 10(-12) and PConditional = 5.19 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 10(-6); and Region 6: rs10069690, P = 7.49 10(-15) and PConditional = 5.35 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 10(-18) and PConditional = 7.06 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.

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