Genome-wide association study identifies two susceptibility loci for osteosarcoma

Sharon A Savage, Lisa Mirabello, Zhaoming Wang, Julie M Gastier-Foster, Richard Gorlick, Chand Khanna, Adrienne M Flanagan, Roberto Tirabosco, Irene L Andrulis, Jay S Wunder, Nalan Gokgoz, Ana Patiño-Garcia, Luis Sierrasesúmaga, Fernando Lecanda, Nilgün Kurucu, Inci Ergurhan Ilhan, Neriman Sari, Massimo Serra, Claudia Hattinger, Piero Picci, Logan G Spector, Donald A Barkauskas, Neyssa Marina, Silvia Regina Caminada de Toledo, Antonio S Petrilli, Maria Fernanda Amary, Dina Halai, David M Thomas, Chester Douglass, Paul S Meltzer, Kevin Jacobs, Charles C Chung, Sonja I Berndt, Mark P Purdue, Neil E Caporaso, Margaret Tucker, Nathaniel Rothman, Maria Teresa Landi, Debra T Silverman, Peter Kraft, David J Hunter, Nuria Malats, Manolis Kogevinas, Sholom Wacholder, Rebecca Troisi, Lee Helman, Joseph F Fraumeni Jr, Meredith Yeager, Robert N Hoover, Stephen J Chanock, Sharon A Savage, Lisa Mirabello, Zhaoming Wang, Julie M Gastier-Foster, Richard Gorlick, Chand Khanna, Adrienne M Flanagan, Roberto Tirabosco, Irene L Andrulis, Jay S Wunder, Nalan Gokgoz, Ana Patiño-Garcia, Luis Sierrasesúmaga, Fernando Lecanda, Nilgün Kurucu, Inci Ergurhan Ilhan, Neriman Sari, Massimo Serra, Claudia Hattinger, Piero Picci, Logan G Spector, Donald A Barkauskas, Neyssa Marina, Silvia Regina Caminada de Toledo, Antonio S Petrilli, Maria Fernanda Amary, Dina Halai, David M Thomas, Chester Douglass, Paul S Meltzer, Kevin Jacobs, Charles C Chung, Sonja I Berndt, Mark P Purdue, Neil E Caporaso, Margaret Tucker, Nathaniel Rothman, Maria Teresa Landi, Debra T Silverman, Peter Kraft, David J Hunter, Nuria Malats, Manolis Kogevinas, Sholom Wacholder, Rebecca Troisi, Lee Helman, Joseph F Fraumeni Jr, Meredith Yeager, Robert N Hoover, Stephen J Chanock

Abstract

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.

Figures

Figure 1. Regional plots of loci associated…
Figure 1. Regional plots of loci associated with osteosarcoma
Regional plots of association results, recombination hotspots and linkage disequilibrium for the (a) 6p21.31:34,046,381–34,243,213 and (b) 2p25.2:6,280,533–6,473,384 osteosarcoma susceptibility loci. Association results from a trend test in –log10P values (y axis, left; gray diamonds, combined GWAS result; sky blue diamonds, TaqMan result; red diamonds, combined result) of the SNPs are shown according to their chromosomal positions (x axis). Linkage disequilibrium structure based on controls (n=2,703) was visualized by snp.plotter software. The line graph shows likelihood ratio statistics (y axis, right) for recombination hotspot by SequenceLDhot software and 5 different colors represent 5 tests of 100 controls without resampling. Physical locations are based on NCBI human genome build 36. Gene annotation was based on the NCBI RefSeq genes from the UCSC Genome Browser.
Figure 1. Regional plots of loci associated…
Figure 1. Regional plots of loci associated with osteosarcoma
Regional plots of association results, recombination hotspots and linkage disequilibrium for the (a) 6p21.31:34,046,381–34,243,213 and (b) 2p25.2:6,280,533–6,473,384 osteosarcoma susceptibility loci. Association results from a trend test in –log10P values (y axis, left; gray diamonds, combined GWAS result; sky blue diamonds, TaqMan result; red diamonds, combined result) of the SNPs are shown according to their chromosomal positions (x axis). Linkage disequilibrium structure based on controls (n=2,703) was visualized by snp.plotter software. The line graph shows likelihood ratio statistics (y axis, right) for recombination hotspot by SequenceLDhot software and 5 different colors represent 5 tests of 100 controls without resampling. Physical locations are based on NCBI human genome build 36. Gene annotation was based on the NCBI RefSeq genes from the UCSC Genome Browser.

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