Abstract 4593: Genome-wide association study identifies novel loci associated with osteosarcoma.
Authors: Savage Sharon A. , Mirabello Lisa , Wang Zhaoming , Gastier-Foster Julie , Gorlick Richard , Khanna Chand , Flanagan Adrienne M. , Tirabosco Roberto , Andrulis Irene L. , Wunder Jay , Gokgoz Nalan , Patino-Garcia Ana , Sierrasesumaga Luis , Lecanda Fernando , Kurucu Nilgun , Ilhan Inci Ergurhan , Sari Neriman , Serra Massimo , Hattinger Claudia , Picci Piero , Spector Logan , Barkauskas Donald A. , Marina Neyssa , Caminada de Toledo Siliva , Petrilli Sergio , Amary Maria Fernanda , Halai Dina , Thomas David , Douglass Chester , Meltzer Paul , Jacobs Kevin , Chung Charles C. , Berndt Sonja I. , Purdue Mark P. , Caporaso Neil E. , Tucker Margaret , Rothman Nathaniel , Landi Maria Teresa , Silverman Debra T. , Kraft Peter , Hunter David J. , Malats Nuria , Kogevinas Manolis , Wacholder Sholom , Troisi Rebecca , Helman Lee , Fraumeni Joseph F. , Yeager Meredith , Hoover Robert , Chanock Stephen J. 
Published: August 2014

Osteosarcoma (OS), the most common primary malignant bone tumor, has a peak incidence during the pubertal growth spurt. OS occurs at increased frequency in several inherited cancer syndromes (e.g., Li-Fraumeni and Rothmund Thomson syndromes). A limited number of common SNPs associated with OS have been identified in biologically plausible pathways (e.g., growth or DNA repair).

We developed an international, multi-institutional study in order to conduct the first genome-wide association study (GWAS) of OS. Participating subjects provided informed consent through local IRBs. Control subjects were cancer free adults derived from large studies in prior GWAS at the NCI. Genotyping of all cases was conducted using the Illumina OmniExpress SNP microarray chip platform in 2 phases. The first phase analyzed 910 osteosarcoma cases. After quality control filtering and assessment of population substructure, 596 cases of European (EUR) ancestry were advanced to the primary GWAS analysis (Phase 1A). We combined data from 2,703 previously genotyped controls drawn from 3 EUR cohorts. There was no evidence for significant population substructure differences between OS cases and controls. The association analysis (1-degree of freedom trend test) was adjusted for study, sex and 4 eigenvectors. The top 30 SNPs (P &lt;10-5) were genotyped by TaqMan in an additional 247 OS cases and 588 EUR controls. DNA from an additional 218 OS cases were subsequently scanned and, after the same quality filtering and population substructure analyses were applied, the data from 98 EUR cases were merged with the initial scan for the final analysis (Phase1B).

The fixed-effects meta-analysis of all 941 OS cases and 3,291 controls identified 2 regions that achieved genome-wide significance. The first, rs1906953 on 6p21.3, is associated with susceptibility to OS (P = 8.1x10-9, odds ratio [OR] 1.57, 95% confidence interval [CI] 1.35-1.83). rs1906953 is in intron 7 of GRM4. GRM4 is expressed in osteoblasts and osteoclasts and involved in glutamate signaling, which is suggested to be involved in cell differentiation and regulation of bone formation.

The second signal resides in an intergenic region on chromosome 2p25.2; rs7591996 (P = 1.0 x 10-8, OR 0.72, 95% CI 0.65-0.81). Another SNP in this region, rs10208273, is moderately correlated with the first signal (r2= 0.32) and approached genome-wide significance (P = 2.9 x 10-7, OR 1.35, 95% CI 1.21-1.52).

A third locus in the ADAMTS6 gene on 5q12.3 is promising but does not yet achieve genome-wide significance: rs17206779 (P = 5.1x10-7, OR 0.75, 95% CI 0.68-0.84). Notably, variants in genes encoding members of the ADAMTS protein family have been associated with height, a known OS risk factor.

We have conducted the first GWAS of OS and identified several novel loci associated with OS risk. Further investigation of these loci will advance understanding of OS etiology and biology.

Citation Format: Sharon A. Savage, Lisa Mirabello, Zhaoming Wang, Julie Gastier-Foster, Richard Gorlick, Chand Khanna, Adrienne M. Flanagan, Roberto Tirabosco, Irene L. Andrulis, Jay Wunder, Nalan Gokgoz, Ana Patino-Garcia, Luis Sierrasesumaga, Fernando Lecanda, Nilgun Kurucu, Inci Ergurhan Ilhan, Neriman Sari, Massimo Serra, Claudia Hattinger, Piero Picci, Logan Spector, Donald A. Barkauskas, Neyssa Marina, Siliva Caminada de Toledo, Sergio Petrilli, Maria Fernanda Amary, Dina Halai, David Thomas, Chester Douglass, Paul 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 Hoover, Stephen J. Chanock. Genome-wide association study identifies novel loci associated with osteosarcoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4593. doi:10.1158/1538-7445.AM2013-4593