Pediatric rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children under 15 years of age. Due largely to its rarity, the etiology of pediatric RMS is poorly understood. Patterns of fetal growth were previously shown to be independent risk factors for RMS among non-Hispanic white (NHW) children; however, the underlying biologic mechanisms remain unclear. Alterations in the insulin-like growth factor (IGF) system, the primary regulator of growth during the fetal and early life period, may provide clues. Using an innovative linkage between the California birth records and cancer registry information, we conducted a population-based case-control study (1982-2009) of candidate genes involved in IGF signaling and risk of pediatric RMS. Fifteen genes involved in the IGF pathway were selected: IGF1, IGF2, IGF1R, IGF2R, IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, IGFBP6, INS, INSR, IRS1, GH1, and GHRH. DNA extracted from the archived newborn blood spots of all available RMS cases (n=644) was genotyped on the Illumina OmniExpress Exome array (n=964,043 SNPs); after stringent quality control (QC), a total of 633 RMS cases (360 embryonal RMS [eRMS] and 197 alveolar RMS [aRMS]) were available for analysis. A total of 815 controls genotyped on the Illumina OmniExpress Exome array and 3,922 controls genotyped on the Affymetrix Axion LAT array (n=801,830 SNPs) from the same base population of California children, with no evidence of RMS, were included in this analysis. After imputation to increase coverage of the genome and post-imputation QC to identify and remove platform effects, a total of 5,556,335 SNPs were available for analysis. Among NHW children, SNPs in IGF1 (rs10860869, p=0.0031) and IGF1R (rs62023616, p=0.00074; rs62023648, p=0.00076) were significantly associated with RMS risk after adjustment for multiple comparisons. Analyses stratified by histologic subtype showed that these associations were limited to eRMS, and of stronger magnitude. Among Hispanic children, 12 SNPs in IGF1R (p-value range: 0.0007-0.0027) and 3 SNPs in IGFBP1 (p-values: 0.0016-0.0023) were significantly associated with eRMS risk. The SNPs found to be associated with RMS were located in intergenic and intronic areas of the genes, areas that may influence gene regulation. Our results support the hypothesis that genetic variation in IGF1 signaling pathway modulate the risk of RMS, especially eRMS, among NHW and Hispanic children.

Citation Format: Libby Morimoto, XIaorong Shao, Anand Chokkalingam, Joseph Wiemels, Xiaomei Ma, Catherine Metayer. Pathway analysis of insulin-like growth factor candidate genes and risk of pediatric rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1273. doi:10.1158/1538-7445.AM2017-1273