Jay S. Wunder

Abstract 5574: High prevalence of germline TP53 mutations in young osteosarcoma cases

Osteosarcoma, the most common primary bone malignancy, has a bimodal age distribution, with a primary peak in adolescence and a smaller peak in the elderly. The etiologic contribution of germline genetic variation to osteosarcoma is not well-understood. It occurs at higher than expected frequencies in individuals with the Li-Fraumeni syndrome (LFS) cancer predisposition syndrome. Approximately 70% of classic LFS families have germline TP53 mutations. Two previous studies reported that 3% of young osteosarcoma cases ( We determined the prevalence of germline TP53 mutations in 765 unselected osteosarcoma cases. DNA was extracted from blood and TP53 sequenced using custom Ampliseq panels. Variants were validated with Sanger sequencing. The IARC germline TP53 database was used to identify TP53 mutations reported in families with LFS (LFS-associated mutations). Variants were considered “likely LFS-associated mutations” if absent from publically available databases (ESP and 1,000 Genomes Project) and predicted non-functional or deleterious using in silico algorithms. Variants were considered “rare exonic variants” if their minor allele frequency (MAF) was There were 32 LFS-associated or rare TP53 variants in 62 osteosarcoma cases. The frequency of cases with an LFS or likely LFS-associated mutation and/or rare exonic variant was 8.1%. Notably, all 32 TP53 variants were present in cases A logistic regression case-case analysis identified a novel significant association between a rare TP53 variant, rs1800372 (p.R213R), and metastasis at diagnosis in cases of European ancestry (odds ratio [OR] 4.27, 95% CI 1.2-15.5, P = 0.026). We additionally confirmed that a common exonic variant, rs1042522 (p.P72R), was significantly associated with osteosarcoma risk (OR 1.22, 95% CI 1.1-1.4, P = 0.0098) and poorer survival (HR 1.35, 95% CI 1.00-1.83, P = 0.048). Our data suggest that genetic susceptibility to young onset osteosarcoma is distinct from adult onset osteosarcoma. The high TP53 mutation prevalence we identified in osteosarcoma cases aged Citation Format: Lisa J. Mirabello, Meredith Yeager, Phuong L. Mai, Julie Gastier-Foster, Richard Gorlick, Chand Khanna, Ana Patino-Garcia, Luis Sierrasesumaga, Fernando Lecanda, Irene L. Andrulis, Jay S. Wunder, Nalan Gokgoz, Donald A. Barkauskas, Xijun Zhang, Aurelie Vogt, Kristine Jones, Joseph F. Boland, Stephen J. Chanock, Sharon A. Savage. High prevalence of germline TP53 mutations in young osteosarcoma cases. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5574. doi:10.1158/1538-7445.AM2015-5574