Abstract 5574: High prevalence of germline TP53 mutations in young osteosarcoma cases
Authors: Mirabello Lisa J. , Yeager Meredith , Mai Phuong L. , Gastier-Foster Julie , Gorlick Richard , Khanna Chand , Patiño-Garcia Ana , Sierrasesúmaga Luis , Lecanda Fernando , Andrulis Irene L. , Wunder Jay S. , Gokgoz Nalan , Barkauskas Donald A. , Zhang Xijun , Vogt Aurelie , Jones Kristine , Boland Joseph F. , Chanock Stephen J. , Savage Sharon A. 
Published: August 2015

Abstract
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 (&lt;20 years old, N = 235) and 7% of all aged cases (N = 95) had germline TP53 mutations.
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 &lt;2% in public databases and they had uncertain clinical significance.
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 &lt;30 years of age (“young cases”, N = 505), 9.5% of young cases, compared with none in older cases (N = 51; P&lt;0.001). TP53 variants did not have an even distribution within the first three age decades in young cases. LFS or likely LFS-associated mutations, which confer significant cancer risk, had the highest frequency in patients aged 0-9 years (4.8% of all cases, and 6.1% of European cases), and rare exonic variants were most frequent in patients aged 10-19 years (6.1% of all cases, and 5.6% of European 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 &lt;20 years of 9.7% is significantly greater than the previously reported prevalence of 3% in unselected cases (P = 0.002). Based on these findings, genetic counseling and TP53-mutation testing of all young patients with osteosarcoma should be considered.
Citation Format: Lisa J. Mirabello, Meredith Yeager, Phuong L. Mai, Julie Gastier-Foster, Richard Gorlick, Chand Khanna, Ana Patiño-Garcia, Luis Sierrasesúmaga, 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