Germline TP53 variants and susceptibility to osteosarcoma

Lisa Mirabello, Meredith Yeager, Phuong L Mai, Julie M 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, Lisa Mirabello, Meredith Yeager, Phuong L Mai, Julie M 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

Abstract

The etiologic contribution of germline genetic variation to sporadic osteosarcoma is not well understood. Osteosarcoma is a sentinel cancer of Li-Fraumeni syndrome (LFS), in which approximately 70% of families meeting the classic criteria have germline TP53 mutations. We sequenced TP53 exons in 765 osteosarcoma cases. Data were analyzed with χ(2) tests, logistic regression, and Cox proportional hazards regression models. We observed a high frequency of young osteosarcoma cases (age <30 years) carrying a known LFS- or likely LFS-associated mutation (3.8%) or rare exonic variant (5.7%) with an overall frequency of 9.5%, compared with none in case patients age 30 years and older (P < .001). This high TP53 mutation prevalence in young osteosarcoma cases is statistically significantly greater than the previously reported prevalence of 3% (P = .0024). We identified a novel association between a TP53 rare variant and metastasis at diagnosis of osteosarcoma (rs1800372, odds ratio = 4.27, 95% confidence interval = 1.2 to 15.5, P = .026). Genetic susceptibility to young onset osteosarcoma is distinct from older adult onset osteosarcoma, with a high frequency of LFS-associated and rare exonic TP53 variants.

Published by Oxford University Press 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

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