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

doi:10.1093/jnci/djv101

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

Pediatrics

Research output: Contribution to journal › Article › peer-review

97 Scopus citations

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 χ² 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.

Original language	English (US)
Journal	Journal of the National Cancer Institute
Volume	107
Issue number	7
DOIs	https://doi.org/10.1093/jnci/djv101
State	Published - Jul 1 2015

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

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10.1093/jnci/djv101

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Mirabello, L., Yeager, M., Mai, P. L., Gastier-Foster, J. M., Gorlick, R., Khanna, C., Patiño-Garcia, A., Sierrasesúmaga, L., Lecanda, F., Andrulis, I. L., Wunder, J. S., Gokgoz, N., Barkauskas, D. A., Zhang, X., Vogt, A., Jones, K., Boland, J. F., Chanock, S. J., & Savage, S. A. (2015). Germline TP53 Variants and Susceptibility to Osteosarcoma. Journal of the National Cancer Institute, 107(7). https://doi.org/10.1093/jnci/djv101

Mirabello, L, Yeager, M, Mai, PL, Gastier-Foster, JM, Gorlick, R, Khanna, C, Patiño-Garcia, A, Sierrasesúmaga, L, Lecanda, F, Andrulis, IL, Wunder, JS, Gokgoz, N, Barkauskas, DA, Zhang, X, Vogt, A, Jones, K, Boland, JF, Chanock, SJ & Savage, SA 2015, 'Germline TP53 Variants and Susceptibility to Osteosarcoma', Journal of the National Cancer Institute, vol. 107, no. 7. https://doi.org/10.1093/jnci/djv101

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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 χ2 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.",

author = "Lisa Mirabello and Meredith Yeager and Mai, {Phuong L.} and Gastier-Foster, {Julie M.} and Richard Gorlick and Chand Khanna and Ana Pati{\~n}o-Garcia and Luis Sierrases{\'u}maga and Fernando Lecanda and Andrulis, {Irene L.} and Wunder, {Jay S.} and Nalan Gokgoz and Barkauskas, {Donald A.} and Xijun Zhang and Aurelie Vogt and Kristine Jones and Boland, {Joseph F.} and Chanock, {Stephen J.} and Savage, {Sharon A.}",

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AU - Yeager, Meredith

AU - Mai, Phuong L.

AU - Gastier-Foster, Julie M.

AU - Gorlick, Richard

AU - Khanna, Chand

AU - Patiño-Garcia, Ana

AU - Sierrasesúmaga, Luis

AU - Lecanda, Fernando

AU - Andrulis, Irene L.

AU - Wunder, Jay S.

AU - Gokgoz, Nalan

AU - Barkauskas, Donald A.

AU - Zhang, Xijun

AU - Vogt, Aurelie

AU - Jones, Kristine

AU - Boland, Joseph F.

AU - Chanock, Stephen J.

AU - Savage, Sharon A.

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N2 - 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 χ2 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.

AB - 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 χ2 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.

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Germline TP53 Variants and Susceptibility to Osteosarcoma

Abstract

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