Mirabello Lisa, Yeager Meredith, Mai Phuong L, Gastier-Foster Julie M, 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
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD (LM, PLM, SJC, SAS); Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD (MY, XZ, AV, KJ, JFB); Nationwide Children's Hospital and The Ohio State University Department of Pathology and Pediatrics, Columbus, OH (JMGF); Albert Einstein College of Medicine, The Children's Hospital at Montefiore, Bronx, NY (RG); Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD (CK); Department Of Pediatrics, University Clinic of Navarra, Universidad de Navarra, Pamplona, Spain (APG, LS, FL); University of Toronto, Litwin Centre for Cancer Genetics, Lunenfeld Tanenbaum Research Institute, Mt Sinai Hospital, Toronto, Ontario, Canada (ILA, JSW, NG); Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA (DAB).
J Natl Cancer Inst. 2015 Apr 20;107(7). doi: 10.1093/jnci/djv101. Print 2015 Jul.
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.
种系基因变异对散发性骨肉瘤的病因学贡献尚未完全明确。骨肉瘤是李-弗劳梅尼综合征（LFS）的标志性癌症，在符合经典标准的家庭中，约70%存在种系TP53突变。我们对765例骨肉瘤病例的TP53外显子进行了测序。数据采用χ²检验、逻辑回归和Cox比例风险回归模型进行分析。我们观察到，年轻骨肉瘤病例（年龄<30岁）中携带已知LFS相关或可能LFS相关突变（3.8%）或罕见外显子变异（5.7%）的频率较高，总体频率为9.5%，而30岁及以上的病例患者中未观察到此类情况（P<.001）。年轻骨肉瘤病例中TP53突变的高患病率在统计学上显著高于先前报道的3%（P = .0024）。我们在骨肉瘤诊断时发现了一种TP53罕见变异与转移之间的新关联（rs1800372，比值比 = 4.27，95%置信区间 = 1.2至15.5，P = .026）。年轻发病骨肉瘤的遗传易感性与老年成人发病骨肉瘤不同，LFS相关和罕见外显子TP53变异的频率较高。
