title: Germline TP53 variants and susceptibility to osteosarcoma.
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.
authors.affiliation: 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). mirabellol@mail.nih.gov.
authors.forename: Lisa
authors.initials: L
authors.lastname: Mirabello
authors.affiliation: 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).
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.affiliation: 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).
authors.forename: Phuong L
authors.initials: PL
authors.lastname: Mai
authors.affiliation: 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).
authors.forename: Julie M
authors.initials: JM
authors.lastname: Gastier-Foster
authors.affiliation: 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).
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
authors.affiliation: 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).
authors.forename: Chand
authors.initials: C
authors.lastname: Khanna
authors.affiliation: 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).
authors.forename: Ana
authors.initials: A
authors.lastname: Patiño-Garcia
authors.affiliation: 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).
authors.forename: Luis
authors.initials: L
authors.lastname: Sierrasesúmaga
authors.affiliation: 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).
authors.forename: Fernando
authors.initials: F
authors.lastname: Lecanda
authors.affiliation: 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).
authors.forename: Irene L
authors.initials: IL
authors.lastname: Andrulis
authors.affiliation: 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).
authors.forename: Jay S
authors.initials: JS
authors.lastname: Wunder
authors.affiliation: 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).
authors.forename: Nalan
authors.initials: N
authors.lastname: Gokgoz
authors.affiliation: 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).
authors.forename: Donald A
authors.initials: DA
authors.lastname: Barkauskas
authors.affiliation: 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).
authors.forename: Xijun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 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).
authors.forename: Aurelie
authors.initials: A
authors.lastname: Vogt
authors.affiliation: 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).
authors.forename: Kristine
authors.initials: K
authors.lastname: Jones
authors.affiliation: 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).
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Boland
authors.affiliation: 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).
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.affiliation: 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).
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Savage
mesh_terms: D000328:Adult; D017668:Age of Onset; D001859:Bone Neoplasms / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics; D008297:Male; D012516:Osteosarcoma / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53