title: Prevalence and functional consequence of TP53 mutations in pediatric adrenocortical carcinoma: a children's oncology group study.
abstract: OBJECTIVE
  Adrenocortical carcinoma (ACC) is a rare pediatric malignancy. It occurs in excess among individuals with the Li-Fraumeni syndrome, which results primarily from germline mutations in the TP53 gene. Prior series exploring frequencies of germline TP53 mutation among children with ACC have been small, geographically limited, or subject to referral bias. The functional consequence of mutations has not been related to phenotype. We provide a genotype-phenotype analysis of TP53 mutations in pediatric ACC and propose a model for tissue-specific effects based on adrenocortical ontogeny.
  
  
  METHODS
  Eighty-eight consecutive, unrelated children with ACC, unselected for family history, underwent germline TP53 sequencing. Rate and distribution of mutations were identified. Functional analysis was performed for novel TP53 variants. Correlation with the International Agency for Research on Cancer p53 database further delineated mutational distribution, association with family history, and risk for multiple primary malignancies (MPMs).
  
  
  RESULTS
  Germline mutations were present in 50% of children. These mutations did not correspond to the conventional hotspot mutations. There was a wide range of mutant protein function. Patients bearing alleles encoding protein with higher functionality were less likely to have a strong family cancer history, whereas those with greater loss of function had MPMs and/or positive family history. In patients with MPMs, ACC was the most frequent initial malignancy. Finally, we demonstrated age-dependent rates of TP53 mutation positivity.
  
  
  CONCLUSIONS
  TP53 mutations are prevalent in children with ACC but decline with age. Mutations result in a broad spectrum of functional loss. Effect of individual mutations may predict carrier and familial disease penetrance with potentially broad implications for clinical surveillance and counseling.
authors.affiliation: Jonathan D. Wasserman, Ana Novokmet, Claudia Eichler-Jonsson, and David Malkin, The Hospital for Sick Children; Jonathan D. Wasserman and David Malkin, University of Toronto; Jonathan D. Wasserman and David Malkin, SickKids Research Institute, Toronto, Ontario, Canada; Raul C. Ribeiro and Gerard P. Zambetti, St Jude Children's Research Hospital, Memphis, TN; and Carlos Rodriguez-Galindo, Dana-Farber/Children's Hospital Cancer Center, Harvard Medical School, Boston, MA. Jonathan.Wasserman@sickkids.ca.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Wasserman
authors.affiliation: Jonathan D. Wasserman, Ana Novokmet, Claudia Eichler-Jonsson, and David Malkin, The Hospital for Sick Children; Jonathan D. Wasserman and David Malkin, University of Toronto; Jonathan D. Wasserman and David Malkin, SickKids Research Institute, Toronto, Ontario, Canada; Raul C. Ribeiro and Gerard P. Zambetti, St Jude Children's Research Hospital, Memphis, TN; and Carlos Rodriguez-Galindo, Dana-Farber/Children's Hospital Cancer Center, Harvard Medical School, Boston, MA.
authors.forename: Ana
authors.initials: A
authors.lastname: Novokmet
authors.affiliation: Jonathan D. Wasserman, Ana Novokmet, Claudia Eichler-Jonsson, and David Malkin, The Hospital for Sick Children; Jonathan D. Wasserman and David Malkin, University of Toronto; Jonathan D. Wasserman and David Malkin, SickKids Research Institute, Toronto, Ontario, Canada; Raul C. Ribeiro and Gerard P. Zambetti, St Jude Children's Research Hospital, Memphis, TN; and Carlos Rodriguez-Galindo, Dana-Farber/Children's Hospital Cancer Center, Harvard Medical School, Boston, MA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Eichler-Jonsson
authors.affiliation: Jonathan D. Wasserman, Ana Novokmet, Claudia Eichler-Jonsson, and David Malkin, The Hospital for Sick Children; Jonathan D. Wasserman and David Malkin, University of Toronto; Jonathan D. Wasserman and David Malkin, SickKids Research Institute, Toronto, Ontario, Canada; Raul C. Ribeiro and Gerard P. Zambetti, St Jude Children's Research Hospital, Memphis, TN; and Carlos Rodriguez-Galindo, Dana-Farber/Children's Hospital Cancer Center, Harvard Medical School, Boston, MA.
authors.forename: Raul C
authors.initials: RC
authors.lastname: Ribeiro
authors.affiliation: Jonathan D. Wasserman, Ana Novokmet, Claudia Eichler-Jonsson, and David Malkin, The Hospital for Sick Children; Jonathan D. Wasserman and David Malkin, University of Toronto; Jonathan D. Wasserman and David Malkin, SickKids Research Institute, Toronto, Ontario, Canada; Raul C. Ribeiro and Gerard P. Zambetti, St Jude Children's Research Hospital, Memphis, TN; and Carlos Rodriguez-Galindo, Dana-Farber/Children's Hospital Cancer Center, Harvard Medical School, Boston, MA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodriguez-Galindo
authors.affiliation: Jonathan D. Wasserman, Ana Novokmet, Claudia Eichler-Jonsson, and David Malkin, The Hospital for Sick Children; Jonathan D. Wasserman and David Malkin, University of Toronto; Jonathan D. Wasserman and David Malkin, SickKids Research Institute, Toronto, Ontario, Canada; Raul C. Ribeiro and Gerard P. Zambetti, St Jude Children's Research Hospital, Memphis, TN; and Carlos Rodriguez-Galindo, Dana-Farber/Children's Hospital Cancer Center, Harvard Medical School, Boston, MA.
authors.forename: Gerard P
authors.initials: GP
authors.lastname: Zambetti
authors.affiliation: Jonathan D. Wasserman, Ana Novokmet, Claudia Eichler-Jonsson, and David Malkin, The Hospital for Sick Children; Jonathan D. Wasserman and David Malkin, University of Toronto; Jonathan D. Wasserman and David Malkin, SickKids Research Institute, Toronto, Ontario, Canada; Raul C. Ribeiro and Gerard P. Zambetti, St Jude Children's Research Hospital, Memphis, TN; and Carlos Rodriguez-Galindo, Dana-Farber/Children's Hospital Cancer Center, Harvard Medical School, Boston, MA.
authors.forename: David
authors.initials: D
authors.lastname: Malkin
mesh_terms: D000293:Adolescent; D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000367:Age Factors; D000483:Alleles; D063646:Carcinogenesis / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005192:Family Health; D005260:Female; D016158:Genes, p53; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D008297:Male; D009367:Neoplasm Staging; D019683:Penetrance; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D055815:Young Adult
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53