title: TP53 p.R337H is a conditional cancer-predisposing mutation: further evidence from a homozygous patient.
abstract: BACKGROUND
  Adrenocortical carcinomas (ACCs) are among the most common childhood cancers occurring in infants affected with the Li-Fraumeni and Li- Fraumeni-like (LFS/LFL) syndromes, which are caused by dominant germline mutations in the TP53 gene. In Brazil, a particular mutation, occurring in the tetramerisation domain of the gene, p.R337H, is exceedingly common due to a founder effect and is strongly associated with ACC. In this report, we describe the phenotype and long-term clinical follow-up of a female child diagnosed with ACC and homozygous for the TP53 p.R337H founder mutation.
  
  
  METHODS
  At age 11 months, the patient was diagnosed with a virilising anaplastic adrenal cortical tumour, which was completely excised without disturbing the adrenal capsule. Family history was consistent with an LFL tumour pattern, and genotyping identified the TP53 p.R337H mutation in both alleles in genomic DNA from lymphocytes and fibroblasts. Haplotype analysis confirmed the occurrence of the mutation in the same founder haplotype previously described in other Brazilian patients. No other germline or somatic TP53 mutations or rearrangements were identified. At age 9 years, the child was asymptomatic and had no evidence of endocrine derangements. Full body and brain magnetic resonance imaging (MRI) failed to detect any suspicious proliferative lesions, and cardiopulmonary exercise testing results were within the normal reference for the child's age, ruling out a major exercise capacity deficiency.
  
  
  CONCLUSIONS
  This is the first clinical and aerobic functional capacity documentation of a patient who carries two mutant TP53 alleles and no wild-type allele. Our results support the hypothesis that TP53 p.R337H, the most common TP53 mutation ever described in any population, is a conditional mutant. Furthermore, our observations over a long period of clinical follow-up suggest that TP53 p.R337H homozygotes do not have a more severe disease phenotype than do heterozygote carriers of the same mutation. Patients with the homozygous TP53 p.R337H genotype will require careful surveillance for lifetime cancer risk and for effects on metabolic capacity later in life.
authors.forename: Juliana
authors.initials: J
authors.lastname: Giacomazzi
authors.forename: Simone
authors.initials: S
authors.lastname: Selistre
authors.forename: Juliana
authors.initials: J
authors.lastname: Duarte
authors.forename: Jorge Pinto
authors.initials: JP
authors.lastname: Ribeiro
authors.forename: Paulo J C
authors.initials: PJ
authors.lastname: Vieira
authors.forename: Gabriel
authors.initials: G
authors.lastname: de Souza Macedo
authors.forename: Cristina
authors.initials: C
authors.lastname: Rossi
authors.forename: Mauro
authors.initials: M
authors.lastname: Czepielewski
authors.forename: Cristina Brinkmann Oliveira
authors.initials: CB
authors.lastname: Netto
authors.forename: Pierre
authors.initials: P
authors.lastname: Hainaut
authors.forename: Patricia
authors.initials: P
authors.lastname: Ashton-Prolla
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D000328:Adult; D000368:Aged; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007223:Infant; D016864:Li-Fraumeni Syndrome / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011379:Prognosis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D055815:Young Adult
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53