Clinical spectrum of Li-Fraumeni syndrome/Li-Fraumeni-like syndrome in Brazilian individuals with the TP53 p.R337H mutation

J Steroid Biochem Mol Biol. 2019 Jun:190:250-255. doi: 10.1016/j.jsbmb.2019.04.011. Epub 2019 Apr 8.


Background: The TP53 p.R337H germline mutation is highly prevalent among children with adrenocortical tumors (ACTs) from South and Southeast Brazil. However, the prevalence of other tumors of the Li-Fraumeni syndrome (LFS) and Li-Fraumeni-like syndrome (LFL) spectrum, the clinical outcomes and the potential tumor occurrence in relatives carrying this distinct TP53 mutation were not fully investigated.

Patients and methods: We investigated tumor profile data and outcomes of individuals and their close relatives with the TP53 p.R337H germline mutation. A questionnaire and the Toronto protocol were used for evaluation of asymptomatic carriers of this TP53 mutation.

Results: The cohort of this study comprised 51 patients from 46 different families; 67% were female. All but one harbored the TP53 p.R337H mutation in heterozygous state; only one child was homozygous for this variant. Maternal allele inheritance occurred in 72% of the cases (p= 0,002). In pediatric group, ACT was the most common primary tumor at the diagnosis (55%; median age= 2 years). No patient of the pediatric group who initially presented with ACT developed a second primary tumor and 11% (n= 3) died due to complications related to the primary tumor (median follow-up time of 81.5 months, range= 3-378 months). In adult group, the main tumors at diagnosis were: adrenocortical carcinoma (ACC) (23%; median age= 29.5 years), breast cancer (12%; median age= 38.5 years), soft tissue sarcoma (8%; median age= 50.3 years) and choroid plexus carcinoma (CPC) (2%; median age= 18 years). Among adult patients who were diagnosed with ACC as the first primary tumor, all presented with aggressive disease as per histologic and clinical criteria at diagnosis, and 75% of patients died (median follow-up time of 19 months, range= 1-69 months). Five adult patients (22%) had a second primary tumor, including bronchoalveolar lung cancer (2 cases), ACC, uterine cervical carcinoma and fibrosarcoma. The diagnosis of these tumors was established from 8 to 36 months after the first primary tumor. Three families presented more than one case of ACT. Nine malignant neoplasms were diagnosed in asymptomatic carriers using Toronto protocol.

Conclusions: This study confirms a high frequency of TP53 p.R337H mutation in pediatric group with ACT. In addition, we observed the occurrence of other tumors of LFS/LFL spectrum and a difference in the aggressiveness of ACTs depending on the age group in which they were diagnosed. The predominance of maternal mutated allele inheritance was first demonstrated in the affected Brazilian's families.

Keywords: Li-Fraumeni syndrome; P.R337H mutation; Pediatric adrenocortical tumor; TP53 gene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adrenal Cortex Neoplasms / epidemiology
  • Adrenal Cortex Neoplasms / genetics*
  • Adult
  • Brazil / epidemiology
  • Child
  • Child, Preschool
  • Cohort Studies
  • Female
  • Germ-Line Mutation
  • Humans
  • Infant
  • Li-Fraumeni Syndrome / epidemiology
  • Li-Fraumeni Syndrome / genetics*
  • Male
  • Middle Aged
  • Point Mutation
  • Tumor Suppressor Protein p53 / genetics*
  • Young Adult


  • TP53 protein, human
  • Tumor Suppressor Protein p53

Supplementary concepts

  • Li-Fraumeni-Like Syndrome