Whole-exome analysis of a Li-Fraumeni family trio with a novel TP53 PRD mutation and anticipation profile

Carcinogenesis. 2017 Sep 1;38(9):938-943. doi: 10.1093/carcin/bgx069.


Li-Fraumeni syndrome is a clinically heterogeneous familial cancer predisposition syndrome with autosomal-dominant inheritance caused by heterozygous germline mutations in the TP53 gene. We here analyze the genetic background of a family with a 4-year-proband presented with a Li-Fraumeni tumor. The mother developed breast cancer at age 37 and the proband died at age 8. We performed Sanger sequencing and whole-exome sequencing on peripheral blood DNA from proband and relatives. Data analysis selected only high-quality score and depth reads, rare variants and protein impact involving missense, non-sense, frameshift and splice disrupt mutations. Disease implicated variants and predicted deleterious alterations were also chosen. TP53 genetic testing revealed a never reported TP53 deletion arose as de novo mutation in the mother and inherited by the proband. We then performed whole-exome analysis of the trio to uncover inherited variants from the father that potentially worsen the already altered genetic background in the proband. No pathogenic variants were inherited in autosomal recessive, de novo dominant or X-linked recessive manner. Comparing proband and father exome we detected 25 predicted deleterious variants including a nonsense mutation in ERCC3. Those inherited mutations are possible candidate modifiers linked to TP53, explaining the proband accelerated tumor onset compared to the mother and providing a possible explanation of the genetic anticipation event in this Li-Fraumeni family.

MeSH terms

  • Adrenocortical Carcinoma / therapy
  • Anticipation, Genetic*
  • Breast Neoplasms / genetics*
  • Child, Preschool
  • DNA Helicases / genetics
  • DNA-Binding Proteins / genetics
  • Exome / genetics
  • Female
  • Genes, p53
  • Genetic Predisposition to Disease
  • Genetic Testing
  • Germ-Line Mutation
  • Heterozygote
  • Humans
  • Li-Fraumeni Syndrome / genetics*
  • Lymphatic Metastasis
  • Male
  • Pedigree
  • Sequence Analysis, DNA
  • Sequence Deletion
  • Tumor Suppressor Protein p53 / genetics*


  • DNA-Binding Proteins
  • Tumor Suppressor Protein p53
  • XPBC-ERCC-3 protein
  • DNA Helicases

Supplementary concepts

  • Adrenocortical Carcinoma, Pediatric