Diagnosis of Li-Fraumeni Syndrome: Differentiating TP53 germline mutations from clonal hematopoiesis: Results of the observational AGO-TR1 trial

Hum Mutat. 2018 Dec;39(12):2040-2046. doi: 10.1002/humu.23653. Epub 2018 Oct 3.


The Li-Fraumeni cancer predisposition syndrome (LFS1) presents with a variety of tumor types and the TP53 gene is covered by most diagnostic cancer gene panels. We demonstrate that deleterious TP53 variants identified in blood-derived DNA of 523 patients with ovarian cancer (AGO-TR1 trial) were not causal for the patients' ovarian cancer in three out of six TP53-positive cases. In three out of six patients, deleterious TP53 mutations were identified with low variant fractions in blood-derived DNA but not in the tumor of the patient seeking advice. The analysis of the TP53 and PPM1D genes, both intimately involved in chemotherapy-induced and/or age-related clonal hematopoiesis (CH), in 523 patients and 1,053 age-matched female control individuals revealed that CH represents a frequent event following chemotherapy, affecting 26 of the 523 patients enrolled (5.0%). Considering that TP53 mutations may arise from chemotherapy-induced CH, our findings help to avoid false-positive genetic diagnoses of LFS1.

Keywords: Li-Fraumeni syndrome; PPM1D; TP53; chemotherapy; clonal hematopoiesis.

Publication types

  • Clinical Trial
  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Case-Control Studies
  • DNA, Neoplasm / blood*
  • Early Detection of Cancer
  • Female
  • Genetic Predisposition to Disease
  • Germ-Line Mutation*
  • Hematopoiesis
  • Humans
  • Li-Fraumeni Syndrome / diagnosis*
  • Li-Fraumeni Syndrome / genetics
  • Middle Aged
  • Tumor Suppressor Protein p53 / blood
  • Tumor Suppressor Protein p53 / genetics*


  • DNA, Neoplasm
  • TP53 protein, human
  • Tumor Suppressor Protein p53