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

Human Mutation
Konstantin Weber-LassalleEric Hahnen

Abstract

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.

References

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Citations

May 28, 2020·European Journal of Human Genetics : EJHG·Thierry FrebourgUNKNOWN European Reference Network GENTURIS
Feb 26, 2020·Blood Advances·Christopher J Gibson, R Coleman Lindsley
Jul 1, 2020·American Society of Clinical Oncology Educational Book·Catherine C CoombsBrian D Crompton
Dec 28, 2019·The Journal of Molecular Diagnostics : JMD·Jessica L MesterKathleen S Hruska
Dec 18, 2020·Cancers·D Gareth EvansThierry Frebourg
Feb 23, 2021·British Journal of Haematology·Simon HusbyKirsten Grønbæk

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