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

Weber-Lassalle K1, Harter P2, Hauke J1, Ernst C1, Kommoss S3, Marmé F4, Weber-Lassalle N1, Prieske K5, Dietrich D6, Borde J1, Pohl-Rescigno E1, Reuss A7, Ataseven B2,8, Engel C9,10, Stingl JC11, Schmutzler RK1, Hahnen E1.

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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 3 out of 6 TP53-positive cases. In 3 out of 6 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. This article is protected by copyright. All rights reserved.