1. Diagnosis of Li-Fraumeni Syndrome: Differentiating TP53 germline mutations from clonal hematopoiesis
- Author
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Jan Hauke, Christoph Engel, Esther Pohl-Rescigno, Stefan Kommoss, Philipp Harter, Julia C. Stingl, Julika Borde, Frederik Marmé, Dimo Dietrich, Nana Weber-Lassalle, Eric Hahnen, Katharina Prieske, Rita K. Schmutzler, Corinna Ernst, Beyhan Ataseven, Konstantin Weber-Lassalle, and Alexander Reuss
- Subjects
Adult ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,endocrine system diseases ,medicine.medical_treatment ,Biology ,Li-Fraumeni Syndrome ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,Internal medicine ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,neoplasms ,Gene ,Early Detection of Cancer ,Germ-Line Mutation ,Genetics (clinical) ,Aged ,Chemotherapy ,Case-control study ,DNA, Neoplasm ,Middle Aged ,medicine.disease ,Hematopoiesis ,Haematopoiesis ,030104 developmental biology ,Li–Fraumeni syndrome ,Case-Control Studies ,030220 oncology & carcinogenesis ,Female ,Observational study ,Tumor Suppressor Protein p53 ,Ovarian cancer - 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.
- Published
- 2018
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