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

Konstantin Weber-Lassalle, Philipp Harter, Jan Hauke, Corinna Ernst, Stefan Kommoss, Frederik Marmé, Nana Weber-Lassalle, Katharina Prieske, Dimo Dietrich, Julika Borde, Esther Pohl-Rescigno, Alexander Reuss, Beyhan Ataseven, Christoph Engel, Julia C Stingl, Rita K Schmutzler, Eric Hahnen

Journal: Human mutation 2019;39(12):2040-2046

PMID: 30216591

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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 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.

Address: Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany.; Department of Gynecology & Gynecologic Oncology, Kliniken Essen-Mitte, Essen, Germany.; Department of Women's Health, Tübingen University Hospital, Tübingen, Germany.; Department of Gynecologic Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.; Department of Obstetrics and Gynecology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.; Department of Gynecology and Gynecologic Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Bonn, Germany.; Coordinating Center for Clinical Trials, Philipps-University of Marburg, Marburg, Germany.; Department of Gynecology & Gynecologic Oncology, Kliniken Essen-Mitte, Essen, Germany.; Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Germany.; Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.; LIFE-Leipzig Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany.; Research Division, Federal Institute for Drugs & Medical Devices, Bonn, Germany.

DOI: 10.1002/humu.23653

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MeSH Terms: Adult, Aged, Case-Control Studies, DNA, Neoplasm, Early Detection of Cancer, Female, Genetic Predisposition to Disease, Germ-Line Mutation, Hematopoiesis, Humans, Li-Fraumeni Syndrome, Middle Aged, Tumor Suppressor Protein p53