Weber-Lassalle, Konstantin (2022). Identifying blood-specific biomarkers for therapy-related clonal hematopoiesis in patients with hereditary or non-hereditary ovarian cancer. PhD thesis, Universität zu Köln.
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Dissertation Konstantin Weber-Lassalle Veroeffentlichung.pdf Download (2MB) |
Abstract
As part of my dissertation project, I was able to demonstrate for the first time that pathogenic germline variants (PVs) in the BARD1 gene, a direct interaction partner of the encoded protein of BRCA1, are associated with early onset of familial breast cancer (BC) but not ovarian cancer (OC). Based on these results, the BARD1 gene was re-evaluated by the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) and included as "core gene" in the TruRisk® panel analysis as a BC risk gene. Now intensified BC surveillance programs can be offered specifically for younger women carrying germline PVs in BARD1. In the second part of the project, I identified two robust biomarkers (PPM1D and TP53) for chemotherapy-induced clonal hematopoiesis (CH). Since there is no diagnostic tool to detect early precursors, such as a CH, of therapy-induced tumors, the new findings were directly incorporated into the evaluation of TP53 mutations in routine diagnostics through an updated SOP for the Center for Familial Breast and Ovarian Cancer in Cologne and all centers of the GC-HBOC. Since the detection of PVs in the tumor suppressor gene TP53 in the blood sample of an index patient in the context of genetic counseling for familial BC/OC alone does not allow a statement about clinical relevance, it must be clarified in the following whether the PV is causal for tumorigenesis. For this purpose, the examination of a second tissue not originating from the hematopoietic system is mandatory to avoid misdiagnosis (e.g. Li-Fraumeni syndrome). Our secondary analysis of the AGO-TR1 study showed that positive germline BRCA1/2 mutation status is not a risk factor for acquiring CH-associated gene mutations. Consequently, patients with heterozygous germline PVs in the BRCA1/2 risk genes are not more prone to CH than patients without these PVs. The number of prior lines of chemotherapy alone appears to be the main risk factor for the development of therapy-related myeloid neoplasia (t-MN) in the patients studied. In the future, collection of blood samples at defined intervals from patients after exposure to chemotherapeutic agents, followed by a specific biomarker assay for CH-associated gene mutations, may allow both early detection of t-MN and optimized clinical management of patients at increased risk for the aforementioned hematologic disorders.
Item Type: | Thesis (PhD thesis) | ||||||||||
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URN: | urn:nbn:de:hbz:38-640211 | ||||||||||
Date: | 2022 | ||||||||||
Language: | English | ||||||||||
Faculty: | Faculty of Medicine | ||||||||||
Divisions: | Faculty of Medicine > Sonstiges > Centrum für integrierte Onkologie (CIO) | ||||||||||
Subjects: | Natural sciences and mathematics Life sciences Medical sciences Medicine |
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Date of oral exam: | 26 September 2022 | ||||||||||
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Refereed: | Yes | ||||||||||
URI: | http://kups.ub.uni-koeln.de/id/eprint/64021 |
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