Identifizierung von Patientinnen und Patienten mit der hereditären Form des Mamma- und Ovarialkarzinoms mittels Next-Generation-Sequencing-(NGS)-Technologie

Identifizierung von Patientinnen und Patienten mit der hereditären Form des Mamma- und Ovarialkarzinoms mittels Next-Generation-Sequencing-(NGS)-Technologie

Identification of patients with hereditary breast and ovarial cancer with next generation technology

Mateja Smogavec

Doctoral thesis

Date of Examination: 2019-06-26

Date of issue: 2019-06-11

Advisor: Burfeind, Peter Prof. Dr.

Referee: Ströbel, Philipp Prof. Dr.

Referee: Schön, Margarete Prof. Dr.

Persistent Address: http://hdl.handle.net/21.11130/00-1735-0000-0003-C127-7

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Abstract

English

Breast cancer is the most frequent malignant female cancer. Beside sporadic forms, 5 % - 10 % of these cancers show a hereditary origin with an identified germline mutation. The main purpose of this study was to analyse DNA-probes from 200 patients with a suspicion of having a hereditary form of breast and ovarian cancer and identify those with a causative mutation in one of 10 core genes (ATM, BRCA1, BRCA2, CHEK2, CDH1, NBN, PALB2, RAD51C, RAD51D and TP53) with a multiple gene panel and next generation sequencing (NGS) technology. The identified variants were compared with clinical and tumor characteristics of the analysed patients. A total of 108 variants of unknown significance and likely pathogenic and pathogenic mutations have been identified among 88 of analysed patients. The mutation detection rate was at 18 %. These data were compared to clinical data of the patients (for example: age at diagnosis, tumor type, receptor status of the breast cancer) and already published data. It could be for example shown, that the mutation detection rate was significantly higher among patients with triple-negative breast cancer as with patients with other receptor status. The detection rate of variants in the 10 core genes has been compared with the detection rate of retrospective patients, which only underwent a genetic analysis of BRCA1 and BRCA2 genes with Sanger sequencing. Furthermore, four patients among the analysed cohort and one additional patient had further genetic analyses to delineate the importance of identified variant. It could be shown that NGS has an important role in the detection of hereditary breast and ovarian cancer and should be used in the daily routine diagnostics.

Keywords: Next generation sequencing; Hereditary breast and ovarian cancer