Germline findings in patients with advanced malignancies screened with paired blood–tumour testing for personalised treatment approaches. (January 2023)

• Record Type: Journal Article
• Authors: Roggia, Cristiana; Armeanu-Ebinger, Sorin; Gschwind, Axel; Seibel-Kelemen, Olga; Hertler, Sonja; Faust, Ulrike; Liebmann, Alexandra; Haack, Tobias B.; Neumann, Manuela; Bonzheim, Irina; Forschner, Andrea; Kopp, Hans-Georg; Herster, Franziska; Hartkopf, Andreas; Bitzer, Michael; Malek, Nisar P.; Brecht, Ines B.; Ruhm, Kristina; Möller, Yvonne; Löwenheim, Hubert; Ossowski, Stephan; Rieß, Olaf H.; Schroeder, Christopher
• Is Part Of: European journal of cancer. Volume 179(2023)
• Page Start: 48
• Page End: 55
• Publication Date: 2023-01
• Subjects: Next-generation sequencing -- Tumour–normal testing -- Precision oncology -- Personalised medicine -- Cancer predisposition syndrome; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2022.11.003
• Languages: English
• ISSNs: 0959-8049

Abstract

Abstract: Background: Sequencing of tumour tissue with comprehensive gene panels is increasingly used to guide treatment in precision oncology. Analysis of tumour–normal pairs allows in contrast to tumour-only assessment direct discrimination between somatic and germline alterations, which might have important implications not only for the patients but also their families. Methods: We performed tumour normal sequencing with a large gene panel in 1048 patients with advanced cancer to support treatment decision. Sequencing results were correlated with clinical and family data. Results: We identified 156 likely pathogenic or pathogenic (LP/P) germline variants in cancer predisposition genes (CPGs) in 144 cases (13.7%). Of all patients, 8.8% had a LP/P variant in autosomal-dominant cancer predisposition genes (AD-CPGs), most of them being genes with high or moderate penetrance ( ATM, BRCA2, CHEK2 and BRCA1 ). In 48 cases, the P/LP variant matched the expected tumour spectrum. A second variant in tumour tissue was found in 31 patients with AD-CPG variants. Low frequency mutations in either TP53, ATM or DNMT3A in the normal sample indicated clonal haematopoiesis in five cases. Conclusions: Tumour–normal testing for personalised treatment identifies germline LP/P variants in a relevant proportion of patients with cancer. The majority of them would not have been referred to genetic counselling based on family history. Indirect functional readouts of tumour–normal sequencing can provide novel links between CPGs and unexpected cancers. The interpretation of increasingly complex datasets in precision oncology is challenging and concepts of interdisciplinary personalised cancer prevention are needed to support patients and their families. Highlights: Significant amount of relevant germline variants is detected by blood-tumour testing. Carriers do not always fulfil clinical criteria for cancer predisposition. Blood–Tumour testing identifies novel links between cancer predisposition genes and cancer types. Family-specific screening strategies are required when cancer predisposition genes are found in atypical tumours.