Original ResearchGermline findings in patients with advanced malignancies screened with paired blood–tumour testing for personalised treatment approaches
Introduction
Advances in next-generation sequencing (NGS) technologies and their broad clinical availability have been instrumental in the rapid development of precision oncology in recent years [1]. The use of comprehensive NGS tumour panels targeting known predictive and prognostic biomarkers to identify potential drug targets has become a routine application for selected patients with advanced malignancies [[2], [3], [4]]. Interdisciplinary molecular tumour boards have been established with the intention to recommend personalised treatment options on the basis of clinical, pathological, medical imaging and genetic information. Although still in its infancy, this biology-driven approach has the potential to improve patient care and outcome [[5], [6], [7]].
While the primary focus of tumour diagnostics lies on the detection of personalised therapeutic options and prognostic markers, a relevant number of patients carries germline variants predisposing to cancer. Published data of adults and children with solid cancers indicate that a cancer predisposition syndrome can be detected in 8–18% of cases, depending on disease stage and tumour entity [4,[7], [8], [9], [10], [11], [12]]. The detection of a likely pathogenic or pathogenic (LP/P) germline variant in a cancer predisposition gene (CPG) is often not only relevant for the patient's treatment but also has important implications for family members and surveillance strategies (e.g. https://www.nccn.org). Interestingly, well-established clinical criteria to identify families at risk for cancer predisposition syndromes fail to detect a relevant fraction of patients with LP/P variants in CPGs [[11], [12], [13]]. In addition, previous literature suggests that paired normal–tumour testing could identify new associations between CPGs and cancer entities.
In this study, we describe the clinical implementation of germline findings as a part of tumour–normal diagnostics in a large cohort of more than thousand patients with solid tumours. Of particular interest, in this context are not only variants in CPGs and their distribution across different tumour entities but also mosaic mutations associated with haematopoiesis of indeterminate potential (CHIP).
Section snippets
Patient cohort
One thousand forty-eight oncology patients with mostly advanced stage cancer were referred to our department between January 2017 and May 2021 for tumour sequencing. In all the cases, the tumour was analysed in parallel with tumour-free tissue (usually blood). Overall, more than 80 different tumour types (classified upon histology and primary site) were analysed. The most common tumour types in our cohort were melanoma (25.4%), carcinoma of the intestine (13.6%), breast cancer (10.6%),
Results
The characteristics of 1048 oncology patients who underwent paired tumour–normal sequencing are listed in Table 1. The median age was 57 years (range 0–89) with 4.5% of patients being 18 years old or younger.
A total of 156 LP/P germline variants in CPGs were detected in 144 patients (13.7%). The distribution of germline variants in autosomal-dominant CPGs among different cancer entities can be found in Fig. 1 and further details are listed in the Supplementary Tables 2, 3 and 4.
Ninety-two
Discussion
Through routine application of paired blood–tumour testing for the identification of therapeutic targets in more than thousand patients with advanced cancer, we identified 13.7% of them to harbour a LP/P germline variant in a cancer susceptibility gene. The detection rate of clinically relevant germline variants in cancer susceptibility genes in this study was comparable to previous studies in advanced cancer patients [4,[8], [9], [10], [11], [12],21]. Small differences can be explained by
Funding
This work was supported by funds from the state of Baden-Württemberg within the Centers for Personalized Medicine Baden-Wuerttemberg (ZPM).
Ethical approval
This study was approved by the local ethics committee (project ID 528/2021BO2).
Data availability
Data is available from the authors upon reasonable request.
Author contributions
Cristiana Roggia: investigation, data curation, formal analysis, project administration, writing-original draft.
Sorin Armeanu Ebinger: conceptualization, data analysis and interpretation, methodology, writing-review and editing.
Axel Gschwind: software, methodology, data curation.
Olga Seibel Kelemen: methodology.
Sonja Hertler: methodology.
Ulrike Faust: methodology, formal analysis, writing-review and editing.
Alexandra Liebmann: conceptualization, writing-review and editing.
Tobias Haack:
Conflict of interest statement
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
The authors thank the patients and their families for contributing to this study. The authors thank Tanja Konrad and Marion Loitz for excellent support in patient management.
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