Elsevier

European Journal of Cancer

Volume 179, January 2023, Pages 48-55
European Journal of Cancer

Original Research
Germline findings in patients with advanced malignancies screened with paired blood–tumour testing for personalised treatment approaches

https://doi.org/10.1016/j.ejca.2022.11.003Get rights and content

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.

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.

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.

References (35)

  • A. Zehir et al.

    Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients

    Nat Med

    (2017)
  • A.M. Tsimberidou et al.

    Initiative for molecular profiling and advanced cancer therapy (IMPACT): an MD Anderson precision medicine study

    JCO Precis Oncol

    (2017)
  • E.M. Fiala et al.

    Prospective pan-cancer germline testing using MSK-IMPACT informs clinical translation in 751 patients with pediatric solid tumors

    Nat Cancer

    (2021)
  • C. Massard et al.

    High-throughput genomics and clinical outcome in hard-to-treat advanced cancers: results of the MOSCATO 01 trial

    Cancer Discov

    (2017)
  • L. Mohrmann et al.

    Comprehensive genomic and epigenomic analysis in cancer of unknown primary guides molecularly-informed therapies despite heterogeneity

    Nat Commun

    (2022)
  • K.A. Schrader et al.

    Germline variants in targeted tumor sequencing using matched normal DNA

    JAMA Oncol

    (2016)
  • S.N. Grobner et al.

    The landscape of genomic alterations across childhood cancers

    Nature

    (2018)
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