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

Background: Sequencing of tumour tissue with comprehensive gene panels is increas-ingly 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 alter-ations, 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 pa-tients 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 vari-ants 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 inter-pretation of increasingly complex datasets in precision oncology is challenging and concepts of interdisciplinary personalised cancer prevention are needed to support patients and their fam-ilies.(c) 2022 Elsevier Ltd. All rights reserved.

Automated summary

Sequencing of tumour tissue with gene panels is used for precision oncology. Tumour-normal pairs allow discrimination between somatic and germline alterations, which is important for patients and families.