Comprehensive germline-genomic and clinical profiling in 160 unselected children and adolescents with cancer

Rabea Wagener,Udo Kontny,Julia Taeubner,Carolin Walter,Christoph Bartenhagen,Michaela Kuhlen,Deya Alzoubi,Ute Fischer,Martin Dugas,Carl-Friedrich Classen,Julia Hauer,Arndt Borkhardt,Andishe Attarbaschi,Layal Yasin,Triantafyllia Brozou

doi:10.1038/s41431-021-00878-x

Abstract

In childhood cancer, the frequency of cancer-associated germline variants and their inheritance patterns are not thoroughly investigated. Moreover, the identification of children carrying a genetic predisposition by clinical means remains challenging. In this single-center study, we performed trio whole-exome sequencing and comprehensive clinical evaluation of a prospectively enrolled cohort of 160 children with cancer and their parents. We identified in 11/160 patients a pathogenic germline variant predisposing to cancer and a further eleven patients carried a prioritized VUS with a strong association to the cancerogenesis of the patient. Through clinical screening, 51 patients (31.3%) were identified as suspicious for an underlying cancer predisposition syndrome (CPS), but only in ten of those patients a pathogenic variant could be identified. In contrast, one patient with a classical CPS and ten patients with prioritized VUS were classified as unremarkable in the clinical work-up. Taken together, a monogenetic causative variant was detected in 13.8% of our patients using WES. Nevertheless, the still unclarified clinical suspicious cases emphasize the need to consider other genetic mechanisms including new target genes, structural variants, or polygenic interactions not previously associated with cancer predisposition.

Highlights

Cancer is a multifactorial disease associated with genetic as well as non-genetic risk factors
Using the following three parameters (i) Charger/CPSR classification, (ii) published data on the variant/gene, and (iii) clinical data of the patient, we identified in eleven patients prioritized variant of unknown significance (VUS), which we suspect to play a role in cancer predisposition. 6/11 patients carried a prioritized VUS in CHEK2, and three of them developed a B-precursor leukemia. 2/11 patients carried prioritized VUSs in NBN (Fig. 1, Table 2)
Genetic testing and the investigation of underlying cancer predisposition syndrome (CPS) in pediatric oncology are of great interest to the affected families, given the high participation acceptance rate of 90% (Supplementary Fig. 1)

Summary

Introduction

Cancer is a multifactorial disease associated with genetic as well as non-genetic risk factors. The frequency of detected predisposing germline variants varied between the different tumor entities. Other studies reported comparable frequencies of about 7–14% of childhood and adolescent cancer patients carrying pathogenic germline variants [1, 3]. These frequencies, quite similar, might be influenced by the workflow applied to identify pathogenic variants, as well as by the recruitment of the patients, since some studies preselected the patients based on their clinical outcome or clinical signs for CPS [3] or included only patients with a certain tumor type [4]

Methods

Results

Conclusion