Clinical trio genome sequencing facilitates the interpretation of variants in cancer predisposition genes in paediatric tumour patients

Abstract

The prevalence of pathogenic and likely pathogenic (P/LP) variants in genes associated with cancer predisposition syndromes (CPS) is estimated to be 8-18% for paediatric cancer patients. In more than half of the carriers, the family history is unsuspicious for CPS. Therefore, broad genetic testing could identify germline predisposition in additional children with cancer resulting in important implications for themselves and their families. We thus evaluated clinical trio genome sequencing (TGS) in a cohort of 72 paediatric patients with solid cancers other than retinoblastoma or CNS-tumours. The most prevalent cancer types were sarcoma (n = 26), neuroblastoma (n = 15), and nephroblastoma (n = 10). Overall, P/LP variants in CPS genes were identified in 18.1% of patients (13/72) and P/LP variants in autosomal-dominant CPS genes in 9.7% (7/72). Genetic evaluation would have been recommended for the majority of patients with P/LP variants according to the Jongmans criteria. Four patients (5.6%, 4/72) carried P/LP variants in autosomal-dominant genes known to be associated with their tumour type. With the immediate information on variant inheritance, TGS facilitated the identification of a de novo P/LP in NF1, a gonadosomatic mosaic in WT1 and two pathogenic variants in one patient (DICER1 and PALB2). TGS allows a more detailed characterization of structural variants with base-pair resolution of breakpoints which can be relevant for the interpretation of copy number variants. Altogether, TGS allows comprehensive identification of children with a CPS and supports the individualised clinical management of index patients and high-risk relatives.

Fig. 1. Summary of the study approach and patient cohorts.

A Study protocol and patient path used in this study. TGS Trio parent-child Genome Sequencing. B Overview of cancer types investigated in this study.

Fig. 2. Karyogram of a patient with mosaic variegated aneuploidy.

Karyotyping revealed several different numerical abnormalities in 10 of 23 analysed mitoses of patients PaedCan07. A Mitosis with 48,XY, + 7, + 15, B 48,XY, + 13, + 15. Panel C shows an example of a mitosis with premature chromatid separation, as it was found in about one third of the analysed cells.

Fig. 3. Patients with genetic findings and Jongmans criteria.

Yellow squares Jongmans criterium is fulfilled, na data not available, mos germline mosaicism, mat maternal, pat paternal, dn de-novo.