Integrated germline and somatic molecular profiling to detect cancer predisposition has a high clinical impact in poor-prognosis paediatric cancer
Fuentes-Bolanos, N. A.; Courtney, E.; Mayoh, C.; Warby, M.; Lau, L. M. S.; Wong-Erasmus, M.; Khuong-Quang, D.-A.; Barahona, P.; Padhye, B.; El-Kamand, S.; Nunag, S.; Ajuyah, P.; Sherstyuk, A.; Altekoester, A.-K.; Sullivan, A.; Poplawski, N.; Kiraly-Borri, C.; O'Sullivan, S.; Marfan, H.; Alli, R.; Curnow, L.; Bhatia, K.; Anazodo, A.; Trahair, T. N.; Mateos, M.; Hansford, J. R.; Dholaria, H.; Josephi-Taylor, S.; Moore, A. S.; Nicholls, W.; Gottardo, N. G.; Downie, P.; Khaw, S.-L.; Tapp, H.; McCowage, G.; Dalla-Pozza, L.; Alvaro, F.; Wood, P. J.; Tyrrell, V.; Haber, M.; Cowley, M. J.; Ekert, P. G
Show abstract
Germline predisposition has a significant role in paediatric cancer. However, the optimal approach to identifying cancer-causing germline pathogenic variants (GPV) in children, and even the prevalence of GPV among children with cancer, remain unclear. Here we report our findings from a comprehensive survey of GPV in 496 children with poor-prognosis cancer. By integrating tumour and germline molecular profiling we identified GPV in 15.5% of patients, 48.1% of whom had not met clinical genetic testing criteria. Although the cancer type was outside the recognised phenotypic spectrum for 43.7% of reported GPV, 63.2% of these were clinically actionable for cancer risk. Integrated germline-tumour analysis increased the GPV detection rate by 8.5%, and informed germline interpretation in 14.3% of patients with GPV, highlighting the value of integrated analyses. Our findings establish the benefit of broad integrated tumour-germline screening, over phenotype-guided testing, to detect GPV in children with poor prognosis cancers.
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