Copy-number alterations reshape the classification of diffuse intrinsic pontine gliomas. First exome sequencing results of the BIOMEDE trial.
Kergrohen, T.; Castel, D.; Le Teuff, G.; Tauziede-Espariat, A.; Lechapt-Zalcman, E.; Nysom, K.; Blomgren, K.; Leblond, P.; Bertozzi, A.-I.; De Carli, E.; Faure-Conter, C.; Chappe, C.; Entz-Werle, N.; Moussa, A.; Ghermaoui, S.; Barret, E.; Picot, S.; Sabourin-Cousin, M.; Beccaria, K.; Vassal, G.; Varlet, P.; Puget, S.; Grill, J.; Debily, M.-A.
Show abstract
Diffuse intrinsic pontine gliomas (DIPG) is an incurable neoplasm occurring mainly in children for which no progress was made in the last decades. The randomized phase II BIOMEDE trial compared three drugs (everolimus, dasatinib, erlotinib) combined with irradiation. The present report describes whole exome sequencing (WES) results for the first 100 patients randomized. Copy-number-Alteration (CNA) unsupervised clustering identified four groups with different outcomes and biology. This classification improved prognostication compared to models based on known biomarkers (Histone H3 and TP53 mutations). The cluster presenting complex genomic rearrangements was associated with significantly worse outcome and TP53 dysfunction. Mutation and CNA signatures confirmed the frequent alteration in DNA repair machinery. With respect to potential targetable pathways, PI3K/AKT/mTOR activation occurred in all the samples through multiples mechanisms. In conclusion, WES at diagnosis was feasible in most patients and provides a better patient stratification and theranostic information for precision medicine.
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