Hereditary predisposition to childhood brain tumors an underappreciated challenge?
It has been well established that pathogenic germline mutations in genes like TP53, PTCH1, SUFU, APC, NF1, SMARCB1, SMARCA4, BRCA2 and the MMR genes are associated with an increased incidence of brain tumors. Most of them are associated with a specific type of brain tumor. It has been estimated that as many as 7-10% of all pediatric tumors (and brain tumors) are based on a highly penetrant germline mutation. However, this might still be an under-appreciation of this enormous clinical and scientific challenge. We have recently shown that ~20% of SHH-driven medulloblastomas have an underlying germline mutation in TP53, PTCH1, SUFU, BRCA2 or PALB2 when only focusing on known cancer predisposition genes. When then doing an unbiased genome-wide screen investigating all genes for truncating germline variants that are exceedingly rare in the normal population, we were able to identify another highly prevalent medulloblastoma predisposition gene, which we are currently futher analyzing in terms of co-occuring mutations and functional impact. This new finding increases the rate of SHH medulloblastomas with a clear germline predisposition to ~30%. It is very likely that similar findings will also further increase this proportion in other pediatric cancers. We are trying to address this question by a genome-wide pediatric cancer germline analysis performed on all publicly available data.
Assistante gestionnaire U830