BLM germline and somatic PKMYT1 and AHCY mutations: genetic variations beyond MYCN and prognosis in neuroblastoma

Abstract Neuroblastoma (NB) is the most common extra cranial solid tumor of childhood and often lethal in childhood. Clinical and biologic characteristics that are independently prognostic of outcome in NB are currently used for risk stratification to optimally the therapy. It includes age at diagnosis, International Neuroblastoma Staging System tumor histopathology and MYCN amplification. However, even in patients with theoretically good prognosis, such as localized tumor and non-amplified MYCN, either disease progress or recurrence may occur. Potential genetic determinants of this unfavorable behavior are not yet fully clarified. The presence of elevated expression of AHCY, PKMYT1, and BLM has accompanied poor prognosis MYCN-amplified neuroblastoma patients. Considering the potential implication of these genes on the clinical management of NB, we hypothesize that the identification of genetic variations may have significant impact during development of the recurrent or progressive disease. Using targeted DNA sequencing, we analyzed the mutation profiles of the genes PKMYT1, AHCY, and BLM in tumor samples of five patients with MYCN amplified and 15 MYCN non-amplified NB. In our study, BLM germline variants were detected in two patients with MYCN-non-amplified neuroblastoma. Our data allow us to hypothesize that, regardless of MYCN status, these mutations partially abolish BLM protein activity by impairing its ATPase and helicase activities. BLM mutations are also clinically relevant because BLM plays an important role in DNA damage repair and the maintenance of genomic integrity. We also found a novel variant in our cohort, PKMYT1 mutation localized in the C-terminal domain with effect unknown on NB. We hypothesize that this variant may affect the catalytic activity of PKMYT1 in NB, specifically when CDK1 is complexed to cyclins. The prognostic value of this mutation must be further investigated. Another mutation identified was a nonsynonymous variant in AHCY. This variant may be related to the slow progression of the disease, even in more aggressive cases. It affects the maintenance of the catalytic capacity of AHCY, leading to the consequent functional effects observed in the NB patients studied. In conclusion, our hypothesis may provide that mutations in BLM, AHCY and PKMYT1 genes found in children with MYCN-amplified or MYCN-non amplified neuroblastomas, may be associated with the prognosis of the disease.