FAM120A-PTPN3 variations in neuroblastoma: Implications for poor prognosis and relapse.

Abstract

e22512 Background: Neuroblastoma (NB), the most common tumor in infants, presents clinical unpredictability of relapse and treatment response. Staging and risk stratification depending on clinical examinations are often undertaken while molecular risk factors are less known. Relapse of high-risk NB remains the greatest clinical challenge. Thus, we conduct this study to investigate the molecular mechanism of NB relapse. Methods: Six patients with neuroblastoma who had both primary tumor and relapse samples were studied to identify key mutations in relapse. A cohort analysis of genetic profiles was then performed in order to find out gene mutations associated with the relapse samples. Mutation distribution and expression profiling in 127 patients from the national cancer institute database were used to identify relapse related gene networks. Kaplan-Meier analysis was performed for Overall survival (OS) on each mutation and Ingenuity pathway analysis (IPA) was consulted for their possible interactions. Gene manipulation in two neuroblastoma cell lines were used for verification. Results: We identified 40 potential mutations that associated with the relapse samples, including FAM120A and PTPN3. Mutation distribution in a larger NB population with 127 patients showed FAM120A mutation rate was 32.3% (41/127) and PTPN3 was 52.8% (67/127). Both had significant impact on OS. The median OS (mOS) with or without FAM120A mutation was 1527±214 days and 2300±139 days, respectively (p = 0.000). mOS with or without PTPN3 mutation was 1822±163 days and 2285±179 days, respectively (p = 0.037). Additionally, mOS in group lacking both mutations (42/127) was 2555±196 days, much higher than 1857±153 days, in those who had only one (62/127), or 1391±266 days, in those who had both (23/127). Furthermore, the prevalence of FAM120A mutation was at Chr.9:93543407 (61.0%, 25/41) and PTPN3 at Chr.9: 109457194 (61.2%, 41/67). Variant at Chr.9:93543407 had more significant impact on OS compared to other sites in FAM120A-mutation subgroup (p = 0.01). Expression of FAM120A was significantly down-regulated in the FAM120A-mutation subgroup compared to non-mutated (p = 0.01). IPA and in vitro assay showed these factors may have an additive effect possibly interacting through TRIM25, MYC and VIRMA. Conclusions: Our results suggest that variations in FAM120A and PTPN3 interact in neuroblastoma resulting in poor prognosis and cancer relapse, and may be a potential target for improvement of current treatment.