512P - Heterozygous germline Fanconi anemia-related gene mutations increase susceptibility to central nervous system germ cell tumors

Background

Central nervous system germ cell tumors (CNS GCTs) are a group of rare heterogeneous CNS tumors. CNS GCTs are usually in midline location and mainly affect children and adolescents. The incidence of CNS GCTs is higher in Asia (11%) than that in Western Europe (4%) with a male predominance. The different tumor distribution demographically and high incidence in East Asia suggests a probable genetic background.

Methods

We collected samples including tissue and blood leukocyte control from 17 patients with CNS GCTs. All samples were tested using a 551-cancer related gene profiling, and somatic mutations, TMB, MSI and germline mutations were analyzed. The pathogenicity of germline mutations was categorized based on American College of Medical Genetics and Genomics guidelines. We screened out the pathogenic and likely pathogenic (P/LP) mutations of germline mutations and calculated the relative risk (RR) in our cohort compared to that in a control population (gnomAD). Then the relationship between mutation characteristics and clinical features were further analyzed, as well as the correlation with patient prognosis.

Results

In 17 patients with CNS GCTs, 4 patients (4/17) were found harboring germline pathogenic or likely-pathogenic mutations, respectively, in FANCA, FANCD2, FANCE, SDHA. All the four genes are Fanconi anemia (FA)-related genes. The RR of total FA mutations in patients with CNS GCTs was 21.589 (95% CI, 28.934-257.728; P value, 3.22E-07) compared to gnomAD controls. Then the 17 patients were divided into two groups, the FA group (with FA-related gene heterozygous germline P/LP mutations) and the non-FA group (without P/LP mutation). The results showed that pathological classification (P=0.00588) and site of lesion (P=0.00714) were significantly different in the two groups. There was no significant difference in gender, age and TMB between the two groups. The 4 recurrent patients were all in the non-FA group, but there was no statistical difference in prognosis between the two groups.

Conclusions

FA-related gene germline P/LP mutations increase the susceptibility to CNS GCTs. Moreover, the germline FA mutation may be related to the pathological subtype, site of lesion and prognosis, which needs to be verified with a large sample.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.