Germline pathogenic SMARCA4 variants in neuroblastoma

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Germline pathogenic variants (GPVs) in *SMARCA4* are associated with rare tumor types.
• Increased *SMARCA4* germline testing has identified variants in various cancers.
• The role of *SMARCA4* in neuroblastoma (NBL) has not been fully established.

Purpose of the Study:

• To investigate the presence and significance of *SMARCA4* GPVs in patients with neuroblastoma.
• To determine if *SMARCA4* functions as a tumor suppressor in neuroblastoma.
• To assess whether neuroblastoma should be considered a *SMARCA4*-associated tumor.

Main Methods:

• Genetic analysis of 11 neuroblastoma patients for germline variants in *SMARCA4*.
• Somatic testing for loss of heterozygosity of the wild-type *SMARCA4* allele.
• Clinical data review including age at diagnosis, sex, and tumor location.

Main Results:

• Eleven patients with neuroblastoma harbored heterozygous germline variants in *SMARCA4*.
• Eight variants were predicted to cause loss-of-function, and four were missense.
• Loss of heterozygosity of the wild-type *SMARCA4* allele was observed in 8/8 cases with somatic testing.
• Tumor location was predominantly the adrenal gland in 8/9 cases.

Conclusions:

• Neuroblastoma should be included in the spectrum of *SMARCA4*-associated tumors.
• *SMARCA4* acts as a tumor suppressor in neuroblastoma, with loss of the wild-type allele being a key event.
• Germline *SMARCA4* variants are a potential predisposing factor for neuroblastoma.