Biallelic loss of GNAS in a patient with pediatric medulloblastoma

Abstract

Genome sequencing was performed on matched normal and tumor tissue from a 6.5-yr-old boy with a diagnosis of recurrent medulloblastoma. A pathogenic heterozygous c.432+1G>A canonical splice donor site variant in GNAS was detected on analysis of blood DNA. Analysis of tumor DNA showed the same splice variant along with copy-neutral loss of heterozygosity on Chromosome 20 encompassing GNAS, consistent with predicted biallelic loss of GNAS in the tumor specimen. This case strengthens the evidence implicating GNAS as a tumor-suppressor gene in medulloblastoma and highlights a scenario in which therapeutics targeting the cAMP pathway may be of great utility.

Keywords: cerebellar medulloblastoma.

© 2019 Tokita et al.; Published by Cold Spring Harbor Laboratory Press.

Figures

Figure 1.

Representative MRI images of the midline posterior fossa medulloblastoma at (A) initial diagnosis and (B) recurrence. (C) H&E stain of the recurrent tumor (200× magnification) showing densely cellular proliferation of “small blue cells” with nodules showing neural differentiation with pale fibrillary background. (D) Reticulin stain of recurrent tumor (200× magnification) showing reticulin deposition within internodular areas, outlining reticulin-negative nodules. (E–G) IGV data showing the de novo c.432+1G>A pathogenic variant in GNAS is present on the paternally inherited allele. GNAS SNVs detected on analysis of proband tumor (top), maternal blood (middle), and paternal blood (bottom). The allele fraction of the paternally inherited SNVs in E and F (NM_080425) in the proband's tumor is similar to the allele fraction of the pathogenic splice variant (G) (NM_000516), indicating that the de novo splice variant has likely occurred on the paternal allele.