Germline MUTYH mutations and high-grade gliomas: Novel evidence for a potential association

Abstract

There is growing body of evidence supporting the role of germline mutations in the pathogenesis of pediatric central nervous system (CNS) tumors, and the widespread use of next-generation sequencing (NGS) panels facilitates their detection. Variants of the MUTYH gene are increasingly recognized as suspected germline background of various extraintestinal malignancies, besides their well-characterized role in the polyposis syndrome associated with biallelic mutations. Using a multigene NGS panel (Illumina TruSight Oncology 500), we detected one H3 G34V- and one H3 K27M-mutant pediatric high-grade diffuse glioma, in association with c.1178G>A (p.G393D) and c.916C>T (p.R306C) MUTYH variants, respectively. Both MUTYH mutations were germline, heterozygous and inherited, according to the subsequent genetic testing of the patients and their first-degree relatives. In the H3 K27M-mutant glioma, amplifications affecting the 4q12 region were also detected, in association with KDR-PDGFRA, KIT-PDGFRA, and KDR-CHIC2 fusions, previously unreported in this entity. Among 47 other CNS tumors of various histological types tested with the same NGS panel in our institution, only one adult glioblastoma harbored MUTYH mutation. Together with a single previous report, our data raises the possibility of an association between germline MUTYH mutations and CNS malignancies, particularly in pediatric histone H3-mutant gliomas.

Keywords: MUTYH; PDGFRA fusion; germline mutation; histone H3-mutant glioma; next-generation sequencing; pediatric glioma.

FIGURE 1

Immunohistochemical profile and characteristics of MUTYH c.1178G>A (p.G393D) mutation in the H3 G34V‐mutant glioma. (A) H&E morphology, (B) GFAP, (C) p53, and (D) ATRX immunohistochemistry of the tumor sample (scale bar: 100 μm). (E) The MUTYH pedigree showing individuals harboring heterozygous mutation with semi‐black shading (black arrow points to the proband). (F) Sequencing revealed the presence of the variant in the peripheral blood of the patient and father, but not in the mother and sibling (red arrows indicate the affected position).

FIGURE 2

Immunohistochemical profile and characteristics of MUTYH c.916C>T (p.R306C) mutation in the H3 K27M‐mutant glioma. (A) H&E morphology, (B) H3 K27M, (C) p53 and (D) ATRX immunohistochemistry of the tumor sample (scale bar: 100 μm). (E) The MUTYH pedigree showing individuals harboring heterozygous mutation with semi‐black shading (black arrow points to the proband). (F) Sequencing revealed the presence of the variant in the peripheral blood of the patient, the mother and the sibling, but not in the father (red arrows indicate the affected position).