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.

Novel, clinically relevant genomic patterns identified by comprehensive genomic profiling in ATRX-deficient IDH-wildtype adult high-grade gliomas

“…Complex genetic events affecting the 4q12 region, containing the PDGFRA and KIT genes, were also detected in some cases. The peculiar complexity of genetic lesions in this region was previously observed by our group 23 and others as well 24 , but these are not clearly associated with ATRX loss. Presence of fusions affecting RTK genes were relatively frequent in our cohort.…”

First report of medulloblastoma in a patient with MUTYH‐associated polyposis

“…There was no family history of colorectal cancer, as expected with germline heterozygous pathogenic variant in MUTYH 23 . One other case of medulloblastoma (with no further description), two cases of glioma and one case of glioblastoma are also reported in children carrying germline heterozygous pathogenic variants in MUTYH 23–25 . However, all these cases could be coincidental due to the high frequency of MUTYH heterozygous in the general population.…”

“…23 One other case of medulloblastoma (with no further description), two cases of glioma and one case of glioblastoma are also reported in children carrying germline heterozygous pathogenic variants in MUTYH. [23][24][25] However, all these cases could be coincidental due to the high frequency of MUTYH heterozygous in the general population. Even though both This report demonstrates that MUTYH deficiency can be involved in the oncogenesis of tumours other than those already described, and especially rare malignant tumours, possibly in association with environmental or genetic co-factors.…”

Evolutionary Origin of MUTYH Germline Pathogenic Variations in Modern Humans

“…Pathogenic germline variations in MUTYH damage its function. The biallelic variation in MUTYH causes the development of MUTYH -associated polyposis (MAP) and colorectal cancer [ 2 ]; the monoallelic variation in MUTYH primes the carriers to develop colorectal cancer, although the risk is lower than for the biallelic germline variation [ 3 ].…”