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

Abstract

AimsThe mutY DNA glycosylase encoded by the MUTYH gene prevents G:C → T:A transversions through the base excision repair DNA repair system. Germline biallelic pathogenic variants in MUTYH cause an adenomatous polyposis called MUTYH‐associated polyposis (MAP), an autosomal recessive disease (OMIM: 608456), with an increased risk of colorectal cancer. Digestive lesions in this context show an excess of G:C → T:A transversions, individualising a specific mutational signature associated with MUTYH deficiency called signature SBS36. Predisposition to other tumours in patients with germline biallelic pathogenic variants in MUTYH is suspected but remains unclear. We report the first case of medulloblastoma in a patient with MAP, carrying the homozygous pathogenic variant c.1227_1228dup, p.(Glu410Glyfs*43) in MUTYH.MethodsWhole exome sequencing was performed on the medulloblastoma to enlighten single nucleotide variants of interest, microsatellite status and mutational signature. The objective was to determine the involvement of MUTYH deficiency in the oncogenesis of this medulloblastoma.ResultsThe medulloblastoma has the mutational signature SBS36 and driver pathogenic variants in CTNNB1, PTCH1 and KDM6A corresponding to G:C → T:A transversions, suggesting a role of MUTYH deficiency in oncogenesis.ConclusionsTherefore, medulloblastoma could be a rare manifestation associated with germline biallelic pathogenic variants in MUTYH.

A second case report of medulloblastoma in a patient carrying biallelic pathogenic MUTYH germline variants

“…4,5 Villy et al described a case of medulloblastoma (MB) in a patient with MAP. 6 The patient affected by MB molecular subgroup WNT carried the homozygous pathogenic variant c.1227_1228dup, p.…”

“…(Glu410Glyfs*43) in MUTYH. 6 They concluded that MB could be an uncommon presentation of a biallelic germline pathogenic variant in MUTYH. 6 Germline-predisposing pathogenic variants are detected in approximately 5% to 6% of individuals with MB and up to 20% in the SHH subgroup.…”

“…6 They concluded that MB could be an uncommon presentation of a biallelic germline pathogenic variant in MUTYH. 6 Germline-predisposing pathogenic variants are detected in approximately 5% to 6% of individuals with MB and up to 20% in the SHH subgroup. 7 Although a definitive consensus list is yet to be established, prominent predisposition genes have been identified, predominantly including Adenomatous polyposis coli (APC), a regulator of the WNT signalling pathway; G Protein-Coupled Receptor 161 (GPR161); Patched 1 (PTCH1) and suppressor of fused homologue (SUFU), both negative regulators of the Hedgehog signalling pathway; Elongator Acetyltransferase Complex Subunit 1 (ELP1); and Tumour Protein P53 (TP53).…”

“…Genetic analysis was also performed on DNA Our case is the second case of MUTYH-associated MB reported in the literature. 6 Villy et al described a case of MB molecular subgroup WNT, which carried a homozygous pathogenic variant in the MUTYH gene and suggested that the MB could be an uncommon presentation of a biallelic germline pathogenic variant in MUTYH. 6 In addition, Kline et al described two paediatric patients with high-grade gliomas associated with an inactivating MUTYH germline pathogenetic variant.…”

“…6 Villy et al described a case of MB molecular subgroup WNT, which carried a homozygous pathogenic variant in the MUTYH gene and suggested that the MB could be an uncommon presentation of a biallelic germline pathogenic variant in MUTYH. 6 In addition, Kline et al described two paediatric patients with high-grade gliomas associated with an inactivating MUTYH germline pathogenetic variant. 14 Patient #2, described in the report, had a previous diagnosis of MB and showed a heterozygous germline loss-of-function variant of MUTYH and a second hit that deleted the wild-type allele of MUTYH in the tumour DNA; thus, MB is associated with MUTYH but is not related to tumour predisposition due to biallelic germline variants of MUTYH and MAP/FAP2.…”