Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma

Abstract

PURPOSE The identification of a heritable tumor predisposition often leads to changes in management and increased surveillance of individuals who are at risk; however, for many rare entities, our knowledge of heritable predisposition is incomplete. METHODS Families with childhood medulloblastoma, one of the most prevalent childhood malignant brain tumors, were investigated to identify predisposing germline mutations. Initial findings were extended to genomes and epigenomes of 1,044 medulloblastoma cases from international multicenter cohorts, including retrospective and prospective clinical studies and patient series. RESULTS We identified heterozygous germline mutations in the G protein-coupled receptor 161 ( GPR161) gene in six patients with infant-onset medulloblastoma (median age, 1.5 years). GPR161 mutations were exclusively associated with the sonic hedgehog medulloblastoma (MBSHH) subgroup and accounted for 5% of infant MBSHH cases in our cohorts. Molecular tumor profiling revealed a loss of heterozygosity at GPR161 in all affected MBSHH tumors, atypical somatic copy number landscapes, and no additional somatic driver events. Analysis of 226 MBSHH tumors revealed somatic copy-neutral loss of heterozygosity of chromosome 1q as the hallmark characteristic of GPR161 deficiency and the primary mechanism for biallelic inactivation of GPR161 in affected MBSHH tumors. CONCLUSION Here, we describe a novel brain tumor predisposition syndrome that is caused by germline GPR161 mutations and characterized by MBSHH in infants. Additional studies are needed to identify a potential broader tumor spectrum associated with germline GPR161 mutations.

Invited Review: DNA methylation‐based classification of paediatric brain tumours

“…This may be particularly relevant for the selection of cases to perform a directed SHH pathway mutation analysis or CTNNB1 testing . Further guidance may be for directed germline testing as germline variants in PTCH1 , SUFU , GPR161 and TP53 are mostly restricted to SHH MBs, whereas APC germline alterations may be specific to WNT tumours and BRCA2 and PALB2 were identified across SHH, Group3 and Group 4 tumours . Recently, highly recurrent hotspot mutations of U1 spliceosomal small nuclear RNAs have been identified in around 50% of SHH MBs .…”

A genome-wide association study on medulloblastoma

“…Germline mutations in APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 occur in up to 6% of all medulloblastoma cases [3]. Another potential medulloblastoma predisposing mutation has been reported in the gene GPR161 [4]. In candidate gene analysis restricted to these seven genes, we observed associations between genetic variants in PALB2 and PTCH1 and medulloblastoma risk.…”

“…In addition to genome-wide analyses, we were specifically interested in seven genes, namely: APC, BRCA2, PALB2, PTCH1, SUFU, TP53, and GPR161 [3,4]. Within these seven candidate genes, the strongest evidence for association was found for rs201458864, located within PALB2 (OR per T allele = 3.76, 95% CI 1.83-7.75, p = 3.2 × 10 -4 ) and rs79036813, located within PTCH1 (OR per A allele = 0.42, 95% CI 0.24-0.74, p = 2.6 × 10 -3 ) ( Figure S3).…”

“…The genes APC, BRCA2, PALB2, PTCH1, SUFU, TP53, and GPR161 were selected for investigation using a candidate gene approach. The selection was based on two recent studies that found germline mutations in one of these genes in 6% of all medulloblastoma cases [3,4]. The 1446 SNPs located within these genes include directly genotyped as well as imputed SNPs.…”

“…A recent study including 1022 medulloblastoma patients found that 6% of all cases had a germline mutation in TP53, APC, PTCH1, SUFU, or in two additional genes with presumed tumor suppressor function: BRCA2 or PALB2 [3]. Another recent study reported a novel medulloblastoma predisposition gene in GPR161 [4]. The somatic genetic changes that occur in sporadic medulloblastoma tumors are also well-described, including alterations in CCND2, CTNNB1, DDX3X, GLI2, SMARCA4, MYC, MYCN, PTCH1, TP53, and KMT2D [5].…”