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BACKGROUND: Ultrahypermutation (>100 mutations/Mb) is rare in childhood cancer genomes and is primarily seen in patients with constitutional mismatch repair deficiency (cMMRD) caused by biallelic germline mutations in DNA mismatch repair (MMR) genes. We report a child with clinical features of cMMRD and an ultrahypermutated medulloblastoma found to harbor a germline mutation in DNA polymerase epsilon (POLE). CASE PRESENTATION: A 5-year-old female presented with clinical features of cMMRD including a malignant brain tumor, >100 hyperpigmented skin papules and café-au-lait macules, and axillary freckling. Additionally, she had a renal cyst, tibial osteochondroma, and 3 subcutaneous nodules. Pathology of the brain mass revealed non-WNT/non-SHH anaplastic medulloblastoma with tumor cells retaining MMR protein expression by immunohistochemistry. GENETIC ANALYSES: Germline genetic analysis of MMR genes revealed no pathogenic mutations. Targeted next-generation sequencing with a 124-cancer gene panel covering ≈1 Mb revealed an ultrahypermutated tumor genome (>150 mutations/Mb) and a mutation signature resembling “signature 10” (Campbell et al., Cell 2017), which is strongly associated with POLE exonuclease domain mutations. Analysis of matched tumor and blood DNA with an expanded 981-cancer gene panel demonstrated a germline heterozygous POLE missense variant (NM_006231.3:c.1366G>C; p.A456P) in the exonuclease domain, previously only reported as a somatic pathogenic variant in hypermutated cancers. The tumor additionally had a somatic heterozygous MSH6 nonsense variant (NM_000179.2:c.2722G>T; p.E908X). DISCUSSION: We report this early-onset brain tumor in a patient with phenotypic features of cMMRD, and a germline POLE p.A456P mutation. Heterozygous germline missense variants in the POLE exonuclease domain cause Polymerase Proofreading-associated Polyposis (PPAP), a cancer predisposition syndrome associated with colorectal polyposis and early-onset, microsatellite-stable colorectal cancer. Several brain tumors have been reported in patients with PPAP including pediatric astrocytoma. Dermatologic features and mutation signature analysis of hypermutated tumors may be associated with germline mutations in either the MMR or polymerase proofreading pathways. |
