Germline POLE mutation in a child with hypermutated medulloblastoma and features of constitutional mismatch repair deficiency

Holly Lindsay, Sarah Scollon, Jacquelyn Reuther, Horatiu Voicu, Surya P. Rednam, Frank Y. Lin, Kevin E. Fisher, Murali Chintagumpala, Adekunle M. Adesina, D. Will Parsons, Sharon E. Plon, Angshumoy Roy

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Ultra-hypermutation (>100 mutations/Mb) is rare in childhood cancer genomes and has been primarily reported in patients with constitutional mismatch repair deficiency (CMMRD) caused by biallelic germline mismatch repair (MMR) gene mutations. We report a 5-yr-old child with classic clinical features of CMMRD and an ultra-hypermutated medulloblastoma with retained MMR protein expression and absence of germline MMR mutations. Mutational signature analysis of tumor panel sequencing data revealed a canonical DNA polymerase-deficiency-associated signature, prompting further genetic testing that uncovered a germline POLE p.A456P missense variant, which has previously been reported as a recurrent somatic driver mutation in cancers. This represents the earliest known onset of malignancy in a patient with a germline mutation in the POLE proofreading polymerase. The clinical features in this child, virtually indistinguishable from those of CMMRD, suggest that polymerase-proofreading deficiency should be considered in the differential diagnosis of CMMRD patients with retained MMR function.

Original languageEnglish (US)
Article numbera004499
JournalCold Spring Harbor Molecular Case Studies
Volume5
Issue number5
DOIs
StatePublished - 2019

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Genetics
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'Germline POLE mutation in a child with hypermutated medulloblastoma and features of constitutional mismatch repair deficiency'. Together they form a unique fingerprint.

Cite this