Germline POLE mutation in a child with hypermutated medulloblastoma and features of constitutional mismatch repair deficiency
- Holly Lindsay1,2,
- Sarah Scollon1,2,
- Jacquelyn Reuther3,
- Horatiu Voicu3,
- Surya P. Rednam1,2,
- Frank Y. Lin1,2,
- Kevin E. Fisher3,
- Murali Chintagumpala1,2,
- Adekunle M. Adesina1,3,
- D. Will Parsons1,2,3,4,
- Sharon E. Plon1,2,3,4 and
- Angshumoy Roy1,3
- 1Department of Pediatrics, Division of Hematology-Oncology, Baylor College of Medicine, Houston, Texas 77030, USA;
- 2Texas Children's Cancer Center, Texas Children's Hospital, Houston, Texas 77030, USA;
- 3Department of Pathology and Immunology, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas 77030, USA;
- 4Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas 77030, USA
- Corresponding author: aroy{at}bcm.edu
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.
Footnotes
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[Supplemental material is available for this article.]
- Received June 14, 2019.
- Accepted August 15, 2019.
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