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

Content Provider	Europe PMC
Author	Lindsay, Holly Scollon, Sarah Reuther, Jacquelyn Voicu, Horatiu Rednam, Surya P. Lin, Frank Y. Fisher, Kevin E. Chintagumpala, Murali Adesina, Adekunle M. Parsons, D. Will Plon, Sharon E. Roy, Angshumoy
Copyright Year	2019
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.
Related Links	https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC6824253&blobtype=pdf
Page Count	12
Journal	Cold Spring Harbor Molecular Case Studies [Cold Spring Harb Mol Case Stud]
Volume Number	5
DOI	10.1101/mcs.a004499
PubMed Central reference number	PMC6824253
Issue Number	5
PubMed reference number	31624068
e-ISSN	23732873
Language	English
Publisher	Cold Spring Harbor Laboratory Press
Publisher Date	2019-10-23
Access Restriction	Open
Rights License	This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License, which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited. © 2019 Lindsay et al.; Published by Cold Spring Harbor Laboratory Press
Subject Keyword	cerebellar medulloblastoma
Content Type	Text
Resource Type	Article
Subject	Biochemistry Genetics Molecular Medicine Genetics (clinical)