Constitutional POLE variants causing a phenotype reminiscent of constitutional mismatch repair deficiency.
POLE
café au lait macules
childhood cancer
constitutional mismatch repair deficiency
driver mutation
medulloblastoma
mismatch repair
polymerase proofreading
polymerase proofreading associated polyposis
tumor mutational burden
Journal
Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
revised:
28
10
2021
received:
01
07
2021
accepted:
03
11
2021
pubmed:
25
11
2021
medline:
1
4
2022
entrez:
24
11
2021
Statut:
ppublish
Résumé
Heterozygous POLE or POLD1 germline pathogenic variants (PVs) cause polymerase proofreading associated polyposis (PPAP), a constitutional polymerase proofreading deficiency that typically presents with colorectal adenomas and carcinomas in adulthood. Constitutional mismatch-repair deficiency (CMMRD), caused by germline bi-allelic PVs affecting one of four MMR genes, results in a high propensity for the hematological, brain, intestinal tract, and other malignancies in childhood. Nonmalignant clinical features, such as skin pigmentation alterations, are found in nearly all CMMRD patients and are important diagnostic markers. Here, we excluded CMMRD in three cancer patients with highly suspect clinical phenotypes but identified in each a constitutional heterozygous POLE PV. These, and two additional POLE PVs identified in published CMMRD-like patients, have not previously been reported as germline PVs despite all being well-known somatic mutations in hyper-mutated tumors. Together, these five cases show that specific POLE PVs may have a stronger "mutator" effect than known PPAP-associated POLE PVs and may cause a CMMRD-like phenotype distinct from PPAP. The common underlying mechanism, that is, a constitutional replication error repair defect, and a similar tumor spectrum provide a good rationale for monitoring these patients with a severe constitutional polymerase proofreading deficiency according to protocols proposed for CMMRD.
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
85-96Subventions
Organisme : Austrian Science Fund FWF
ID : KLI 734
Pays : Austria
Organisme : Cancer Research UK
ID : C569/A24991
Pays : United Kingdom
Informations de copyright
© 2021 The Authors. Human Mutation published by Wiley Periodicals LLC.
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