TY - JOUR

T1 - Constitutional POLE variants causing a phenotype reminiscent of constitutional mismatch repair deficiency

AU - Sehested, Astrid

AU - Meade, Julia

AU - Scheie, David

AU - Østrup, Olga

AU - Bertelsen, Birgitte

AU - Misiakou, Maria Anna

AU - Sarosiek, Tomasz

AU - Kessler, Elena

AU - Melchior, Linea C.

AU - Munch-Petersen, Helga Fibiger

AU - Pai, Reetesh K.

AU - Schmuth, Matthias

AU - Gottschling, Hendrik

AU - Zschocke, Johannes

AU - Gallon, Richard

AU - Wimmer, Katharina

N1 - Publisher Copyright: © 2021 The Authors. Human Mutation published by Wiley Periodicals LLC.

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

U2 - 10.1002/humu.24299

DO - 10.1002/humu.24299

M3 - Journal article

C2 - 34816535

AN - SCOPUS:85120422422

VL - 43

SP - 85

EP - 96

JO - Human Mutation

JF - Human Mutation

SN - 1059-7794

IS - 1

ER -