Di-genic inheritance of germline POLE and PMS2 pathogenic variants causes a unique condition associated with pediatric cancer predisposition.
Clin Genet
; 101(4): 442-447, 2022 04.
Article
en En
| MEDLINE
| ID: mdl-34967012
Polymerase proofreading-associated polyposis (PPAP) and Lynch syndrome, caused by mutated POLE and mismatch repair (MMR) genes, respectively, are associated with adult-onset cancer. PPAP and MMR-deficient tumors are both hypermutated, and each has a unique mutational signature. We describe a 4.5-year-old boy with multiple café au lait spots who presented with metastatic Sonic Hedgehog-activated medulloblastoma, with partial response to intensive chemotherapy and immunotherapy. The tumor showed microsatellite stability, loss of PMS2 nuclear expression, and an exceptionally high tumor mutational burden of 276 Mut/Mb. Germline molecular analysis revealed an inherited heterozygous pathogenic POLE variant and a de novo heterozygous PMS2 pathogenic variant. The tumor featured the MMR, POLE, and POLE+MMR mutational signatures. This is the first description of a di-genic condition, which we named "POL-LYNCH syndrome," manifested by an aggressive ultra-mutant pediatric medulloblastoma with a unique genomic signature.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias Colorrectales Hereditarias sin Poliposis
/
Neoplasias Cerebelosas
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ADN Polimerasa II
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Proteínas de Unión a Poli-ADP-Ribosa
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Meduloblastoma
Tipo de estudio:
Etiology_studies
/
Risk_factors_studies
Límite:
Child, preschool
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Humans
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Male
Idioma:
En
Revista:
Clin Genet
Año:
2022
Tipo del documento:
Article
País de afiliación:
Israel