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
in En
| MEDLINE
| ID: mdl-34967012
ABSTRACT
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Colorectal Neoplasms, Hereditary Nonpolyposis
/
Cerebellar Neoplasms
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DNA Polymerase II
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Poly-ADP-Ribose Binding Proteins
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Medulloblastoma
Type of study:
Etiology_studies
/
Risk_factors_studies
Limits:
Child, preschool
/
Humans
/
Male
Language:
En
Journal:
Clin Genet
Year:
2022
Type:
Article
Affiliation country:
Israel