Di-genic inheritance of germline POLE and PMS2 pathogenic variants causes a unique condition associated with pediatric cancer predisposition.

December 29, 2021

Michaeli O1, Ladany H2, Erez A3, Shachar SB4, Izraeli S1 5, Lidzbarsky G6, Basel-Salmon L5 6, Biskup S7, Maruvka YE2, Toledano H# 1 5, Goldberg Y# 5 6


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. 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. This article is protected by copyright. All rights reserved.

Keywords: Di-genic; Genomic Signature; LYNCH; Medulloblastoma; PMS2; POLE.