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

Authors

Michaeli O¹, Ladany H², Erez A³, Shachar SB⁴, Izraeli S^{1 5}, Lidzbarsky G⁶, Basel-Salmon L^{5 6}, Biskup S⁷, Maruvka YE², Toledano H^{# 1 5}, Goldberg Y^{# 5 6}

1. Department of Pediatric Hematology and Oncology, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel.
2. Biotechnology and Food Engineering, Technion – Israel Institute of Technology, Haifa, Israel.
3. Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
4. Clalit Research Institute & Department of Genetics, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel.
5. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
6. Raphael Recanati Genetic Institute, Rabin Medical Center-Beilinson Hospital, Petach Tikva, Israel.
7. CeGaT Center for Genomics and Transcriptomics, Tuebingen, Germany.
# Contributed equally.

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. 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.

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