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

Orli Michaeli, Hagay Ladany, Ayelet Erez, Shay Ben Shachar, Shai Izraeli, Gabriel Lidzbarsky, Lina Basel-Salmon, Saskia Biskup, Yosef E. Maruvka, Helen Toledano, Yael Goldberg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)442-447
Number of pages6
JournalClinical Genetics
Volume101
Issue number4
DOIs
StatePublished - Apr 2022

Keywords

  • LYNCH
  • PMS2
  • POLE
  • di-genic
  • genomic signature
  • medulloblastoma

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