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

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ID: 275001
2021
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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.
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michaeli2021digenicclinical Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Michaeli, Orli;Ladany, Hagay;Erez, Ayelet;Ben Shachar, Shay;Izraeli, Shai;Lidzbarsky, Gabriel;Basel-Salmon, Lina;Biskup, Saskia;Maruvka, Yosef E;Toledano, Helen;Goldberg, Yael;
Journal Clinical genetics
Year 2021
DOI
10.1111/cge.14106
URL
Keywords
medulloblastoma genomic signature lynch pms2 pole di-genic

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