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
Department of Pediatric Hematology and Oncology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, Israel.
Clin Genet. 2022 Apr;101(4):442-447. doi: 10.1111/cge.14106. Epub 2022 Jan 7.
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.
聚合酶校对相关息肉病（PPAP）和林奇综合征分别由POLE基因和错配修复（MMR）基因突变引起，与成人期癌症相关。PPAP和MMR缺陷型肿瘤均具有高度突变，且各有独特的突变特征。我们描述了一名4.5岁的男孩，有多处咖啡牛奶斑，患有转移性声波刺猬因子激活型髓母细胞瘤，对强化化疗和免疫治疗有部分反应。肿瘤显示微卫星稳定性、PMS2核表达缺失，以及异常高的肿瘤突变负荷，为276个突变/兆碱基。胚系分子分析发现一个遗传性杂合致病性POLE变异和一个新生杂合PMS2致病性变异。肿瘤具有MMR、POLE和POLE+MMR突变特征。这是首次描述一种双基因疾病，我们将其命名为“POL-LYNCH综合征”，其表现为侵袭性超突变型小儿髓母细胞瘤，具有独特的基因组特征。
