Identification and Analyses of Extra-Cranial and Cranial Rhabdoid Tumor Molecular Subgroups Reveal Tumors with Cytotoxic T Cell Infiltration

Hye-Jung E. Chun; Pascal D. Johann; Katy Milne; Marc Zapatka; Annette Buellesbach; Naveed Ishaque; Murat Iskar; Serap Erkek; Lisa Wei; Basile Tessier-Cloutier; Jake Lever; Emma Titmuss; James T. Topham; Reanne Bowlby; Eric Chuah; Karen L. Mungall; Yussanne Ma; Andrew J. Mungall; Richard A. Moore; Michael D. Taylor; Daniela S. Gerhard; Steven J.M. Jones; Andrey Korshunov; Manfred Gessler; Kornelius Kerl; Martin Hasselblatt; Michael C. Frühwald; Elizabeth J. Perlman; Brad H. Nelson; Stefan M. Pfister; Marco A. Marra; Marcel Kool

Identification and Analyses of Extra-Cranial and Cranial Rhabdoid Tumor Molecular Subgroups Reveal Tumors with Cytotoxic T Cell Infiltration

2019

Summary: Extra-cranial malignant rhabdoid tumors (MRTs) and cranial atypical teratoid RTs (ATRTs) are heterogeneous pediatric cancers driven primarily by SMARCB1 loss. To understand the genome-wide molecular relationships between MRTs and ATRTs, we analyze multi-omics data from 140 MRTs and 161 ATRTs. We detect similarities between the MYC subgroup of ATRTs (ATRT-MYC) and extra-cranial MRTs, including global DNA hypomethylation and overexpression of HOX genes and genes involved in mesenchymal development, distinguishing them from other ATRT subgroups that express neural-like features. We identify five DNA methylation subgroups associated with anatomical sites and SMARCB1 mutation patterns. Groups 1, 3, and 4 exhibit cytotoxic T cell infiltration and expression of immune checkpoint regulators, consistent with a potential role for immunotherapy in rhabdoid tumor patients. : Chun et al. report similarities between the MYC subgroup of cranial and extra-cranial rhabdoid tumors (RTs) at genetic, gene-expression, and epigenetic levels. They identify five DNA methylation subgroups of RTs across multiple organ sites, and some subgroups exhibit increased levels of immune cell infiltration and immune checkpoint expression. Keywords: Malignant rhabdoid tumor, atypical teratoid rhabdoid tumor, pediatric cancer, SMARCB1, molecular subgroups, genomic and epigenomic dysregulation, HOX dysregulation, cytotoxic T cell infiltration, tumor-infiltrating immune cells

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