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

doi:10.1016/j.celrep.2019.10.013

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

Cell Rep. 2019 Nov 19;29(8):2338-2354.e7. doi: 10.1016/j.celrep.2019.10.013. Epub 2019 Nov 7.

Authors

Hye-Jung E Chun¹, Pascal D Johann², Katy Milne³, Marc Zapatka⁴, Annette Buellesbach², Naveed Ishaque⁵, Murat Iskar⁴, Serap Erkek⁶, Lisa Wei¹, Basile Tessier-Cloutier⁷, Jake Lever¹, Emma Titmuss¹, James T Topham¹, Reanne Bowlby¹, Eric Chuah¹, Karen L Mungall¹, Yussanne Ma¹, Andrew J Mungall¹, Richard A Moore¹, Michael D Taylor⁸, Daniela S Gerhard⁹, Steven J M Jones¹⁰, Andrey Korshunov⁶, Manfred Gessler¹¹, Kornelius Kerl¹², Martin Hasselblatt¹³, Michael C Frühwald¹⁴, Elizabeth J Perlman¹⁵, Brad H Nelson¹⁶, Stefan M Pfister², Marco A Marra¹⁷, Marcel Kool¹⁸

Affiliations

¹ Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC V7Z 1L3, Canada.
² Hopp Children's Cancer Center, Heidelberg 69120, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), and German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg 69120, Germany; Department of Pediatric Hematology and Oncology, University Hospital Heidelberg, Heidelberg 69120, Germany.
³ Deeley Research Centre, BC Cancer, Victoria, BC V8R 6V5, Canada.
⁴ Department of Molecular Genetics, DKFZ, Heidelberg 69120, Germany.
⁵ Center for Digital Health, Berlin Institute of Health and Charité-Universitätsmedizin Berlin, Berlin 10117, Germany; Heidelberg Center for Personalized Oncology, DKFZ, Heidelberg 69120, Germany.
⁶ Hopp Children's Cancer Center, Heidelberg 69120, Germany.
⁷ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
⁸ Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
⁹ Office of Cancer Genomics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
¹⁰ Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC V7Z 1L3, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
¹¹ Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry; and Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg 97074, Germany.
¹² Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster 48149, Germany.
¹³ Institute of Neuropathology, University Hospital Muenster, Muenster 48149, Germany.
¹⁴ University Children's Hospital Augsburg, Swabian Children's Cancer Center, Augsburg 86156, Germany.
¹⁵ Department of Pathology and Laboratory Medicine, Lurie Children's Hospital, Northwestern University's Feinberg School of Medicine and Robert H. Lurie Cancer Center, Chicago, IL 60611, USA.
¹⁶ Deeley Research Centre, BC Cancer, Victoria, BC V8R 6V5, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada; Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC V8P 3E6, Canada.
¹⁷ Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC V7Z 1L3, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada. Electronic address: [email protected].
¹⁸ Hopp Children's Cancer Center, Heidelberg 69120, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), and German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg 69120, Germany. Electronic address: [email protected].

Abstract

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.

Keywords: HOX dysregulation; Malignant rhabdoid tumor; SMARCB1; atypical teratoid rhabdoid tumor; cytotoxic T cell infiltration; genomic and epigenomic dysregulation; molecular subgroups; pediatric cancer; tumor-infiltrating immune cells.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Child
DNA Methylation / genetics
DNA Methylation / physiology
Female
Humans
Lymphocytes, Tumor-Infiltrating / metabolism
Lymphocytes, Tumor-Infiltrating / pathology
Male
Mutation / genetics
Rhabdoid Tumor / metabolism*
Rhabdoid Tumor / pathology*
SMARCB1 Protein / genetics
SMARCB1 Protein / metabolism
Skull Base Neoplasms / metabolism
Skull Base Neoplasms / pathology
T-Lymphocytes / metabolism
T-Lymphocytes / pathology
T-Lymphocytes, Cytotoxic / metabolism*
T-Lymphocytes, Cytotoxic / pathology*
Teratoma / metabolism
Teratoma / pathology

Substances

SMARCB1 Protein
SMARCB1 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding