Identification and Analyses of Extra-Cranial and Cranial Rhabdoid Tumour Molecular Subgroups Reveal Tumors with Cytotoxic T Cell Infiltration
This week we profile a recent publication in Cell Reports from Elizabeth Chun (pictured) in the
laboratory of Dr. Marco Marra at Canada’s Michael Smith Genome Sciences Centre.
Can you provide a brief overview of your lab’s current research focus?
Dr. Marco Marra is the Director of Canada’s Michael Smith Genome Sciences Centre at BC Cancer (GSC). A current focus of Dr. Marra’s research lab is the development and application of Next-Generation Sequencing approaches to characterize cancer genomes, transcriptomes and epigenomes, aiming to comprehensively identify genetic and epigenetic changes that drive cancer progression. His team has described the strikingly high frequency of mutations in transcriptional regulators, including chromatin modifiers, implying that they are “cancer genes” and that mutations in them drive cancers. Dr. Marra’s team is analyzing cancer regulatory networks impacted by epigenome dysregulation using cell biology, genetics, genomics, bioinformatics and functional genomics tools, and aims to understand the selective advantages conferred to cancer cells as a consequence of such dysregulation. With such data, and as co-Leader of BC Cancer’s Personalized OncoGenomics project, Dr. Marra’s objective is a new generation of diagnostic, prognostic and treatment strategies to benefit cancer patients.
What is the significance of the findings in this publication?
Rhabdoid tumours (RTs) are rare and highly aggressive pediatric cancers typically diagnosed before the age of two. These invasive tumours spread rapidly throughout the infant’s body, and even with surgical interventions and aggressive chemotherapy, the outcome is often devastating. With a four-year survival rate of just over 20 per cent, novel therapies are urgently needed to help save the lives of children with RTs.
Scientists at the GSC studied the biology of RTs, integrating multiple data types that profiled molecular characteristics of RTs. In their study published in Cell Reports, the researchers conducted extensive analyses of the genomes, epigenomes and transcriptomes of RTs from multiple anatomical locations. Dr. Marra’s graduate student, Ms. Elizabeth Chun, was a co-first author of the paper. In collaboration with scientists at the German Cancer Research Center (DKFZ) in Heidelberg, the team analyzed data generated from 301 RTs, which is the largest RT cohort to date. Their work revealed that not only were tumours from the same anatomical location diverse, but in some cases, brain RTs were actually more similar to non-brain RTs than to other RTs within the brain. Digging deeper, the team identified five distinct subgroups. Upon further examination of the RT subgroups, the team discovered that some RTs appeared to be interacting extensively with the immune system. Within the tumour tissues, they observed the presence of immune cells, called cytotoxic T cells, and their genomics data and extensive validation experiments corroborated these findings. Because these traits have been seen in other cancer types that respond well to a particular type of immune-based treatments called immune checkpoint inhibitors, this discovery raises a hypothesis that immune checkpoint inhibitors may be of utility for a subset of RT patients.
What are the next steps for this research?
The GSC is unique in that it is embedded within a cancer clinic, allowing for meaningful collaborations between scientists and clinicians. While this study provides the groundwork for further validation, as well as for research and identification of potential therapeutics for different RT subgroups, there are many remaining questions that dedicated researchers are striving to solve. To help test the hypothesis of potential utility of immunotherapy for RT patients, this work has been presented to oncologists involved in the Children’s Oncology Group in the US and in the Terry Fox PROFYLE (PRecision Oncology For Young peopLE) Initiative.
This work was funded by:
Dr. Marra was funded by BC Cancer, the BC Cancer Foundation, the Canada Foundation for Innovation, the Canada Research Chairs program, and the Canadian Institutes of Health Research (FDN-143288). Ms. Chun was funded through the Roman M. Babicki Fellowship in Medical Research from the University of British Columbia. The DKFZ team was funded by the Heidelberg School of Oncology and the Deutsche Forschungsgemeinschaft. BC Cancer’s participation in this project is through a subcontract with Leidos Biomedical Research, Inc., which operates the Frederick National Laboratory for Cancer Research on behalf of the National Cancer Institute.