NEW YORK (GenomeWeb) – Researchers have analyzed the genomes and epigenomes of nearly 200 tumor samples from a rare but very aggressive childhood cancer and have identified three distinct subtypes that could have implications for disease treatment.
As they wrote today in Cancer Cell, the researchers analyzed atypical teratoid rhabdoid tumors (ATRT), a rare but highly malignant childhood cancer that is most frequently seen in the central nervous system, but also in kidneys or other soft tissue. Patients with the cancer typically do not survive longer than one year after diagnosis.
The team performed exome, whole-genome, and transcriptome sequencing, as well as copy number and methylation profiling on 191 primary tumor samples and 10 cell lines.
Previous research has indicated that the gene SMARC1B is involved and up to 35 percent of all patients with ATRT have alterations in that gene. The gene plays a role in the SWI/SNF chromatin-remodeling complex, indicating that epigenetic mechanisms are involved, but the specific mechanisms that drive tumorigenesis are unclear.
Sequencing of the samples found that there were low rates of coding mutations, but 379 copy number alterations. In 20 percent of cases, these alterations affected cell adhesion, neural development, and chromatin remodeling genes. In addition, the loss of SMARC1B seemed to be caused predominantly by structural alterations, indicating that current diagnostic methods, which look only at coding mutations, "may underestimate the frequency of SMARCB1alterations in ATRTs," the authors wrote.
Looking at the epigenetic alterations, the researchers identified three epigenetic classes, which they called group 1, group 2A, and group 2B. The three epigenetic subtypes correlated with "distinct tumor locations, patient age, lineage-enriched methylation and transcriptional signatures, and unique global and SMARC1B-specific genotypes," the authors wrote.
For instance, group 2A tumors predominantly arose in the cerebellum/brain stem regions while group 1 tumors arose mostly in the supratentorial/cerebral regions. Group 1 tumors were seen in the oldest children, with a median age of 24 months, while group 2A tumors were seen in the youngest patients, with a median age of 12 months. Meantime group 2B tumors were located in more heterogeneous areas and were seen across a broader age distribution.
In addition, SMARC1B loss was linked to different events in the three subtypes. Group 1 tumors tended to have focal alterations, while group 2B tumors had large deletions that encompassed the entire gene. Looking deeper into the epigenome and transcriptome, the researchers found that the group 2A tumors tended to have an open chromatin structure that correlated with increased gene expression patterns, while the group 1 tumors had less gene expression. Group 2B tumors had an intermediate profile.
Next, they used cell lines to test targeted drugs. They found that small-molecule inhibitors that target epigenetic regulation reduced growth of group 1 tumor cells but not group 2A or 2B. Multi-tyrosine kinase inhibitors dasatinib and nilotinib both inhibited growth of tumor cells from group 2A and group 2B, though they had no impact on group 1. The authors wrote that further testing showed that dasatinib and nilotinib could be "promising repurposed drugs for ATRT."
Overall, "these observations have significant implications for the fundamental understanding and targeting of SWI/SNF function in neoplastic growth and clinical management of ATRTs," they added.