A UK team found multiple targets of non-coding mutations, highlighting the importance of broadening the search for cancer drivers into the regulatory genome.
A recent study has identified a new group of genes involved in the onset of multiple myeloma. The discovery of these genes may help drive development of more targeted, personalized treatments for the disease, according to Richard Houlston, MD, PhD, Professor of Molecular and Population Genetics at The Institute of Cancer Research, London, and colleagues.
“We need smarter, kinder treatments for myeloma that are more tailored to each person's cancer,” Houlston said in a prepared statement. “Exhaustive genetic research like this is helping us to make that possible.”
According to the study, much of the research into driver mutations for myeloma has focused on the protein-coding component of the genome driven by the large-scale sequencing on myeloma exomes. However, increasing affordability of whole genome sequencing means that it is possible to examine non-coding regions of cancer genomes as well.
“Although mutation recurrence is an indicator of positive selection in tumors, the sheer size of the non-coding genome imposes a high statistical burden on robustly establishing recurrent mutations,” the researchers wrote. “Cis-regulatory elements (CREs) and promoters modulating gene expression represent a highly enriched subset of the non-coding genome in which to search for driver mutations.”
Houlston and colleagues analyzed whole genome sequencing from 765 patients with multiple myeloma from the CoMMpass study and whole exome sequencing from 804 patients with myeloma.
They found that 16 genes were disrupted in coding regions of the DNA and 15 were disrupted in non-coding areas. Tumor suppressors PAX5 and HOXB3 were found to be downregulated by non-coding mutations, consistent with their decreased expression, contributing to the development and progression of myeloma, also seen in other B-cell cancers.
The researchers also added TWEAK, TRAF2, and PRKD2 to the list of genes in myeloma that are disrupted by coding mutations, COBLL1 as dysregulated by mutations in non-coding DNA, and MAP3K14 as upregulated by DNA reorganization.
“We have identified multiple targets of non-coding mutations, highlighting the importance of broadening the search for cancer drivers into the regulatory genome,” the researchers wrote. “Validation of the candidates we have identified will be contingent on functional studies including, for example, CRISPR [Clustered Regularly Interspaced Short Palindromic Repeats]-mediated genome editing, in vitro reporter assays, and proliferation assays coupled with transcriptional profiling.”