Understanding the Mutations that Cause Multiple Myeloma May Help Drive Personalized Treatment

Affordable whole genome sequencing has helped researchers from the United Kingdom identify the mutations that drive the development of multiple myeloma and link that to potential opportunities to personalize treatment.

In a recent study by Richard Houlston, MD, PhD, Professor of Molecular and Population Genetics at The Institute of Cancer Research, London, new genes were identified that are involved in the development of multiple myeloma.

The study was based on genomic data gathered by the MMRF's CoMMpas study with whole genome sequencing from 765 patients and whole exome sequencing from 804 patients.

Sixteen genes were found to be mutated in regions that code the DNA. Fifteen genes were mutated in non-coding areas. Some examples of their findings include:

A mutation of the NBPF1 promoter (which is regulated byNF-κB). This gene is part of the neuroblastoma breakpoint family which is also over-expressed in sarcomas and non-small-cell lung cancer. This discovery could suggest the development of new myeloma drugs targeting this protein.
The increase of MYC through gene amplification or translocations is well known in myeloma to be problematic, but Houlston and colleagues also fond that MYC could be altered in additional ways.
The tumor suppressors PAX5 and HOXB3 is consistent with their lowered expressing contributing to development and progression of myeloma and other B-cell cancers. They added TWEAK, TRAF2, and PRKD2 to the list of genes disrupted via coding mutations.
They showed COBLL1 as mutated in a non-coding regulatory region, and identifed MAP3K14 as increased through translocation to the IG loci.

"Our findings provide integrated analysis of novel coding and non-coding drivers in multiple myeloma, demonstrating the genetic complexity contributing to this malignancy. Thus by developing a more comprehensive picture of the underlying genetic basis of MM, we extend the list of genes and pathways for which novel therapeutic agents may be identified through network-based drug search methodologies, offering the prospect of future individualized therapy in multiple myeloma."