Structural chromosomal rearrangements and the multi-step progression of multiple myeloma
Gareth MorganPhD, MD, FRCPath, FRCP
New York University School of Medicine
Project Term: July 1, 2019 - June 30, 2022
Two newly identified structural DNA changes, termed chromothripsis and chromoplexy, result in the formation of new chromosomal structures where multiple genes can be deregulated simultaneously. These events involve the relocation of super-enhancers to the sites of oncogenes, which provides a strong drive for cancer progression, an association with high-risk status, adverse prognosis, and punctuated evolution.
In multiple myeloma (MM) chromosomal structural variants deregulate oncogene function by complex rearrangements termed chromoplexy and chromothripsis that place strong gene control element, a super-enhancer, next to a critical target gene or combination of genes. Using next generation sequencing as a tool to screen the non-coding regions of the MM genome, we will identify these events, determine their molecular associations, contribution to clinical outcome, and the mechanisms by which multiple target genes are deregulated. This work will inform a generalizable mechanism that can be therapeutically targeted in both MM and other cancers.