In a paper published in Nature Communications, researchers at the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine have shown that copy number variation signatures can accurately predict whether multiple myeloma patients have catastrophically smashed and aberrantly reassembled chromosomes (chromothripsis). These findings could help clinicians better understand a patient’s risk and guide treatment.
“Chromothripsis is a complex genomic event, in which one or more of the chromosomes is shattered and the pieces rejoined,” said co-senior author Francesco Maura, M.D., assistant professor and co-PI in the Myeloma Genomic Lab. “Rejoining so many chromosomal pieces creates these multiple copy number variations, which is a strong prognostic factor for patient outcomes in multiple myeloma.”
In the study, the researchers used whole genome sequencing data from 752 myeloma patients to measure copy number variations (CNVs) signatures and determine whether they are linked to chromothripsis. Later, the team performed a similar analysis using whole exome sequencing (which only includes gene sequences) from 677 myeloma patients.
In both analyses, CNVs were strongly linked to chromothripsis. This is important because exome sequencing only covers a small portion of the genome and is easier and less costly to perform.
The study also showed that chromothripsis behaves differently in multiple myeloma. In solid tumors, chromothripsis tends to happen far into cancer progression, after many chromosomal and genomic quality control mechanisms have been corrupted. However, the researchers found it is often an early event in myeloma.
“Even in patients with precursor myeloma, we find chromothripsis many years before they progress to full-blown disease,” Dr. Maura said. “Also, chromothripsis is usually conserved over time, which means that once the chromosomes are damaged in this way, they don’t recover.”
This ability to detect chromothripsis in early stage patients could offer therapeutic benefits. Increased CNVs may indicate a patient is more likely to progress from a precursor condition, such as smoldering myeloma, to multiple myeloma, providing opportunities to get a head start on aggressive treatment.
Looking at Long-term Implications
The authors note that more work needs to be done to better understand the long-term implications of chromothripsis in myeloma patients. Overall, these chromosomal rearrangements tend to indicate poor outcomes — but not for every patient. Scientists need to unwind the events that lead to chromothripsis to better understand the process.
“The uniqueness of the early stage catastrophic events in this disease have definite clinical implications,” said co-senior author Ola Landgren, M.D., Ph.D., professor of medicine, chief of the Myeloma Service and PI of the Myeloma Genomic Laboratory. “Some patients are asymptomatic for years and screening for copy number variations could affect their course of treatment. On the other hand, we need to really understand which patients are going to progress, and for that we are conducting carefully designed clinical trials to decipher the underlying biology of progressive versus stable disease. We are establishing a world-leading Institute focusing on these questions here in Miami.”