Multiple Myeloma’s Timeline Revealed
Summary
- Multiple myeloma initiates from DNA-damaging events that occur two to four decades before diagnosis.
- This and other findings emerged from a study that uncovered the timeline of DNA damage during development of the disease, led partly by Sylvester researchers.
- The results broaden the understanding of the condition and may lead to new precision medicine strategies.
Cancer is a riot of DNA damage. Chromosomes break, others duplicate. Chunks of DNA attach to new regions of the genome. Changes in the four-letter DNA code push cells to divide, survive, thrive and strive to take over the body.
All this damage doesn’t happen at once. It begins quietly, often with only one mutation setting the stage for further genomic mishaps that slowly nudge cells to a cancerous state.
Scientists know that sequential accumulation of damage is typical across tumor types. But key aspects of the timeline, such as which mutations precede others, are murky.
A new study maps out the timeline of DNA damage for multiple myeloma, the second most common blood cancer. The findings may lead to better ways to group patients by the state of their DNA and define new subtypes of disease to predict treatment strategies and outcomes.
“Better definition of biological subtypes of multiple myeloma is critical for the development of precision medicine treatment strategies,” said study author C. Ola Landgren, M.D., Ph.D., director of the Sylvester Myeloma Institute at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine. “The goal is to optimize clinical outcomes for patients.”
The findings also back up previous estimates of a very long timeframe for multiple myeloma development. The first initiating genomic events can occur as early as four decades before diagnosis, the new data reveal.
The findings were published in Nature Genetics.
A Giant Dataset
The study involved multiple institutions, including Sylvester, Memorial Sloan Kettering Cancer Center (MSKCC) and the German Cancer Research Center (DKFZ) in Heidelberg, Germany.
“Each institution has its own unique skill set. And our institution is well-versed in computational biology,” said co-first author Marcella Kaddoura, M.D., a Sylvester physician-scientist and assistant professor in the Miller School’s Myeloma Division who works closely with Dr. Landgren.
Dr. Kaddoura focused on teasing out key timeline information from a large dataset: 421 whole-genome sequencing profiles obtained from tumors of 382 multiple myeloma patients. Each of these profiles is a snapshot of mature disease. They were obtained primarily from newly diagnosed patients, with some patients also sequenced after treatment.
The trick was to extract historical information from the data. The genomes contained a host of DNA alterations. Which ones came first and which ones next?
To answer that question, Dr. Kaddoura and her colleagues turned to the molecular time model, developed partly by co-first author Francesco Maura, M.D., an MSKCC physician-scientist.
Peering into the Past
The molecular time model leverages an internal molecular clock within the genome. DNA accumulates a certain type of damage, called a point mutation, at a steady rate. Each point mutation is a single change in the AGCT code of DNA, such as a C turning into a G. And while some point mutations might be dangerous and promote cancer, almost all of them are benign.
These benign point mutations come along as travelers when a chromosome goes rogue and makes an extra copy of itself in a step toward tumor development. After that, the rogue chromosome begins to diverge and accumulate unique benign mutations.
The number of these unique mutations provides information about the timing of the duplication event. A low number indicates that the extra chromosome is young. A high number indicates that the extra chromosome has been around the cell for a while, accumulating benign point mutations over years.
The model incorporates such information to arrive at estimated timeframes for certain DNA damage events. The timing of translocations—wayward chunks of DNA attached to new chromosomes—is calculated similarly.
“The strength of this kind of analysis is that it can put cancer-driving mutations into a clinical and temporal context. In other words, we can effectively put an absolute time stamp estimate on when an aberration occurred,” said study author Benjamin Diamond, M.D., assistant professor in the Miller School’s Myeloma Division and a member of the Myeloma Institute and the Myeloma Genomics Lab.
The Multiple Myeloma Timeline
Multiple myeloma typically develops from an asymptomatic stage (MGUS) through smoldering multiple myeloma and, finally, to full-blown disease. This progression can take decades and mirrors the accumulation of DNA damage.
The researchers homed in on several key genomic events that often occur during this progression. These events include:
• The translocation of a DNA region called IGH to a region containing a cancer-promoting gene (canonical IGH translocation)
• The accumulation of at least two extra chromosomes (hyperdiploidy)
• The duplication of the long arm of chromosome 1 (chr 1q gain)
Major findings include:
• IGH translocation was the key initiating event in patients whose tumors also had hyperdiploidy. IGH translocation always preceded hyperdiploidy in these 10% of patients.
• Patients who acquired a chr 1q gain early in disease fared much worse clinically than patients who acquired it later. This finding suggests that the timing of chr 1q gain could serve as a prognostic indicator for patient outcome.
• Chr 1q gain also occurred in response to exposure to melphalan, a drug used prior to stem cell or bone marrow transplantation.
• DNA damage initiates many years before disease is evident. Consistent with other studies, initiating events typically occurred when people were in their 20s and 30s, decades before diagnosis.
“Until recently, I don’t think anyone really appreciated how early these events are occurring in some patients,” said Dr. Kaddoura.
The new study raises questions for future research, said Dr. Kaddoura. Can the DNA damage timeline reveal additional potential prognostic indicators, in addition to chr 1q gain? How might early DNA-damage events influence subsequent events? How do resistance mutations arise after treatment?
In the future, researchers may be able to develop a version of the molecular time model suitable for the clinic. Perhaps the model could be used to estimate patient survival or even potentially guide treatment, said Dr. Kaddoura.
“There is power in the timing of when these events occur in multiple myeloma,” said Dr. Kaddoura. “It’s not just about what the tumor is, but how it became that way and when.”
Tags: blood cancers, cancer research, clinical trials, Dr. Benjamin Diamond, Dr. C. Ola Landgren, Dr. Marcella Kaddoura, multiple myeloma, Newsroom, Sylvester Comprehensive Cancer Center