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 better 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, MD, PhD, 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 appear in the Aug. 20 issue of the journal 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, MD, a Sylvester physician-scientist who works closely with Landgren.
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, Kaddoura and colleagues turned to a method called the molecular time model, developed partly by co-first author Francesco Maura, MD, an MSKCC physician-scientist.
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, MD, a member of the Sylvester Myeloma Institute and the Myeloma Genomics Lab.
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 accumulation of at least two extra chromosomes (hyperdiploidy); the translocation of a DNA region called IGH to a region containing a cancer-promoting gene (canonical IGH translocation), and 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 percent 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, their 50s and beyond.
“Until recently, I don’t think anyone really appreciated how early these events are occurring in some patients,” Kaddoura said.
The new study raises questions for future research, she added. 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.
“There is power in the timing of when these events occur in multiple myeloma,” Kaddoura said. “It’s not just about what the tumor is, but how it became that way and when.”
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