Mary Lou McMaster, MD, has spent her entire career at the National Cancer Institute (NCI) searching for the genetic underpinnings that give rise to Waldenstrom's macroglobulinemia (WM).
After searching for decades, she has yet to uncover a "smoking gun," though a few tantalizing clues have emerged along the way.
"Our questions are pretty basic: Why are some people more susceptible to developing WM, and why does WM sometimes cluster in families?" she explained. It turns out that the answers are not at all simple.
Dr. McMaster described some of the clues that her team at the Clinical Genetics Branch of the NCI has unearthed in a presentation at the recent International Waldenstrom's Macroglobulinemia Foundation (IWMF) 2021 Virtual Educational Forum.
Commenting after the presentation, Steven Treon, MD, PhD, professor of medicine, Harvard Medical School, Boston, who is collaborating with Dr. McMaster on this work, said: "From these familial studies, we can learn how familial genomics may give us insights into disease prevention and treatment."
Identifying affected families
Work began in 2001 to identify families in which two or more family members had been diagnosed with WM or in which there was one patient with WM and at least one other relative with a related B-cell cancer, such as chronic lymphocytic leukemia.
For a frame of reference, they enrolled some families with only one member with WM and in which there was no known family history of the disease.
"Overall, we have learned that familial WM is a rare disease but not nearly as rare as we first thought," Dr. McMaster said.
For example, in a referral hospital setting, 5% of WM patients will report having a family member with the same disorder, and up to 20% of WM patients report having a family member with a related but different B-cell cancer, she noted.
NCI researchers also discovered that environmental factors contribute to the development of WM. Notable chemical or occupational exposures include exposures to pesticides, herbicides, and fertilizers. Infections and autoimmune disease are additional factors.
"This was not a surprise," Dr. McMaster commented regarding the role of occupational exposures. The research community has known for decades that a "lymphoma belt" cuts through the Midwest farming states.
Focusing on genetic susceptibility, Dr. McMaster and colleagues first tried to identify a rare germline variant that can be passed down to offspring and that might confer high risk for the disease.
"We used our high-risk families to study these types of changes, although they may be modified by other genes and environmental factors," Dr. McMaster explained.
Much to their collective disappointment, the research team has been unable to identify any rare germline variant that could account for WM in many families. What they did find were many small changes in genes that are known to be important in B-cell development and function, but all of those would lead to only a small increase in WM risk.
"What is holding us back is that, so far, we are not seeing the same gene affected in more than one family, so this suggests to us either that this is not the mechanism behind the development of WM in families, or we have an unfortunate situation where each family is going to have a genetic change that is private to that family and which is not found in other families," Dr. McMaster acknowledged.
Sheer difficulty
Given the difficulty of determining whether these small genetic changes had any detrimental functional effect in each and every family with a member who had WM, Dr. McMaster and colleagues have now turned their attention to genes that exert only a small effect on disease risk.
"Here, we focused on specific genes that we knew were important in the function of the immune system," she explained. "We did find a few genes that may contribute to risk, but those have not yet been confirmed by us or others, and we cannot say they are causative without that confirmation," she said.
The team has gone on to scan the highway of our genetic material so as to isolate genetic "mile markers." They then examine the area around a particular marker that they suspect contains genes that may be involved in WM.
One study they conducted involved a cohort of 217 patients with WM in which numerous family members had WM and so was enriched with susceptibility genes. A second cohort comprised 312 WM patients in which there were few WM cases among family members. Both of these cohorts were compared with a group of healthy control persons.
From these genome studies, "we found there are at least two regions of the genome that can contribute to WM susceptibility, the largest effect being on the short arm of chromosome 6, and the other on the long arm of chromosome 14," Dr. McMaster reported. Dr. McMaster feels that there are probably more regions on the genome that also contribute to WM, although they do not yet understand how these regions contribute to susceptibility.
"It's more evidence that WM likely results from a combination of events rather than one single gene variant," she observed. Dr. McMaster and colleagues are now collaborating with a large consortium of WM researchers to confirm and extend their findings. Plans are underway to analyze data from approximately 1,350 WM patients and more than 20,000 control persons within the next year.
"Our hope is that we will confirm our original findings and, because we now have a much larger sample, we will be able to discover additional regions of the genome that are contributing to susceptibility," Dr. McMaster said.
"A single gene is not likely to account for all WM, as we've looked carefully and others have looked too," she commented.
"So the risk for WM depends on a combination of genes and environmental exposures and possibly lifestyle factors as well, although we still estimate that approximately 25% of the heritability of WM can be attributed to these kinds of genetic changes," Dr. McMaster predicted.
Dr. McMaster has disclosed no relevant financial relationships. Dr. Treon has served as a director, officer, partner, employee, advisor, consultant, or trustee for Janssen, Pfizer, PCYC, and BioGene.
A version of this article first appeared on Medscape.com