The old adage that looks can be deceiving certainly applies to Kaden and Kristian Knecht. On the surface, the brothers seem strikingly different.
Light-haired Kaden, nearly 18, is serious, driven and goal-oriented, while slightly darker-featured Kristian, 15, sports a laid-back and fun-loving demeanor.
But the teens have one thing in common that neither would have chosen: Both were diagnosed two years apart with Hodgkin lymphoma, a cancer of the white blood cells in the lymph nodes. Now clinicians at St. Jude Children’s Research Hospital are determining whether the Knecht brothers also share a genetic mutation that may have caused the cancer to develop.
This St. Jude study, known as the FAMHL clinical trial, is on track to be the largest study ever conducted for families with a high frequency of Hodgkin lymphoma. It’s also the only such effort using whole-genome sequencing, which provides the most comprehensive DNA analysis possible.
The Knecht boys’ mother, Laura Duthu, was told that lightning doesn’t strike twice. She hated learning it actually could, but is thrilled that St. Jude may unearth the reason two of her four children developed the same type of cancer. Both underwent chemotherapy treatments at St. Jude and are now in remission.
“If they can figure out if there’s a genetic link, or what’s causing this, maybe in the future we could prevent something like this from happening to another family,” Duthu says. “You don’t often hear of the same type of cancer in siblings like this. I thought the study was a great idea.”
A gathering storm
Established research has shown that Hodgkin lymphoma—diagnosed in about 8,300 people in the U.S. each year—may run in families. But scientists have never identified possible genetic underpinnings of the condition, even in families where multiple cases strongly suggest an inherited risk.
St. Jude treats about 30 new Hodgkin patients each year. More than 20 families throughout the years have had more than one person diagnosed with the disease, including parents and children, says oncologist Jamie Flerlage, MD. She is running the FAMHL trial with colleagues Monika Metzger, MD, of St. Jude Oncology and Jun J. Yang, PhD, of Pharmaceutical Sciences.
Flerlage says there’s a two- to six-fold increase in the risk of developing Hodgkin lymphoma when a close family member has also had it. But she’s been stymied in her desire to explain why. Exposure to the Epstein-Barr virus—which causes mononucleosis—is a known risk factor (and one the Knecht brothers share), but not everyone who’s exposed to the virus gets Hodgkin. And little else would suggest the malignancy might occur more frequently in certain people.
“We don’t know the genetic risk—we just know from large population studies that there is a genetic link,” Flerlage says. “Right now, there’s no way to test anyone to say, ‘You don’t have it; you don’t have to worry.’ Even if you have someone in your family with Hodgkin, there’s nothing we can do except watch for clinical symptoms.”
We’re comparing genomes in each family, and comparing one family to another, to see if there’s a common gene or if there are specific genes in each family.
Glimmers of sunlight
Fortunately, survival rates for Hodgkin lymphoma remain quite high as the St. Jude research—expected to bear fruit in three to five years—continues.
“Today, more than 90% of patients survive and go on to lead normal, productive lives,” Flerlage says.
Like the Knechts, the vast majority of Hodgkin patients are adolescents or young adults, and the disease almost never strikes before age 10. Incidence peaks in the 20s and falls in the 40s, peaking again around age 65. Most Hodgkin lymphoma patients find telltale lumps or bumps, often in their necks, Flerlage says. Other key symptoms include unexplained fevers, weight loss and drenching night sweats. A tissue biopsy is needed to confirm diagnosis.
The Knecht boys’ treatment path mirrored that of most patients, who undergo two to six months of chemotherapy. Some patients also receive radiation, though Flerlage says doctors skip it whenever possible to avoid side effects and the associated risk of patients developing secondary cancers.
“In the past, everybody used to receive radiation as part of their treatment,” she says. “It’s only in recent years that we’ve found there are certain groups of patients who respond well enough to chemotherapy to not need radiation. And St. Jude was one of the institutions that led the effort.”
Research sparks discovery
Enrolling more than a dozen families so far since late 2016, the FAMHL study is centered around families in which the patient is 21 or younger and has a parent, sibling or child who has also had Hodgkin lymphoma. DNA samples are taken from those with a history of Hodgkin as well as from family members who’ve been unaffected in order to compare any differences. The study is being conducted in collaboration with the National Cancer Institute, which is also contributing samples collected over the last four decades from at least 30 families affected by Hodgkin lymphoma. This collaboration will expand the St. Jude efforts, strengthening the eventual findings.
Whole genome sequencing, a technique that deciphers every letter of a person’s genetic code, has been used by St. Jude investigators to identify potential disease-causing variants in participants’ germline DNA. Germline mutations are present in every cell of the body since birth, including tumor cells and normal cells, while so-called somatic mutations are only present in tumor cells.
A common current
Unaffected family members participating in the study are mostly close relatives, but can include cousins if a particular family tree suggests an aunt or uncle may have also had the disease, Flerlage notes. But every family in the study has at least one first-degree relative with Hodgkin lymphoma.
“We’re comparing genomes in each family, and comparing one family to another, to see if there’s a common gene or if there are specific genes in each family,” Flerlage explains, adding that this part of the process should take one to two years. The analysis will be done through Yang’s group and experts in the St. Jude Cancer Predisposition Division, who are specialists in identifying novel genetic variants.
All the families happen to be similar in at least one other aspect: They’re united in their commitment to the research.
“Every single family has been more than willing to participate, because they all have more than one person affected and have been asking the question ‘why’ the entire time,” Flerlage says. “Families also have the option to learn about their own results, and every family wants to do that because it may have implications for others in their family, or their kids. They’re worried about this already.”
The FAMHL clinical trial is on track to be the largest study ever done on families with a high frequency of Hodgkin lymphoma. It’s also the only such effort using whole-genome sequencing, which provides the most comprehensive DNA analysis possible.
Cause and effect
Flerlage and her colleagues believe that understanding the origins of Hodgkin lymphoma—whether critical genetic defects or variations related to risk—will accomplish several goals. Chief among them are the ability to proactively predict whether a patient’s family members will develop the cancer, as well as to create targeted drugs based on its biological and molecular features.
If researchers do find a particular mutation running in a family that places members at a higher risk for cancer, those consenting to receive that information may benefit from genetic counseling, she says.
Flerlage specifically hopes a gene defect is discovered that definitively means Hodgkin will develop in an affected person. Such a clear cause-effect link would translate into less gray space in helping families understand what to expect and how to cope.
“Because Hodgkin is widely curable,” she says, “it’s less of a goal to prevent it than find a way to offer predisposition counseling to other family members and offspring and then to find a new target for treatments.”
An eye on the sky
After ushering two children through cancer treatments, Duthu is justifiably worried that Hodgkin lymphoma may strike yet another of her offspring, who include a 20-year-old daughter and 7-year-old son. But she says she’s relieved that St. Jude clinicians are doing everything possible to figure out whether that’s a possibility.
“They may find something, they may not…maybe 10 years down the line, maybe never, maybe tomorrow,” she says. “My hopes are they are able to come to some conclusion on why this is happening or what caused this, but if they don’t, I’m OK with that.
“Despite the cancer, the whole St. Jude experience has been God-sent,” she adds.
From Promise, Spring 2018