Medical mystery: Madeleine Martin and her mom, Katie, both developed kidney cancer as children. Yet, no mutations have been found to account for the disease. “There has to be a genetic link, with both of them getting cancer at the exact same age,” Madeleine’s dad says. “We just haven’t found it yet.”
Madeleine Martin has her mom’s rich, brown eyes and her dad’s broad, engaging smile. She has her mother’s hair and her daddy’s hands. But one similarity has befuddled both her family and the medical community: Like her mom, Madeleine developed a cancer of the kidney called Wilms tumor.
The odds of a parent and child having this rare cancer are miniscule.
In 1979, Madeleine’s mom, Katie, then 18 months old, received Wilms tumor treatment at St. Jude Children’s Research Hospital. When Katie grew up and became a nurse practitioner, she learned her baby would have only a 1 to 3 percent chance of having that cancer. Nevertheless, soon after Madeleine’s birth, Katie requested an ultrasound—not because her baby had exhibited symptoms, but because of a small, nagging concern.
Sure enough, the scan showed Madeleine had Wilms tumor.
Genetic testing revealed no mutation that would account for the disease in both mother and daughter. The Martins enrolled in a Wilms tumor study at another medical center. Again, no common mutation was found.
“There has to be a genetic link, with both of them getting cancer at the exact same age,” says Katie’s husband, Justin. “We just haven’t found it yet.”
In search of medical mysteries
St. Jude recently opened a new study aimed at uncovering answers to this and other unexplained familial cancers. It is the largest effort to date at St. Jude to discover additional cancer predisposition genes.
The SJFAMILY clinical trial is designed to find out why some cancers run in families and why certain individuals get more than one cancer. The study is open not only to St. Jude patients, but also to families worldwide who have possible hereditary cancers.
“We want to talk with families like the Martins, who have gone through testing already to figure out the link and have come up negative,” says Chimene Kesserwan, MD, of St. Jude Oncology.
She and her colleagues are seeking individuals who developed one or more cancers, with the first cancer before age 26, and who also have close relatives (such as children, parents, siblings, aunts, uncles or grandparents) diagnosed with cancer before age 50. The researchers would like to enroll members of these families into the research study, both those with and those without cancer. The researchers are also looking for people who have known genetic conditions that increase the risk of cancer.
The ambitious project aims to enroll about 3,000 participants over the next 10 years. Kesserwan, the study’s principal investigator, has already received inquiries from physicians as far away as Argentina, Australia, Ireland and Lebanon.
“The word is out,” she says.
Birth of a registry
Kim Nichols, MD, director of the St. Jude Cancer Predisposition Division, envisions the study will result in a rich registry of clinical data and biological samples. Researchers will delve into that resource to identify new cancer predisposition genes and syndromes.
“We know the causes for some familial cancers,” Nichols says. “But some families—like the Martins— have members with cancer and we don’t know why. Sometimes, people in the same family may develop more than one cancer. Why does that happen? The answer may lie in the genes. But the genes that cause those particular cancers have not yet been identified. That’s what we hope to do through the SJFAMILY study.”
Participation is easy, and can occur without traveling to St. Jude. Individuals in the study simply provide blood samples and health information that will be used for current and future research. When possible, scientists will also collect and store other biological specimens such as leftover tumor or bone marrow samples.
Thus far, St. Jude has enrolled about 60 families, including the Martins.
SJFAMILY is open not only to St. Jude patients, but also to families worldwide who have possible hereditary cancers.
Researching genetic inheritance
Changes in DNA can lead to cancer and other diseases. Through SJFAMILY, scientists will use DNA sequencing to look for genetic changes in the donated samples. This technology “reads” each letter of DNA to find mutations that may contribute to cancer development. Nichols and Kesserwan emphasize the research study does not take the place of clinical genetic testing or counseling.
The samples and information submitted for SJFAMILY will be used as part of a larger ongoing research project. Scientists in the St. Jude Computational Biology Department will use innovative approaches and visualization tools to analyze the massive amounts of data that will be accumulated through the project.
Because this long-term study is designed to find connections among samples, every family may not necessarily receive details about their specific situation. Families who are interested in learning such information should pursue clinical genetic counseling and testing.
Mark the markers
In addition to identifying new genes, researchers hope to find genetic markers that might influence how a known genetic syndrome presents within a particular family. For instance, in some families, cancers occur in younger individuals. In other families, the cancers may only affect a given organ. What influences whether a person gets cancer?
“There are some people who have increased risk to have a certain disease but they don’t get that disease,” Nichols explains. “One reason may be that certain people have a genetic modifier. For example, there are people who harbor changes in a cancer predisposition gene who never develop cancer despite having an increased risk. Sometimes in the same family we even see two people with the same mutation where one person develops cancer and the other does not.
“So, the second aim of the study is to try to identify genetic markers that might influence how a disease manifests in a family with a known genetic condition.”
How does St. Jude find the connections?
The SJFAMILY study will use whole-genome and whole-exome sequencing to discover new cancer predisposing genes.
looks at a slice of the human genome—about 1–2%
determines the exact order of the 3 billion nucleotides in our DNA
These processes enable researchers to find as many genetic abnormalities as possible. The findings may lead to new and better ways to diagnose and care for people with familial cancer.
The big picture
St. Jude researchers predict the project’s findings may also extend far beyond childhood cancer.
Studying rare familial syndromes can have broad implications to our understanding of cancer biology. For instance, RB1 was the first gene identified that was linked to a familial form of cancer: the eye cancer retinoblastoma. Only 250 to 300 children in the United States are found to have retinoblastoma each year. About 40 percent of those have a hereditary form of the disease.
So why study a familial link that affects so few people?
“It turns out the genes altered in the healthy cells of people with familial cancers are often the same genes altered more broadly in cancer cells in general,” Nichols explains. “The RB1 gene and genetic pathway is one of the mostly commonly altered genes in all of human cancers.”
For example, in addition to retinoblastoma, RB1 mutations are also implicated in the development of bladder cancer as well as some cancers of the lung, breast, bone and skin.
Today’s research, tomorrow’s cures
Many families who take part in SJFAMILY simply want to help St. Jude make discoveries that will help future generations.
For the Martins, participation is a way to give back to the hospital that saved the lives of both Katie and Madeleine. But the family also understands the intrinsic value of research.
“Scientific advancement is the reason Madeleine’s alive,” Justin says. “And it’s got to keep going. Cancer happens when genes have an error. If scientists can figure out how to stop that error from happening so others won’t have to go through significant treatment, it would be a fantastic objective and worth achieving.”
Learn more: stjude.org/SJFAMILY
From Promise, Winter 2018