Understanding genomes helps identify kids more likely to develop second cancers

Dr. Kim E. Nichols was a medical student and then a junior oncologist in training when a series of landmark discoveries transformed her field. For centuries, doctors recognized hereditary cancers from family histories, but in the late twentieth century, scientists started to identify the genetic mutations responsible for driving the development of some cancers. In the mid 1980s, scientists identified mutations in the RB1 gene as drivers in retinoblastoma, a rare eye cancer often diagnosed in children under age 3. 

In the mid-1990s, scientists discovered the BRCA1 and BRCA2 genes. Mutations in either of these genes were responsible for predisposing women to breast and ovarian cancer. Researchers found that mutations in BRCA1 could increase a woman’s lifetime risk for developing breast cancer by 10 times. Once researchers could identify gene mutations driving these cancers, they next developed genetic testing for earlier detection and management of risk. Doctors started offering women testing for their hereditary risk of breast cancer in 1996, and the results were being used to guide clinical care.

Against this backdrop of discovery, Nichols hoped to capitalize on the emerging understanding of the role that genes and ancestry play in the development of cancer. It made her wonder if she could develop a predisposition program for children with cancer, too. 

At the time, her idea was new, and it led to some debate.

“Back in the 1990s my colleagues thought, ‘Why would you want to test children for hereditary cancer? There is nothing you can do if you learn that a child tests positive for an underlying predisposition. All that this information might do is cause worry on the part of the parents or the patient.” 

In the beginning “there was much reluctance to even consider genetic testing of children for hereditary cancer risk,” said Nichols, MD, who is Director of the Division of Cancer Predisposition at St. Jude Children’s Research Hospital®. 

Undaunted, she chose that path, starting a cancer predisposition clinic at the Children’s Hospital of Philadelphia. But she eventually came to St. Jude in 2014, inspired by the hospital’s strong research focus and its emphasis on studying the genetic origins of childhood cancer and seeking new cures. 

The Pediatric Cancer Genome Project (PCGP), a collaboration launched in 2010 between St. Jude and the Washington University School of Medicine, became the world’s most ambitious effort to study the genetics of pediatric cancer by mapping out the genomes of both normal and tumor cells of over 800 children with cancer. This data enabled identification of the genetic changes that drive the development of cancer in many children who are diagnosed with this disease.

“The PCGP served as a catalyst for transformative research,” St. Jude President and CEO James R. Downing, MD, said. “St. Jude Cloud, the world’s largest storehouse of childhood cancer genomics; pre-clinical resources such as PROPEL and the Childhood Solid Tumor Network; and the St. Jude Cancer Predisposition Clinic can all be traced back to the project.”

Discoveries made by the PCGP laid the foundation for the Cancer Predisposition Clinic that Dr. Nichols and her team run, which, since 2015, has seen more than 5,200 patients and identified over 1,100 with an underlying predisposition syndrome. 

“I knew there would be a tremendous opportunity to set up a program that could capitalize on the advances of the PCGP to improve the outcomes for children and families with hereditary cancer” Nichols said. “I feel very fortunate Dr. Downing was very keen on having me come help transition genomic testing from the research space that had been established through the PCGP into the clinical space.”

Data and insights generated from sequencing the genomes of childhood cancer patients have fueled the work Nichols and her colleagues are doing to determine why some kids are more prone to cancer than others. Those insights have also shown doctors what can be done to catch new cancers early when they can be more readily treated and cured.

The benefits of using insights gained from genetic testing can be seen in patients like Claudia, who was referred to St. Jude in 2015, when she was 8 years old and diagnosed with rhabdomyosarcoma, a cancerous tumor that develops in soft tissue. She was treated on a clinical trial protocol that included chemotherapy and surgery to remove the tumor. 

“You’re just running on adrenaline at that point. You’re not even processing everything you’re hearing, but all I was thinking was, ‘I’ve got to get my daughter the best treatment,’” Claudia’s mother Amanda said.

In addition to treatment for her rhabdomyosarcoma, St. Jude offered something else critical for Claudia. Because Claudia’s initial rhabdomyosarcoma diagnosis suggested the likelihood of a germline DICER1 gene mutation, St. Jude recommended genetic testing for that mutation. Notably, today, all St. Jude patients are offered general screening of 123 genes associated with cancer predisposition as part of clinical genomics testing, a major legacy of the PCGP. 

Nichols said most families whose children have cancer express interest in genetic testing because they want to know why their child might have gotten cancer in the first place and whether their child is at increased risk for additional cancers in the future.  

In Claudia’s case, the testing confirmed she had a DICER1 mutation which causes a syndrome that makes developing cancers more likely. These cancers can develop in various organs, including the lungs, kidneys, thyroid, brain, eyes and elsewhere. The goal of the genetic testing is to provide knowledge that will not only guide St. Jude physicians in treating Claudia but also in providing Claudia’s family with an understanding of the hereditary condition so they can make informed choices affecting their own health.  

Based on the knowledge of her syndrome, St. Jude doctors recommended surveillance for the development of new tumors. “Surveillance is not going to prevent cancer,” Nichols said. “But the goal is to pick up subsequent tumors at their earliest and most curable stages.” Smaller tumors need less invasive surgery, she said, and can sometimes be treated with less or even no chemotherapy.

Surveillance for new cancers led to the discovery of Claudia’s thyroid cancer in 2018 and later an ovarian tumor in 2019. Doctors were able to cure these tumors thanks to the early detection and treatment allowed by earlier surveillance.

“It was such a relief for me that we knew about (the thyroid cancer) so soon,” Amanda said. 

“In the past, people with genetic predisposition were identified based on specific clinical features like family history of cancer, physical differences and specific tumor types”, Nichols said. However, these features do not help doctors identify all patients with predisposition. So, Nichols said, the only way to identify all patients is through broad molecular testing, where clinics like hers offer patients genetic testing for a large number of cancer predisposition genes. In applying this approach, Nichols and her team have identified that almost 1 in 5 children with cancer carry a cancer predisposing change in one or more of these genes. 

“This information is critical as it may explain why the child got cancer and it also informs future cancer screening, cancer prevention, and testing of other family members,” she said. “For many patients this clinically relevant information would have been missed had one followed the traditional genetic counseling/risk assessment approach.”

In a study published last year, Nichols said her clinic followed 274 patients with an underlying predisposition syndrome for a median of 3 years, and found that 10% of those children developed new cancers by screening. They also learned that some of the children already undergoing treatment for an existing cancer had developed a different kind of cancer. Significantly, early discovery through surveillance allowed surgeons to completely remove close to three quarters of the tumors, meaning that the cancer was discovered early enough for good local control, a factor critical for ensuring the best outcomes for patients.

“Previously, oncologists might have waited to screen for second cancers until they had finished treating a child’s first cancer, Nichols said. Now, she said, they know to act quickly and to begin screening as soon as it is determined that a child has an underlying cancer predisposition. 

Diagnosis of DICER1 syndrome through genetic testing, early detection due to surveillance based on cancer predisposition and routine follow ups at St. Jude helped Claudia survive thyroid and ovarian cancers. 

Today, Claudia is 18 and in college, where she plans to study nursing. She is a part-time nanny for a family with young children and spends her free time with friends on the beach, watching movies and painting.

“She’s different from most kids her age,” Amanda said. “She doesn’t have teenage drama…because when you have been through what she’s been through you don’t let petty things bog you down.” 

Amelia Salas lost her son Juan to brain cancer. She’s counting on what researchers and doctors at St. Jude Children’s Research Hospital are learning from genetic testing to give her younger son Javier the best possible chance at detecting cancer early and understanding his risk.

With a referral from her local hospital, the Arizona mother brought Juan to St. Jude to receive treatment for a rare brain tumor when he was 9. While he was in treatment, she was diagnosed with breast cancer.

When Amelia told Juan’s doctor about her cancer, he asked if she would be interested in genetic testing through the Cancer Predisposition Clinic at St. Jude to look at possible hereditary predispositions to cancer. Juan was tested and the results showed a mutation in a gene called TP53, which carries instructions for making a tumor-suppressing protein of the same name. TP53 mutations are common in many different cancers and are associated with a rare genetic cancer predisposing condition known as Li-Fraumeni syndrome.

People with Li-Fraumeni Syndrome have a high likelihood of developing cancer. Half develop some type of cancer by 30. By 60, the risk soars to 80 to 90 percent. People with Li-Fraumeni syndrome are also more likely to develop multiple cancers.

Did she want to know? Amelia asked herself. It could explain Juan’s brain cancer. Her breast cancer. What would it mean for Javier?

The results of testing showed that Amelia and Javier had the same TP53 mutation as did Juan.

Diagnosed with Li-Fraumeni syndrome, Javier is now a patient in the Cancer Predisposition Clinic, where he is seen for tumor surveillance. Twice a year, he undergoes scans and lab work at St. Jude so if any cancer develops, doctors will catch it early.

Now, 16 years old, Javier is working with doctors to transition to managing his own health care. Having a cancer predisposition syndrome likely increases the risk of developing cancers later in life, so Javier is learning about the importance of continuing health care into adulthood. He is being prepared to tell primary care providers about his Li-Fraumeni Syndrome and the risks it poses so that he can be an advocate in his own healthcare. Javier is learning how regular screenings can help to detect new cancers early, thus improving his chances for a successful outcome. The transition clinic will help him find adult healthcare providers in his community, transfer medical records to those providers and educate those providers about his cancer predisposition and related health care needs so the transition from St. Jude to adult healthcare is smooth. 

“Cancer predispositions are often lifelong – thus learning how to advocate for one’s health to ensure a successful graduation from St. Jude is very important,” said Kim E. Nichols, MD, director of the Cancer Predisposition Division. “My team has developed a transition program to help teens and young adults with genetic predisposition and their parents prepare for this process. We are also carrying out several research studies to assess the impact of this transition program. Our hope is that this program will ensure the best outcomes for our patients and their families.”