Amanda Flinn grew up worried about why so many of her family members had been diagnosed with cancer and died. Autumn, her sister, passed away when she was 3 years old from a brain tumor. Her cousin, Marty, was 8. Five other adult family members also passed away, including her father, who died from leukemia at age 46 – when Flinn was just 8.
“None of us could ever grasp the why, when, what of it all,” said Flinn, now 40, of Minden, Nevada. “Why so many? Why so young? Why our family? When will it stop? What is happening?”
Flinn first heard the words Li-Fraumeni syndrome after her cousin, Steven, passed away nearly 20 years ago. But at the time, not much was known about the genetic cause. When her brother, Paul, a 44-year-old nonsmoker, was diagnosed with Stage 4 lung cancer in 2017, he recommended she visit City of Hope to get tested for the syndrome and because he had heard City of Hope was a leader in diagnosis and treatment for Li-Fraumeni.
“The fear that came with this diagnosis was overwhelming,” said Flinn, who met with Jeffrey Weitzel, M.D., director of City of Hope’s Division of Clinical Cancer Genomics, Dr. Norman & Melinda Payson Professor in Medical Oncology and a well-known expert on Li-Fraumeni syndrome. “I was so nervous to hear what my future would hold, but for the first time I was educated, informed and was given a plan. I had hope.”
And now, there is even more hope for patients such as Flinn. City of Hope has received an $8.5 million, five-year grant from the National Institutes of Health to advance research and treatment for this serious syndrome, which can cause multiple cancers, including sarcomas, brain and breast tumors and adrenocortical cancers.
Seeking Better Screening, Treatment
“This is a devastating syndrome to have – we’ve cared for families with babies who had brain tumors at 18 months,” said Weitzel, the grant’s co-principal investigator. “City of Hope and our partner institutions are determined to develop a better understanding of the cancer risks associated with different TP53 mutations so we can better tailor screening, prevention and treatment for these patients. We are seeing the light at the end of the tunnel, but more research is needed.”
The project, termed LiFTUP (Li-Fraumeni and TP53 Understanding and Progress), which is co-led by Judy E. Garber, M.D., M.P.H., of Dana-Farber Cancer Institute, and Christopher I. Amos, Ph.D., of Baylor College of Medicine, will provide the largest and most comprehensive examination of TP53-associated cancer risk.
Traditionally, clinical TP53 testing was limited to individuals and families who met specific criteria (typically multiple cancers at very young ages). With the introduction of next generation-based multigene panel testing, which sequences a person’s genome faster and is less costly than previous genetic tests, TP53 testing is now performed on large numbers of people who do not meet the syndrome’s criteria. However, the testing has also raised concerns about false positives, or a test result that incorrectly indicates the syndrome is present.
That’s because blood samples are often used for genetic testing and people may develop TP53 gene mutations in rapidly growing blood cells as they age. Researchers will also examine this group of people to find out why some people in this group develop blood cancers while others do not.
A rare syndrome
The inherited syndrome is rare. Only about 1,000 children and adults nationwide are included in the Li-Fraumeni Exploration Consortium, and researchers working on this project will also recruit TP53 carriers identified through broader, more agnostic approaches to testing, including commercial genetic testing laboratories, the Geisinger MyCode project, the PROMPT study of individuals with germline mutations and the ORIEN tumor/germline sequencing project.
“Carriers of true germline TP53 mutations may bear the psychological, medical and financial costs of striking personal and family cancer risks, the burden of intensive surveillance, the high risks of cancer deaths at disproportionately young ages and the weight of possibly passing TP53 variants to offspring,” according to the team.
Consequently, a crucial question researchers want to answer is why some people with a TP53 mutation develop cancer while others do not.
“We’re looking at thousands of markers across the whole genome to find out if there are patterns that influence why two TP53 carriers with the same mutation have different outcomes,” Weitzel added. “We will do a clinical and molecular interrogation of the factors that influence the development of cancer.”
“Our hope is that by focusing more research on children and adults with the TP53 mutation, we will be able to take better care of these individuals,” Weitzel said.
Flinn couldn’t agree more. Weitzel advises patients with Li-Fraumeni syndrome to be examined every six months. They also receive a whole-body MRI (magnetic resonance imaging) every year, and adult women also receive an annual breast MRI. Although Flinn’s first body MRI was negative for cancer, a breast MRI six months later revealed a curable breast tumor.
Flinn received a double mastectomy and chemotherapy in fall 2018, a year after giving birth to a baby boy, Chance Alexander. She encouraged all family members to get tested. Her brother Paul’s daughter, Rylee Dosch, 22, was also found to carry the mutation.
“My brother was the catalyst that brought me to City of Hope,” said Flinn. “He wanted nothing more than for Rylee and me to have a fighting chance against this dreaded disease. I pray the brilliant minds at City of Hope find a cure, a way to flip the switch on this TP53 genetic mutation, a new way to fight.”
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For City of Hope's Rick Kittles, Ph.D., exploring genes and environments to understand health disparities among different populations isn’t just a scientific pursuit — it is a passion driven by social justice concerns.
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