22/10/2019
HOPE IN THE SHADOW OF THE LI-FRAUMENI SYNDROME
Source : Dana Farber Blog
-This post was originally published on Discoveries, the blog of Boston Children’s Hospital-
Jake was diagnosed with his first cancer — osteosarcoma — in 2007 when he was only 16 years old. Meanwhile, his mom was being treated for recurrent cancer and his brother also would soon be diagnosed with cancer. Within the space of a few years, all three family members had died. This was not the result of terrible coincidence but rather, a hereditary condition known as Li-Fraumeni syndrome (LFS).
It’s a story painfully familiar to families with LFS, a rare cancer predisposition syndrome caused by a mutation (alteration) in the TP53 gene. The cells that make up the human body use the TP53 gene sequence as a blueprint to produce the p53 protein, nicknamed the “guardian of the genome.” The p53 protein functions as a tumor suppressor, protecting us from developing certain cancers, such as leukemia, sarcoma, breast, and adrenal cancer. When TP53 has a mutation, a damaged form of the p53 protein is produced that does not function properly and allows cancer cells to develop and grow unopposed.
In patients with LFS who inherit a mutation in the TP53 gene, all the cells of their body produce some of this dysfunctional p53 protein, often resulting in the development of cancer at an unusually young age. More than 20 percent of those with LFS will develop a TP53-related cancer before their 20th birthday. Clinicians and scientists who study this syndrome hope that early detection of cancers in these patients will improve outcomes.
Jake’s mother was unaware she had LFS until it had already impacted the next generation of her family. And although diagnostic testing for LFS was available, by the time her family underwent testing, it was already too late to benefit her or her sons.
The search for tumor DNA in the blood
When he met Jake, Brian Crompton, MD, a pediatric oncologist, was a fellow at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. As Crompton’s career progressed, from trainee to physician scientist running his own lab, Jake’s story was never far from his mind.
Fresh out of his fellowship, he focused his research on the genomics of Ewing sarcoma. Soon after publishing his first study, describing the landscape of Ewing sarcoma mutations, Crompton says, “There were these papers coming out indicating you could find traces of cancer DNA circulating in the blood. It got me thinking, can we find tumor DNA in the blood of pediatric patients with Ewing sarcoma and other pediatric solid tumors?”
During the next few years, Crompton and his colleagues at Dana-Farber/Boston Children’s, along with collaborating researchers at other institutions, worked to develop assays that detect tumor DNA from blood samples, often called “liquid biopsies.” This novel, noninvasive approach, would allow molecular profiling of a tumor without having to obtain tumor tissue by a conventional surgical biopsy. Their published research established the mechanism by which circulating tumor DNA (ctDNA) can be detected and measured in patients with five of the most common pediatric solid tumors: Ewing sarcoma, osteosarcoma, neuroblastoma, rhabdomyosarcoma, and Wilms tumor.
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Learn about the creation of a multi-institute consortium, working to identify ways to detect cancer early in patients with Li-Fraumeni syndrome.
