Dr. Maureen Murphy, Ira Brind Professor and program leader of the Molecular & Cellular Oncogenesis Program of The Wistar Institute Cancer Center, has been investigating the importance of inherited mutations in the gene encoding p53 tumor suppressor protein to determine cancer susceptibility in people of African descent and people of Ashkenazi Jewish descent, for the past twenty-two years.
Dr. Murphy published her most recent scientific findings in the journal Cancer Research, together with her research collaborators from more than eleven research hospitals throughout the country, including the University of Pennsylvania and Children’s Hospital of Philadelphia.
The p53 protein is one of the body’s best defenses against cancer and is necessary for response to chemotherapy, overseeing the cell’s fate after assaults that cause DNA damage and other stress stimuli. Controlling several different cellular responses, just like the director of an orchestra keeps all the instrument sections and their musical notes synchronized, p53 decides if cell damage can be repaired or calls for the extreme solution — eliminating the affected cells to prevent malignant transformation. It is through the fundamentally important scientific studies connecting basic science with clinical care, such as Dr. Murphy’s latest publication, that the world is becoming better positioned to implement targeted personalized medicine approaches to improve health care.
Dr. Murphy describes p53 as the most important protein in our body. She explained the significance of the new study and how it came to be in this Q&A.
Q: Since p53 is so important, what happens when it doesn’t work?
A: Mutations in the p53 gene that are acquired during one’s life can compromise the protein’s function and its ability to restrain cancer development. Indeed, p53 is the most mutated gene in cancer. People who are born with inherited p53 mutations have a 90 percent chance of developing cancer in their lifetime, including soft tissue and bone sarcomas, breast cancer and leukemia, a rare condition called Li-Fraumeni Syndrome (LFS). Often, these tumors arise during childhood or early in life, and individuals have multiple tumors throughout their lifetime. These families frequently describe their experience as being "stalked by cancer".
Q: How important is it for these individuals to know their genetic background?
A: Diagnosis of LFS is critical to help affected families understand their risk and seek appropriate screening for early cancer detection. In these cases, cancer screening is extremely aggressive. Unfortunately, there are many different p53 mutations that correspond to a wide variety of cancer types and risk levels, and we do not yet know if all mutations require the same level of screening. Therefore, it’s very important to identify those mutations and understand what they mean for patients in terms of cancer risk and age of onset.
Q: What did you discover in this new study?
A: Studying eight different families, we identified a rare, lower-risk p53 mutation that is associated with LFS cancer types, but at slightly lower rates and with significantly later age of onset of pediatric cancers. This mutation causes a milder defect in p53 function than other LFS p53 mutations — something we call ‘hypomorphic mutations,’ which result in reduced expression or functional performance of a protein, but not a complete loss. Hypomorphic mutations are rare and typically tend to recur within one ethnicity. We refer to these as ‘founder’ mutations because one or more ancestors in the affected population were carriers of the altered gene and passed it down to their descendants. This specific mutation tracks within the Ashkenazi Jewish population.
Q: How did you start this collaboration with so many other institutions to study this p53 mutation?
A: I gave a seminar at Penn and Dr. Maxwell was in the audience. A few days later, she wrote to me saying she had interesting cancer cases in her clinic and we decided to work together to figure out whether there was a new hypomorphic mutation behind those cases. Science at its best is when we are able to join forces and combine our questions and expertise to solve a biological puzzle and ultimately advance patient treatment.
Q: What pieces of the p53 puzzle are still missing?
A: We need to continue these types of studies to better understand the p53 genetic landscape across populations and the implications of each mutation. I believe that will inform better clinical management of patients and, importantly, help find new specific therapies. We know that people who carry these hypomorphic mutations respond poorly to standard cancer therapy. At the same time, their genetic differences might result in specific vulnerabilities of their tumors. The focus and passion of my lab is to look for these therapeutic vulnerabilities and exploit them to find drugs that can do better for these patients so that we can ultimately tailor therapy to their specific genetic background. We think that a personalized medicine approach, based upon the genetics of the individual and the tumor, is the next frontier for cancer research, and we aim to be at the cutting edge of this frontier.