June 2024 | George M. Pikler, M.D., Ph.D., FACP, Lead Oncology Advocate N1X10

Why Does Everyone in My Family Get Cancer?

In 1967, epidemiologist Frederick Li attended a dinner party that would change the course of his career. Someone brought up the case of the Kilius family in Baltimore, in which the young father and his infant son had both been diagnosed with unusual cancers. Li knew the odds of this happening by chance were astronomical, so he visited the family to find out more. Over five generations, 14 out of 35 family members had developed cancers and 10 had died young. A family survivor described the tragic family events in the Saturday Essay of the Wall Street Journal on May 10, 2024.

Li and his colleague Joseph Fraumeni published their findings in 1969, but it wasn’t until the 1990s that the underlying cause of Li-Fraumeni Syndrome (LFS), a complex autosomal dominantly inherited disorder associated with early-onset cancers in diverse tissues of origin, was discovered: an inherited mutation in the TP53 tumor-suppressor gene encoding p53, a transcription factor triggered as a protective cellular mechanism against different stressors. Loss of p53 function renders affected individuals highly susceptible to a broad range of solid and hematologic cancers: breast cancer, central nervous system (CNS) tumors and sarcomas are particularly common, tumors can ultimately occur almost anywhere in the body.

Germline TP53 mutations are identified in 75% of patients with classic LFS. The lifetime likelihood of a TP53 mutation carrier developing cancer approaches 75% in males and almost 100% in females. Several genetic modifiers have been implicated to account for the phenotypic variability within and across LFS families; however, efforts to develop predictive algorithms of age of onset and type of cancers in individual patients have not yet found clinical use.

Although it is not possible to prevent cancers from forming in LFS patients, the primary focus for improving the prognosis is early tumor detection, leading to improvements in survival. All patients with LFS should be offered cancer surveillance as soon as the clinical or molecular LFS diagnosis is established: a combination of physical exams, blood tests, and regular imaging beginning at birth. Caregivers of LFS patients must also address the psychosocial needs of individuals and families with LFS.

A recent publication reports the use of a multimodal liquid biopsy with cell-free DNA (cfDNA) for the early cancer detection in LFS patients. This approach showed earlier detection of cancer in patients with LFS. The cfDNA assay provides improved accessibility and sensitivity, complementing current clinical surveillance methods to provide better care for these patients.

Cancer Discov. 2024. 14 (1): 104-119

Erica Cross, PA


Erica is a board certified Physician Assistant. She obtained her Master’s degree in Physician Assistant studies from Our Lady of the Lake College in Baton Rouge, LA. She began practicing in 2011 and has worked clinically in Orthopedics and Dermatology. The majority of her career has been spent in a Dermatology practice where she assisted in Mohs surgery, treating various types of skin cancer. She also teaches in the medical simulation department at the University of South Alabama and enjoys every aspect of medical education.