Gray Matters- Brain Tumors and Li-Fraumeni Syndrome

In 1969, Dr. Frederick Li was having a casual conversation with a couple of colleagues at the National Cancer Institute. He became intrigued by hearing of a family who had 3 young patients with rare soft tissue sarcomas. This cancer was so rare- it was estimated at the time only 1 person per 100,000 would be expected to develop it. Upon further examination, Dr. Li noticed other cancers in family members. Dr Li and Dr. Joseph Fraumeni examined charts in 17 different hospitals across the US to see if there was a link between these sarcomas and a family history of cancer.  They found 24 families, 151 family members who fit into this group. Each family had a member who developed sarcoma before age 45 and at least 2 other relatives with cancer before age 45. Only 10% of cancers are expected to develop in this age group. Close to 60% of the cancers were breast and sarcomas. 14 patients were found to have brain tumors. The syndrome was temporarily referred to as Sarcoma, Breast, Leukemia, Adrenocortical Carcinoma Syndrome. SBLA.

At that point- there was a definite suspected genetic link. It was years later that a germline mutation in the p53 tumor suppressor gene was identified and the syndrome was named after the 2 young clinical researcher's who traveled the country looking for clues. For decades, p53 and it's roles in cancer have been researched. Each new discovery seems to open more doors to new pathways, treatment potentials and control of errant cancer.

Most of the Core LFS cancers behave badly. They are angry, they don't respond well to therapy and they crowd out the healthy needed cells. Brain tumors are known for their aggressive nature in LFS. It is estimated that 13% of tumors in LFS before age 45 are brain tumors. The majority of those tumors are astrocytomas. In 2002, an examination of the roles of p53 in various brain neoplasms helped illuminate one of the roots of the problem. Cellular studies revealed that when wild type(functioning) p53 was expressed in brain tumor cells- it suppressed the aberrant growth. On the other hand- when there was a loss of p53 function(as there is in mutant p53) the cells immortalized- they kept growing and growing and growing. Mouse studies show that inactivation of p53 correlates with the beginning of tumor formation. There is also a noticeable relationship between p53 and the aggressiveness of brain tumors. Mutant p53 plays a role in the progression of cells from low grade to high grade cancer and p53 status is used to determine prognosis.  What does this mean for people with germline p53 mutation? Routine screening for brain tumors- promotes the chance of catching tumors early, before they progress to  high grade tumors.  The Toronto Protocol and MDAnderson's LEAD Program both recommend annual brain MRIs for LFS screening.

The good news is that with earlier screening and detection, many are LIVING healthy lives even after having a brain tumor.

Li, F.P and Fraumeni, J.F. Jr. Soft-Tissue Sarcomas, breast cancer and other neoplasms: a family syndrome? Ann. Intern. Med., 71-747-752, 1969

Li FP. Keynote lecture. The familial syndrome of sarcomas and other neoplasms. Princess Takamatsu Symp. 1987;18:243-9. Review.

Sakar, C. p53 in Brain Tumors: Basic Science Illuminates Clinical Oncology. Indian J. Hum. Gen 2002;8:52-9.