A City of Hope team may have significantly improved diagnosis of a major inherited cancer syndrome. The study, the largest of its kind, could help at-risk families manage risk for associated diseases.

The researchers, led by Jeffrey N. Weitzel, M.D., chief of the Division of Clinical Cancer Genetics, and former City of Hope researcher Steve Sommer, M.D., Ph.D., analyzed family characteristics linked to Li Fraumeni syndrome, an inherited genetic disorder that almost invariably leads to cancer.

Jeffrey Weitzel (Photo by Alicia Di Rado)

People with Li Fraumeni syndrome have mutations in the p53 gene. When normal, the p53 gene gives rise to a protein that prevents many cancers from developing. However, mutations in that gene cripple the protective protein, allowing cancer to begin and grow.

Health professionals currently use several different sets of criteria, which examine family history, to diagnose Li Fraumeni syndrome. City of Hope researchers then applied these criteria to 525 patients they screened for the mutations that cause the syndrome.

Researchers found that 95 percent of patients who had disease-causing mutations fell into two of the standard sets of criteria — called classic Li Fraumeni syndrome and Chompret’s classification.

Taken separately, the two sets of criteria found only 56 percent and 35 percent of patients with mutations, respectively.

“More importantly, we were able to use unique data from a real-world group of patients undergoing clinical testing to create tables that aid clinicians in selecting patients for testing,” said Weitzel.

City of Hope’s Molecular Diagnostic Laboratory, which tests patient samples for genetic diseases, already employs the new table.

“We’re finding this information extremely helpful in estimating the likelihood of a patient having a p53 mutation,” said Juan-Sebastian Saldivar, M.D., director of molecular diagnostics. “It’s a simple tool that really helps us give our clients, and ultimately their patients, accurate diagnoses.”

Researchers note that the syndrome is rare: Only about 400 people from 64 families have it. However, it virtually guarantees a cancer diagnosis, with 50 percent of carriers developing tumors by age 40 and 90 percent developing tumors by age 60.

The disorder may cause many cancers but most often causes four types: breast cancer, brain tumors, certain tumors of the adrenal gland and sarcomas, which occur in muscle, other soft tissue and bone.

The researchers found that every patient in their study with a p53 mutation had at least one family member under age 50 with one of these tumors. The study confirms these types of cancer as “core” cancers for Li Fraumeni syndrome, according to the report.

“What’s more interesting is that patients without a family member having one of these tumors were very unlikely to have a p53 mutation,” said Weitzel. “No one has ever shown that before.”

The National Comprehensive Cancer Network (NCCN), which sets national practice guidelines for cancer care, found the researchers’ findings so influential they changed their genetic screening guidelines for younger women with breast cancer to include p53 gene mutations.

Previous NCCN guidelines limited screening to BRCA gene mutations, which point to a high likelihood of developing breast cancer.

“Our patients who have breast cancer before age 30 often are not found to have BRCA mutations,” said Weitzel. “This study demonstrated that it was reasonable to test for p53 mutations.”

This is the second study from Weitzel’s group to result in guideline changes. A 2006 study moved the NCCN to change surgery guidelines for many ovarian cancer patients.

Said Weitzel: “This work clearly demonstrates how City of Hope is changing care in the community.”

Other City of Hope researchers on the current study include Dongqing Gu, Cindy Wen-Fong, Jennifer Han and Jeffrey Longmate, Ph.D., and former City of Hope researchers Kelly Gonzalez, Katie Noltner, Carolyn Buzin, Ph.D., and Vu Nguyen. The study appeared in the March 10 issue of the Journal of Clinical Oncology.