10 Oct Multi-Gene Panels Identifies More Cancer Prone Families
Medical Research: What is the background for this study? What are the main findings?
Dr. Rana: – Li-Fraumeni syndrome (LFS) is thought to be a rare, inherited condition that causes high lifetime risks for multiple cancers. It is caused by mutations in the TP53 gene. Traditionally, only people with striking personal or family histories of cancer underwent genetic testing for TP53 mutations, as there are well-established testing criteria. This gene was usually tested for in isolation, meaning not combined with testing of other genes. Due to technological advances, namely multi-gene panels (MGP), many more people are having their TP53gene analyzed. This included a patient of mine who somewhat surprisingly tested positive for a TP53 mutation. This led us to investigate whether people who test positive for TP53 mutations on MGPs are different from ones who test positive on traditional or single-gene (SG) testing.
We compared individuals tested for TP53 single gene versus multigene panel testing to determine if there were differences in the percent of mutation carriers meeting current testing criteria for LFS. Our data showed that 73% of individuals sent in for single gene testing of TP53 met Classic or Chompret (2009) criteria for LFS, whereas only 30% of those sent in for multi-gene panel testing met criteria (p=0.0000001). When we looked at the most up-to-date testing criteria, which includes Classic, Chompret, or a personal diagnosis of early-onset breast cancer (age at ≤35), 85% of individuals in the single gene group who were positive met criteria, while only 53% of the mutation carriers identified on a multi-gene panel did. These data suggest that multi-gene panel testing enables us to identify TP53 mutation carriers who may not have otherwise been identified if testing were limited to those who meet established LFS criteria.
Medical Research: What should clinicians and patients take away from your report?
Dr. Rana: This is one of the largest cohort of patients with TP53 mutations to date, and our data suggests that TP53 mutations may be more common than previously thought. Prior to the availability of panel testing, we were only identifying the most cancer-prone LFS families. What this shows us, is that there is much more variability in TP53 mutation positive families than previously recognized. It also means that we may need to reevaluate the penetrance and prevalence of the condition and in turn how we counsel and manage individuals who carry a TP53 mutation. Multi-gene panels allow for the identification of a greater number mutation carriers and an opportunity to more thoroughly understand these complexities so we can better serve our patients.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Rana: Prospective cohorts are needed to evaluate the true cancer risks in non-classic LFS families identified through multi-gene panel testing. Our colleagues in the laboratory are continuing to do critical work in determining how specific mutations affect tumor growth. Additionally, current testing criteria and cancer risk estimates may need to be revised to reflect the broader phenotypic spectrum of TP53 mutation carriers identified through multi-gene panel testing.
Citation: Presented at ASHG 2015 October 2015
Single gene (SG) vs. Multi-gene panel (MGP) testing for TP53 germline mutations in Li Fraumeni syndrome (LFS).
Authors: H. Q. Rana ; R. Gelman ; J. Thompson ; R. McFarland ; H. LaDuca ; E. Dalton ; V. Speare ; J. S. Dolinsky ; E. Chao [2,3]; J. E. Garber 
1) Dana-Farber Cancer Institute, Boston, MA; 2) Ambry Genetics, Aliso Viejo, CA; 3) University of California, Irvine, Irvine CA
Huma Q. Rana, MD (2015). Multi-Gene Panels Identifies More Cancer Prone Families