Originally published as JCO Early Release 10.1200/JCO.2008.16.6959 on February 9 2009

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Beyond Li Fraumeni Syndrome: Clinical Characteristics of Families With p53 Germline Mutations

Kelly D. Gonzalez, Katie A. Noltner, Carolyn H. Buzin, Dongqing Gu, Cindy Y. Wen-Fong, Vu Q. Nguyen, Jennifer H. Han, Katrina Lowstuter, Jeffrey Longmate, Steve S. Sommer, Jeffrey N. Weitzel

From the Departments of Molecular Diagnosis, Molecular Genetics, Clinical Cancer Genetics, and Information Sciences, and the Bioinformatics Group, City of Hope, Duarte, CA.

Corresponding author: Jeffrey N. Weitzel, MD, Department of Clinical Cancer Genetics, Beckman Research Institute/City of Hope National Medical Center, 1500 E Duarte Rd, Duarte, CA 91010-0269; e-mail: jweitzel{at}coh.org.

Purpose A clinical testing cohort was used to gain a broader understanding of the spectrum of tumors associated with germline p53 mutations to aid clinicians in identifying high-risk families.

Patients and Methods Full sequencing of the coding exons (2 to 11) and associated splice junctions of the p53 gene was performed on 525 consecutive patients whose blood samples were submitted for diagnostic testing. Clinical features of p53 germline carriers in this cohort were characterized, clinical referral schemes based on reported p53-associated family phenotypes were evaluated, and practical mutation prevalence tables were generated.

Results Mutations were identified in 91 (17%) of 525 patients submitted for testing. All families with a p53 mutation had at least one family member with a sarcoma, breast, brain, or adrenocortical carcinoma (ACC). Every individual with a choroid plexus tumor (eight of eight) and 14 of 21 individuals with a childhood ACC had a mutation regardless of family history. Based on reported personal and family history, 95% of patients (71 of 75) with a mutation met either classic Li Fraumeni syndrome (LFS) or Chompret criteria. A simplified prevalence table provides a concise summary of individual and family characteristics associated with p53 mutations.

Conclusion This is, to our knowledge, the largest single report of diagnostic testing for germline p53 mutations, yielding practical mutation prevalence tables and suggesting clinical utility of classic LFS and Chompret criteria for identifying a subset of cancer-prone families with p53 germline mutations, with important implications for diagnosis and management.

S.S.S. and J.N.W. contributed equally as senior authors.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

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