Date of Graduation

5-2014

Document Type

Thesis (MS)

Program Affiliation

Genetic Counseling

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Louise Strong, MD

Committee Member

Jasmina Bojadzieva, MS

Committee Member

Michelle Jackson, MS, CGC

Committee Member

Ralf Krahe, PhD

Committee Member

Thereasa Rich, MS, CGC

Committee Member

Wenyi Wang, PhD

Abstract

Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome caused by heterozyogous germline mutations in the TP53 gene and characterized by an excess of early-onset cancers, high lifetime risk of cancer, and a wide range of tumor types. Recent studies suggesting a benefit in comprehensive screening protocols for both children and adults make the timely identification of individuals with LFS increasingly important.

A number of criteria have been proposed to identify patients with LFS. The National Comprehensive Cancer Network (NCCN) combines several in its Clinical Practice Guidelines for TP53 genetic testing. Prior studies have shown that the cumulative sensitivity of criteria included in these guidelines approaches 100% in populations referred for testing due to clinical suspicion based on personal and family histories at the time of test requisition. Because NCCN guidelines are created and revised by panels of experts and are commonly utilized by both providers and insurance companies, we choose to evaluate these guidelines in order to assess the performance of current of TP53 genetic testing criteria.

By retrospectively analyzing the cancer histories of positive and negative families within the M.D. Anderson Cancer Center TP53 Research database, estimates of the individual and cumulative sensitivities and specificities of criteria schemes included in the NCCN guidelines were made at the time of the index patient’s initial cancer diagnosis and again at the time of last contact with each family. Out of 122 TP53 positive families in our sample, 22% (27/122) were missed by NCCN guidelines at the time of the index patient’s initial cancer diagnosis. ‘De novo’ mutations and inherited mutations exhibiting incomplete penetrance were particularly likely to be missed, indicating a need for additional criteria able to identify TP53 mutation carriers in the absence of significant family history. Interestingly, in 22 of the 27 families missed by NCCN guidelines, the index patient had sarcoma diagnosed diagnosis, suggesting that TP53 genetic testing should be considered in any individual with early-onset sarcoma, regardless of family history.

Keywords

Li fraumeni syndrome, sarcoma, tp53, genetic testing

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