Author ORCID Identifier

0009-0009-2561-4141

Date of Graduation

5-2026

Document Type

Thesis (MS)

Program Affiliation

Genetic Counseling

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Jessica Corredor, MS, CGC

Committee Member

Claire Singletary, MS, CGC

Committee Member

Banu Arun, MD

Committee Member

Courtney DiNardo, MD, MSCE

Committee Member

Rachael Shilbauer, MS, CGC

Abstract

Li-Fraumeni Syndrome (LFS) is caused by germline pathogenic or likely pathogenic (P/LP) variants in TP53 and is characterized by a predisposition to several types of cancer. TP53 P/LP variants identified at lower-than-expected variant allele frequencies (VAF) or in individuals who do not meet clinical LFS criteria may not be of true germline origin. These variants could be explained by somatic causes such as clonal hematopoiesis (CH), active hematologic malignancy, or tumor interference. These possible scenarios warrant different recommendations with regards to clinical management, cancer risks, and implications for family members compared to true germline variants. Therefore, it is important to know the true etiology of a TP53 variant. Historically, additional testing in these circumstances was not recommended, but due to advancements in knowledge of TP53, National Comprehensive Cancer Network ® (NCCN ®) now recommends consideration of further testing which may include testing of family members, skin punch biopsy, tumor testing, and/or bone marrow biopsy. This study aimed to describe the clinical workflow and follow-up for TP53-positive results at a large academic institution and determine which personal and family history characteristics were associated with completing additional testing steps. A review of 84 individuals with P/LP TP53 variants seen at MD Anderson Cancer Center (MDACC) with no known family history of LFS and who did not meet clinical LFS criteria was completed. Notable characteristics that showed a statistically significant association with completing additional testing recommendations compared to those that did not complete additional testing included having testing ordered at an institution other than MDACC (p = 0.036 and 0.029) and being seen at MDACC within the past year (p = 0.024). Patients were considered to have “presumed LFS” if their personal and/or family histories were suggestive of LFS based on clinical judgement despite not meeting established clinical criteria. When patients with “presumed LFS” were removed from analysis, additional characteristics were significant, including younger age at the time of first cancer diagnosis (p = 0.002) and younger age at the time of initial genetic testing (p = 0.001). The diagnostic outcome of patients was different than expected based on clinical judgement in at least 16 cases (19%), which underscores the importance of additional testing for all TP53-positive patients without a known family history who do not meet clinical LFS criteria since there can be drastic differences in screening and management. These results highlight potential steps in the diagnostic process that can be targeted and patient characteristics that can be considered to improve uptake of additional workup with the goal of ensuring that patients are receiving the appropriate surveillance while avoiding unnecessary screening and procedures.

Keywords

Li-Fraumeni Syndrome, TP53, clonal hematopoiesis

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