The incorporation of panel-based germline genetic testing for assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, prostatic and pancreatic cancer in NCCN guidelines and wide adoption of cell-free circulating DNA sequencing (liquid biopsy) for patients with advanced solid tumors has increased the identification of pathogenic TP53 variants in blood of patients with solid tumors. The variant allelic frequency (VAF) of the pathogenic variant is often used to help infer the compartment of origin (germline vs somatic) with near heterozygous (~50%) VAF favoring germline; however, when VAF is low (sub heterozygous) potential considerations include mosaic Li Fraumeni syndrome, clonal hematopoiesis, or incidental myeloid neoplasms, and determining the origin of the TP53 mutation can be a challenge with important surveillance and treatment implications. We describe a cohort of patients with solid tumors or hematologic malignancies in whom pathogenic or likely pathogenic TP53 variants of uncertain origin were identified by clinical genetic testing of peripheral blood, next generation sequencing (NGS) using an 81 gene hematologic malignancy-based panel, or cell-free DNA sequencing/liquid biopsy. In a subset of patients for whom solid tumor, adjacent normal tissue and/or bone marrow (BM) was available, immunohistochemistry for p53 protein was performed. Patients (n= 17) included 11 (61%) women and 7 (39%) men with a median age of 54 years (range 8-7) at initial cancer diagnosis, with 17 unique TP53 variants with a median VAF of 16% (range, 2-50%). The most common indication for referral for additional investigation of the TP53 origin was sub-heterozygous VAF on germline testing of blood (8/47%) or saliva (1/6%); TP53 variant identified in plasma when the concurrent solid tumor was TP53 wild-type (3/18%) followed by presence of a pathogenic TP53 variant in remission BM of patients with history of hematologic malignancies (4/24%). Additional germline testing of skin fibroblasts and/or BM examination was performed in in 9 (53%) and 8 (47%) patients, respectively. p53 IHC was performed on 3 BM biopsies and 2 solid tumor tissues. A multimodality/multidisciplinary interpretation of these results allowed appropriate classification of the TP53 variants in 12/18 patients (67%). These included Li Fraumeni syndrome (5/12; 42%); clonal hematopoiesis (5/12; 42%); donor-derived clonal hematopoiesis (1/12;8%) and therapy-related myelodysplastic syndrome (1/12; 8%) patients. Appropriate awareness and distinction of clonal hematopoiesis and potential myeloid neoplasms from mosaic germline TP53 in the setting of subheterozygous VAF identified on peripheral blood or bone marrow analyses can be challenging. Multimodality testing and a multidisciplinary approach for accurate interpretation is required. Immunohistochemical staining for p53 can be useful in making this distinction in a subset of patients.

Citation Format: Sanam Loghavi, Yoheved Gerstein, Mark J Routbort, Keyur P Patel, Koichi Takahashi, Molly Daniels, Julie Moskowitz, Danielle E Hammond, Kelly Chien, L. Jeffrey Medeiros, Farhad Ravandi, Hagop M Kantarjian, Guillermo Garcia-Manero, Banu Arun, Joseph D Khoury, Courtney D DiNardo. Distinguishing Mosaic Li Fraumeni Syndrome, Clonal Hematopoiesis and Incidental Myeloid Neoplasms in Patients with Solid Tumors with Pathogenic TP53 Mutations Identified by Germline Testing or Cell-Free Circulating DNA Sequencing [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A50.