Clinical Characteristics and Chemosensitivity in Germline TP53 Pathogenic Variant Cases Identified by Cancer Genomic Testing.

Background/aim: The widespread implementation of cancer genomic profiling (CGP) has led to an increase in the detection of germline TP53 pathogenic variants (gTP53v) in patients who do not meet the classical Li-Fraumeni syndrome (LFS) criteria. The present study aimed to characterize the clinical features and treatment outcomes of gTP53v cases identified through routine CGP testing.

Patients and methods: We conducted a retrospective analysis of 43 patients with gTP53v identified through CGP testing between June 2019 and August 2024. Clinical characteristics, molecular features, and treatment outcomes were analyzed and compared with TP53 wild-type cases from the same database (n=6,515).

Results: The median age at diagnosis was 38 years (range=1-83 years), with 58.1% of cases presenting with non-core LFS tumors. A genomic analysis revealed diverse variant types (missense: 32, frameshift: 8, and nonsense: 3) with variant allele frequencies ranging between 0.10 and 0.696. Among 37 patients who received first-line chemotherapy, the objective response rate was 62%, which was significantly higher than in TP53 wild-type cases (32%, p=0.02). Complete responses were observed in six patients and partial responses in 14.

Conclusion: The present results suggest that gTP53v carriers identified through CGP represent a broader clinical spectrum than classical LFS, while demonstrating potentially favorable treatment outcomes. These results challenge traditional paradigms and emphasize the need for individualized approaches to patient care, particularly in cases with atypical presentations requiring the careful interpretation of mosaicism, de novo mutations, and clonal hematopoiesis.