Spectrum of TP53 Mutation in Hematologic Malignancies

Background

Mutations in the tumor suppressor gene TP53 are among the most common genetic alterations in cancers cells. Although TP53 mutations are less frequent in hematological malignancies compared to solid tumors, TP53-mutated hematologic malignancies exhibit similar characteristics, such as missense mutations in DNA-binding domain and a strong association with adverse prognosis. We investigated the spectrum of TP53 mutations across various types of hematologic malignancies.

Methods

We conducted a retrospective analysis of 971 patients with hematologic malignancies who were diagnosed at Seoul National University in South Korea, between January 2018 and September 2022. TP53 mutations were analyzed in DNA from bone marrow aspiration samples, using two types of targeted sequencing panels. Samples from years 2018 to 2020 were evaluated with an in-house target sequencing panel covering 76 genes, and samples from years 2021 to 2022 were analyzed with a commercial target sequencing panel covering 104 genes. We applied the evolutionary action (EAp53) score [Panagiotis Katsonis et al Genome Res 2014] and the relative fitness score (RFS) [Eran Kotler et al. Mol Cell 2018] which are previously proposed prediction scoring systems based on the mutation point on the DNA-binding domain of TP53, to the patients of our cohort.

Results

The median age at diagnosis was 62.1 years (range, 3.5-97.0). Of the 971 patients, 245 (25.2%) were diagnosed with acute myeloid leukemia (AML), and 188 (19.4%) had multiple myeloma (MM) or amyloidosis. TP53 mutations were detected in 75 patients (7.7%). The frequency of TP53 was the highest in myelodysplastic syndrome (MDS) (14.4%), followed by AML (12.7%).

The most common subtype of TP53 mutation was missense mutations in the DNA-binding domain (73.3%), followed by missense mutations outside the DNA-binding domain (16.0%), frameshift (5.3%), and indels (1.3%). The number of TP53 mutations in a single patient was one in most cases (81.3%), but double or triple mutations were also observed (16.0 % and 2.7 %, respectively).

Logistic regression analysis revealed a statistically significant correlation between age and the frequency of TP53 mutation (odds ratio, 1.01; 95% CI,1.00-1.04; P=0.04). In addition, there was a weak negative correlation between age and TP53 VAF, although not statistically significant (rho = -0.17; P=0.14).

TP53 mutation was associated with decreased overall survival (OS) compared with wild-type TP53 (median OS, 12.6 months vs. not reached; hazard ratio for death (HR), 4.9; 95% CI, 3.4-7.1; P<0.001). In the AML/MDS subgroup, the impact of TP53 mutation on OS was significant as well. (median OS, 7.3 months vs. not reached; HR, 4.9; 95% CI, 3.2-7.4; P<0.001). In the lymphoid malignancies subgroup (acute lymphocytic leukemia, chronic lymphocytic leukemia, MM, lymphoma), there was no survival difference between the TP53 mutant and wild-type groups (median OS, not reached vs. not reached; HR, 2.2; 95% CI, 0.9-5.6; P=0.10).

There was no survival difference when comparing disruptive mutations to non-disruptive mutations (HR, 0.9; 95% CI, 0.5-1.9; P=0.88).

When we used EAp53 and RFS tools specified for missense mutations on DNA binding domain for our patients, we found that the overall survival did not differ between EAp53 high and EAp53 low patients (HR, 0.9; 95% CI, 0.5-1.9; P=0.83), nor between RFS high and RFS low patients (HR, 0.9; 95% CI, 0.5-1.9; P=0.78). In the AML/MDS subgroup, no impact of EAp53 and RFS on survival was observed (P=0.65 and P=0.13, respectively).

Conclusions

TP53 mutations are relatively common in myeloid malignancies compared to lymphoid malignancies. The clone size of TP53-mutated cells varied among various hematologic malignancies. In some patients with small TP53-mutated clones, there is a possibility of an emergence of TP53 mutation in normal hematopoietic stem/progenitor cells of the patients' bone marrow, rather than cancer cells. This raises the necessity of cell type-specific target panel sequencing on tumor-cell sorted populations.

The presence of TP53 mutation is definitely a poor prognostic factor associated with decreased survival in hematologic malignancies. However, whether these mutations are disruptive or not did not affect the survival outcomes. Further investigation to enhance the understanding of the clinical significance of TP53 mutations in various hematologic malignancies is warranted.

Koh:Takeda: Consultancy; Tomocube: Current holder of stock options in a privately-held company; Sanofi Genzyme: Research Funding; NOBO medicine: Current equity holder in private company; Proteina: Current holder of stock options in a privately-held company; GC Cell: Consultancy; Celltrion: Honoraria, Speakers Bureau; GSK: Consultancy; Johnson & Johnson - Janssen: Consultancy; Curocell: Current equity holder in publicly-traded company; DeppMetrics: Current equity holder in private company; Novartis: Consultancy; Amgen: Speakers Bureau. Yoon:Janssen: Honoraria; F. Hoffmann-La Roche Ltd, Genentech, Inc.: Research Funding; Janssen, Novartis, F. Hoffmann-La Roche Ltd, Genentech, Inc.: Consultancy. Shin:Boryung Pharmaceuticals, Abbvie: Research Funding.