TP53 Mutation Status Possesses Prognostic Implications in MDS

Elli Papaemmanuil, PhD

Patients with myelodysplastic syndromes (MDS) who have biallelic TP53 have worse outcomes, such as treatment-resistant disease, rapid disease progression, and low overall survival, versus those with monoallelic mutations, according to results from a study published in Nature Medicine.¹

“In recent years, we have characterized which mutations are present in MDS and have established diagnostic tests that map which mutations are present in every patient. This information is used to guide treatment decisions; this is the vision of precision medicine,” Elli Papaemmanuil, PhD, the senior author of the paper and a molecular geneticist with Memorial Sloan Kettering Cancer Center told OncLive.

“Our study shows that precise interpretation of TP53 mutations for treatment decisions in MDS requires the mapping of TP53 state,” Papaemmanuil added. “This can identify truly high-risk patients. Importantly, our findings also indicated that patients with 1 mutation may benefit from standard-of-care therapy. These important clinical findings also uncover important insights about TP53 biology in hematopoietic stem cells.”

Results showed distinct differences in overall survival (OS), as well as disease transformations in patients with acute myeloid leukemia (AML), between the different TP53 allelic states. Patients in the multi-hit state were found to have a median OS of 8.7 months (95% CI, 7.7-10.3) versus 2.5 years in patients in the monoallelic state (HR, 3.7; 95% CI, 2.7-5.0; P = 2 × 10−16, Wald test). Significant differences were also noted in 5-year cumulative incidence of AML transformation between the 2 patient groups; this occurred in 44% of those in multi-hit state and 21% of those in the monoallelic state (HR, 5.5; 95% CI, 3.1-9.6; P = 5 × 10−9, Wald test).

Despite being 1 of the most commonly mutated cancer genes that is known to lead to worse outcomes in patients across all cancer types, it has not been clear how the TP53 allelic state affects prognosis. To learn more, investigators at Memorial Sloan Kettering Cancer Center launched this study dedicated to examining how TP53 allelic state impacts patients with MDS.²

To better assess the impact of TP53 allelic state on genome stability, investigators accrued a cohort of 3,324 peridiagnostic and treatment-naïve patients with MDS or closely related myeloid neoplasms. Investigators defined 4 TP53-mutant patient subgroups: those with a monoallelic mutation (n = 125; 33%), those with multiple mutations without deletion or cnLOH impacting the TP53 locus (n = 90; 24%), mutation(s) and concomitant deletion (n = 85; 22%), and mutation(s) and concomitant cnLOH (n = 78; 21%).

Through the use of computational methods, investigators found that two-thirds of patients with TP53-mutated disease were found to have multi-hits with at least 1 residual wild-type allele, while one-third of patients had monoallelic mutations consisting of a single wild-type allele.

For patients in the monoallelic state, TP53 mutations were enriched for subclonal presentation (median VAF = 13%, median sample purity = 86%) versus patients who had multiple mutations, which were found to be predominantly clonal (median VAF = 32%, median sample purity = 85%). “Thus, TP53 allelic state—and, by extension whether a wild-type TP53 allele is retained—points toward different evolutionary trajectories or potential for clonal dominance,” the study authors wrote.

Truncating mutations were found to be enriched in the multi-hit state (28 versus 14%, OR=2.3, 95% CI: 1.3–4.2), whereas hotspot mutations accounted for 25% of mutations found in the monoallelic state, as well as 20% in the multi-hit state.

Additional results showed that in all subgroups—those with more than 1 gene mutation, mutation and deletion, and mutation and cnLOH—in the multi-hit state who were examined on the study had equally dismal outcomes. “The OS distinction of 2 states was significant across World Health Organization classes and Revised International Prognostic Scoring System (IPSS-R) risk groups, and multi-hit TP53 identified patients with poor survival across IPSS-R strata,” the study authors wrote.

Because 10% of patients in the multi-hit state were classified to have IPSS-R risk of very good to intermediate, this indicates that evaluation of TP53 allelic state is imperative to help identify patients with high-risk disease, according to the authors.

Moreover, multivariable Cox proportional hazard models identified a multi-hit TP53 state to be an independent predictor for risk of death and AML transformation (HROS = 2.04; 95% CI, 1.6-2.6; P = 5 × 10−8; HRAML = 2.9, 95% CI, 1.8-4.7; P = 7 × 10−6, Wald test) while a monoallelic TP53 state was not found to differ from that of wild-type TP53. Moreover, investigators noted that multi-hit TP53 as well as complex karyotype are independent predictors for adverse outcomes; as such, mapping the state of TP53 along with complex karyotype can be used for accurate risk estimation, noted the study authors.

Investigators concluded that the multi-hit TP53 state in patients with MDS underlies associations with treatment resistance, genomic instability, progressive disease, and poor outcomes.

“Our findings imply that diagnostic and prognostic precision in MDS requires the assessment of TP53 allelic state,” study authors concluded. “We propose that biallelic TP53 should be distinguished from monoallelic TP53 mutations in future revisions of IPSS-R and in correlative studies of treatment response.”

Large, evidence-based studies are needed to inform how to translate the findings yielded in this study into treatment strategies for patients with MDS, concluded Papaemmanuil.

References

1. Bernard E, Nannya Y, Hasserjian RP, et al. Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes. Nature Medicine. Published online August 3, 2020. doi:10.1038/s41591-020-1008-z
2. Large international study pinpoints impact of TP53 gene mutations on blood cancer severity. News release. Memorial Sloan Kettering Cancer Center. August 3, 2020. Accessed August 6, 2020. https://bit.ly/30QQy8L.