In a new study published in Nature Medicine, researchers evaluated the effect of the TP53 allelic state on the clinical presentation and outcomes of patients with myelodysplastic syndromes (MDS) and determined that the multi-hit mutation state – more than the presence of the TP53 mutation itself – predicted genome instability, treatment resistance, and disease progression. Multi-hit status also identified patients with very-high-risk disease, while outcomes did not appear to differ among those with monoallelic mutations or with wild-type TP53, according to study authors, led by Elsa Bernard, PhD, of Memorial Sloan Kettering Cancer Center in New York.
Based on these results, Dr. Bernard and researchers suggested that clinicians should assess the TP53 allelic state in patients with MDS for diagnostic and prognostic precision in managing the disease.
The investigators assessed genome-wide allelic imbalances and TP53 mutations in a sample of 3,324 patients with MDS. Overall, 11% of patients (n=360) had ≥1 copy neutral loss of heterozygosity region, whereas 47% (n=1571) had ≥1 chromosomal aberration.
There were 486 putative oncogenic mutations in TP53 at variant allele frequency (VAF) of ≥2% in 378 patients. Of these, 274 patients had a single TP53 mutation (72.5%), 100 had two TP53 mutations (26.5%), and 4 had three TP53 mutations (1%).
Two-thirds of TP53-mutated patients had multiple hits (more than one gene mutation, mutation and deletion, or mutation and copy neutral loss of heterozygosity), resulting in biallelic loss, the authors reported:
- monoallelic TP53 state with 1 residual wild-type TP53 copy (n=125)
- multi-hit TP53 state with ≥2 TP53 hits in each patient and probably no residual TP53
function in clonal cells (n=253)
In the overall cohort, the median age at the time of MDS diagnosis was 71 years. The most common diagnosis was de novo MDS (n=2,855), followed by therapy-related MDS (n=229), secondary MDS (n=51), and MDS with undetermined cause (“missing data” [n=189]).
A significantly greater proportion of patients with TP53 mutations had ≥1 chromosomal deletion compared with wild-type cases (67% vs. 5%, respectively; odds ratio [OR] = 35; 95% CI 27-46), and approximately 85% of multi-hit patients had del5q, compared with 34% of monoallelic patients (OR=10; 95% CI 6.1-18).
The median overall survival (OS) for patients with multi-hit TP53 state was 8.7 months, compared with 2.5 years for monoallelic cases (hazard ratio [HR] = 3.7; 95% CI 2.7-5.0; p<0.001). The median OS in wild-type patients was significantly longer, at 3.5 years (95% CI 3.4-3.9; p<0.001).
In addition, multi-hit TP53 state was associated with a higher 5-year cumulative incidence of transformation to acute myeloid leukemia (AML), compared with monoallelic state (44% vs. 21%; HR=5.5; 95% CI 3.1-9.6; p<0.001).
“Of note, all subgroups (more than one gene mutation, mutation and deletion, mutation and copy neutral loss of heterozygosity) in multi-hit state had equally dismal outcomes,” the authors wrote.
According to a multivariable analysis adjusting for age at diagnosis, cytogenetic risk score, and established predictive features, the presence of multi-hit TP53 was an independent predictor of the risk of death (HR=2.04; 95% CI 1.6-2.6; p<0.001) and AML transformation (HR=2.9; 95% CI 1.8-4.7; p<0.001). Patients with monoallelic TP53 mutations as well as a VAF >22% had a significantly greater risk of mortality compared with wild-type patients (HR=2.2; 95% CI 1.5-3.2; p<0.001).
“Surprisingly, monoallelic TP53 patients did not differ from TP53 wild-type patients with regard to response to therapy, OS, and AML progression,” the researchers observed. “The shift in survival for monoallelic patients with the number of co-mutations indicates diversity of disease pathogenesis and highlights the need for future prognostic models that consider a large spectrum of gene mutations.”
The authors concluded “that biallelic TP53 should be distinguished from monoallelic TP53 mutations in future [editions] of Revised International Prognostic Scoring System and in correlative studies of treatment response.” And, since TP53 tends to be “the most frequently mutated gene in cancer, the representation and effect of TP53 allelic state warrant investigation across cancer indications,” they added.
Study authors report relationships with Celgene and the MDS Foundation.
Bernard E, Nannya Y, Hasserjian RP, et al. Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes. Nat Med. 2020;26:1549-1556.