Not all single-hit TP53 mutations in MDS are equal: a functional score separated outcomes

Design

Retrospective analysis of two independent cohorts

Population

4505 patients with myelodysplastic neoplasms, 271 with monoallelic TP53

Primary outcome

Leukaemia-free survival by TP53 state and phenotype score

Effect

Monoallelic high vs low phenotype score: median LFS 12.6 vs 43.3 months (p<0.001)

This analysis pooled pretreatment samples from 4505 patients with myelodysplastic neoplasms in two independent cohorts, including 271 with monoallelic and 499 with multi-hit TP53 alterations. Each variant was given a phenotype score from saturation mutagenesis data, capturing dominant-negative and loss-of-function effects.

Median leukaemia-free survival was 37.2 months for wild-type, 19.2 for monoallelic and 7.8 for multi-hit TP53. Within the monoallelic group, a high phenotype score (7 or above) was associated with median survival of 12.6 months against 43.3 months for a low score. Combined with variant allele frequency, monoallelic cases with a high score and VAF of at least 22% had survival close to multi-hit cases (9.2 vs 7.8 months, p=0.3), while low-score, low-VAF cases matched wild type (44.7 vs 37.2 months, p=0.8).

For laboratories reporting myeloid NGS panels, this suggests the variant itself and its VAF both carry prognostic weight beyond the single-hit versus multi-hit call used in current classifications. It is a retrospective analysis and the phenotype score is not yet part of IPSS-M or WHO criteria, so reports should continue to follow current classification rules.

• Report the exact TP53 variant and its variant allele frequency on every myeloid NGS report.
• State clearly whether TP53 status is monoallelic or multi-hit, including copy-number or loss-of-heterozygosity findings.
• Flag a monoallelic TP53 variant with VAF of 22% or more for haematology discussion, given its poorer outcome here.
• Continue to apply current WHO and ICC definitions; the phenotype score is not yet in routine classification.

Why it matters

The monoallelic TP53 label covers patients whose outcomes range from near-normal to as poor as multi-hit disease.

Don't overread it

This retrospective scoring has not been validated prospectively or adopted in classification systems.

The statistics, in plain English

The survival differences are large and consistent across two cohorts, which makes chance unlikely. The non-significant comparisons (p=0.3 and p=0.8) are being used to show similarity, but a non-significant difference does not prove two groups are the same, especially in small subgroups.

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