TP53基因突变 (TP53MT) 在各种基因组构型中出现。特别是，双等位体失活与癌症的不良总生存率有关。只影响一个等位体的突变可能不直接导致白血病，因此质疑在预后不良的情况下是否存在隐藏的双等位体亚克隆。我们收集了7400例骨髓肿瘤患者的临床和分子数据，并应用了一种新的模型，通过在生存数据上使用具有统计鲁棒性的基于抽样回归的策略来识别最佳的变异等位基因频率(VAF)截断值，从而准确地分类TP53等位基因构型并更准确地评估预后。总体而言，1010例患者发现了TP53MT。按照传统标准，36%的病例被归类为单突，而64%的病例具有双突的基因组构型。使用一种新开发的分子算法，我们发现579例（57%）患者明确为双等位体，239例（24%）可能是双等位体，而192例（19%）最有可能是单等位体的TP53MT。有趣的是，我们的方法能将352例(54.5%)传统上被认为是单突的病变重新分类为可能是双等位体。在重新分类后，通过建立基于生存的模型进一步证实了这种分类。在传统上被认为是单等位体的病例中，可能是单等位体突变的患者的总生存率与野生型患者相似，且优于具有双等位体构型的患者。结果是，不论疾病亚型 (AML或MDS)，具有确定的双等位体突变的患者预后相似。当该模型应用于外部队列时，也获得类似的结果。此外，单细胞DNA研究揭示了以前被认为是单等位体病例的双等位体性质。我们的新方法更准确地解决了TP53基因组构型，并揭示了临床设置中的遗传莫赛尼格用于改善预后评估。© 2023. BioMed Central Ltd., part of Springer Nature.

TP53 mutations (TP53MT) occur in diverse genomic configurations. Particularly, biallelic inactivation is associated with poor overall survival in cancer. Lesions affecting only one allele might not be directly leukemogenic, questioning the presence of cryptic biallelic subclones in cases with dismal prognosis.We have collected clinical and molecular data of 7400 patients with myeloid neoplasms and applied a novel model by identifying an optimal VAF cutoff using a statistically robust strategy of sampling-based regression on survival data to accurately classify the TP53 allelic configuration and assess prognosis more precisely.Overall, TP53MT were found in 1010 patients. Following the traditional criteria, 36% of the cases were classified as single hits, while 64% exhibited double hits genomic configuration. Using a newly developed molecular algorithm, we found that 579 (57%) patients had unequivocally biallelic, 239 (24%) likely contained biallelic, and 192 (19%) had most likely monoallelic TP53MT. Interestingly, our method was able to upstage 192 out of 352 (54.5%) traditionally single hit lesions into a probable biallelic category. Such classification was further substantiated by a survival-based model built after re-categorization. Among cases traditionally considered monoallelic, the overall survival of those with probable monoallelic mutations was similar to the one of wild-type patients and was better than that of patients with a biallelic configuration. As a result, patients with certain biallelic hits, regardless of the disease subtype (AML or MDS), had a similar prognosis. Similar results were observed when the model was applied to an external cohort. In addition, single-cell DNA studies unveiled the biallelic nature of previously considered monoallelic cases.Our novel approach more accurately resolves TP53 genomic configuration and uncovers genetic mosaicism for the use in the clinical setting to improve prognostic evaluation.© 2023. BioMed Central Ltd., part of Springer Nature.