Novel scheme for defining the clinical implications of TP53 mutations in myeloid neoplasia.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Our novel approach more accurately resolves TP53 genomic configuration and uncovers genetic mosaicism for the use in the clinical setting to improve prognostic evaluation.

Novel Scheme for Defining the Clinical Implications of TP53 Mutations in Myeloid Neoplasia.

Background: TP53 mutations ( TP53 MT ) 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. Methods: We have collected clinical and molecular data of 7400 patients with myeloid neoplasms and applied a novel model to properly resolve the allelic configuration of TP53 MT and assess prognosis more precisely. Results: Overall, TP53 MT were found in 1010 patients. Following the traditional criteria, 36% of 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 TP53 MT . 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. These results were recapitulated by single-cell DNA studies, which unveiled the biallelic nature of previously considered monoallelic cases. Conclusion: Our novel approach more accurately resolves TP53 genomic configuration and uncovers genetic mosaicism for the use in the clinical setting to improve prognostic evaluation.

Identifying miRNAs in multiple sclerosis gray matter lesions that correlate with atrophy measures.

OBJECTIVE: Multiple sclerosis (MS) is an inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS). Though MS was initially considered to be a white matter demyelinating disease, myelin loss in cortical gray matter has been reported in all disease stages. We previously identified microRNAs (miRNAs) in white matter lesions (WMLs) that are detected in serum from MS patients. However, miRNA expression profiles in gray matter lesions (GMLs) from progressive MS brains are understudied. METHODS: We used a combination of global miRNAs and gene expression profiling of GMLs and independent validation using real-time quantitative polymerase chain reaction (RT-qPCR), immuno-in situ hybridization, and immunohistochemistry. RESULTS: Compared to matched myelinated gray matter (GM) regions, we identified 82 miRNAs in GMLs, of which 10 were significantly upregulated and 17 were significantly downregulated. Among these 82 miRNAs, 13 were also detected in serum and importantly were associated with brain atrophy in MS patients. The predicted target mRNAs of these miRNAs belonged to pathways associated with axonal guidance, TGF-ß signaling, and FOXO signaling. Further, using state-of-the-art human protein-protein interactome network analysis, we mapped the four key GM atrophy-associated miRNAs (hsa-miR-149*, hsa-miR-20a, hsa-miR-29c, and hsa-miR-25) to their target mRNAs that were also changed in GMLs. INTERPRETATION: Our study identifies miRNAs altered in GMLs in progressive MS brains that correlate with atrophy measures. As these miRNAs were also detected in sera of MS patients, these could act as markers of GML demyelination in MS.