Genomic context and TP53 allele frequency define clinical outcomes in TP53-mutated myelodysplastic syndromes

Montalban‐Bravo, Guillermo; Kanagal‐Shamanna, Rashmi; Benton, Christopher B.; Class, Caleb A.; Chien, Kelly S.; Sasaki, Koji; Naqvi, Kiran; Alvarado, Yesid; Kadia, Tapan M.; Ravandi, Farhad; Daver, Naval; Takahashi, Koichi; Jabbour, Elias; Borthakur, G.; Pemmaraju, Naveen; Konopleva, Marina; Soltysiak, Kelly A.; Pierce, Sherry; Bueso‐Ramos, Carlos E.; Patel, Keyur P.; Kantarjian, Hagop; Garcia‐Manero, Guillermo

doi:10.1182/bloodadvances.2019001101

Cited by 96 publications

(102 citation statements)

References 34 publications

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“…In addition to TP53 mutations, TP53 VAF has also been reported to be of prognostic significance in MDS [17][18][19] . This is probably explained by the strong correlation between high VAF and biallelic targeting.…”

Section: Nature Medicinementioning

confidence: 99%

Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes

Bernard¹,

Nannya²,

Hasserjian³

et al. 2020

Nat Med

430

380

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Tumor protein p53 (TP53) is the most frequently mutated gene in cancer 1,2. In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease 3,4 , rapid transformation to acute myeloid leukemia (AML) 5 , resistance to conventional therapies 6-8 and dismal outcomes 9. Consistent with the tumor-suppressive role of TP53, patients harbor both mono-and biallelic mutations 10. However, the biological and clinical implications of TP53 allelic state have not been fully investigated in MDS or any other cancer type. We analyzed 3,324 patients with MDS for TP53 mutations and allelic imbalances and delineated two subsets of patients with distinct phenotypes and outcomes. One-third of TP53-mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting. Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System (IPSS-R) 11. Surprisingly, monoallelic patients did not differ from TP53 wild-type patients in outcomes and response to therapy. This study shows that consideration of TP53 allelic state is critical for diagnostic and prognostic precision in MDS as well as in future correlative studies of treatment response. In collaboration with the International Working Group for Prognosis in MDS (Supplementary Table 1), we assembled a cohort of 3,324 peridiagnostic and treatment-naive patients with MDS or closely related myeloid neoplasms (Extended Data Fig. 1 and Supplementary Fig. 1). Genetic profiling included conventional G-banding analyses (CBA) and tumor-only, capture-based, next-generation sequencing (NGS) of a panel of genes recurrently mutated in MDS, as well as genome-wide copy number probes. Allele-specific copy number profiles were generated from NGS data using the CNACS algorithm 7 (see Methods and Code availability). An additional 1,120 samples derived from the Japanese MDS consortium (Extended Data Fig. 2) were used as a validation cohort. To study the effect of TP53 allelic state on genome stability, clinical presentation, outcome and response to therapy, we performed a detailed characterization of alterations at the TP53 locus. First, we assessed genome-wide allelic imbalances in the cohort of 3,324 patients, to include arm-level or focal (~3 Mb) ploidy alterations and regions of copy-neutral loss of heterozygosity (cnLOH) (Extended Data Fig. 3, Supplementary Figs. 2-4 and Methods).

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Section: Nature Medicinementioning

confidence: 99%

Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes

Bernard¹,

Nannya²,

Hasserjian³

et al. 2020

Nat Med

430

380

View full text Add to dashboard Cite

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“…62 studies were assessed full‐text articles for eligibility and 15 studies included qualitative synthesis, and 47 records were excluded for insufficient VAF data, no enough survival data, or other related articles. Finally, we include 11 articles 5,13‐22 covering 4003 cohort patients, 1138 TP53 mutant patients, and 1278 mutant TP53 sites. The selection process was documented in a flow chart recommended by the PRISMA (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

The prognostic impact of variant allele frequency (VAF) in TP53 mutant patients with MDS: A systematic review and meta‐analysis

Deng

Ling

et al. 2020

European J of Haematology

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Tumor protein p53 (TP53) is frequently expressed in patients with myelodysplastic syndromes (MDS). Studies have already reported the poor prognostic impact of TP53 gene mutations in MDS patients. However, parts of this subgroup of patients with low-risk MDS still have relatively better survival and longer remission times. Therefore, we performed a meta-analysis to evaluate the prognostic difference intragene of variant allele frequency (VAF). The primary endpoint was overall survival (OS), and event-free survival (EFS) was selected as the secondary endpoint. We extracted the hazard ratio (HR) and 95% confidence interval (CI) for OS and EFS from univariate and multivariate Cox proportional hazard models. A total of 4003 MDS patients and 1278 TP53-mutated patients from 13 cohorts of 11 studies up to February 24, 2020, were included in our meta-analysis. Pooled HRs suggested that a high mutant VAF had an adverse impact on OS (HR = 2.11, 95% CI: 1.48-3.01, P < .0001) but no impact on EFS (HR = 15.57, 95% CI: 0.75-324.44, P = .003) in MDS patients. Twenty percent is a proper threshold to set (HR = 2.02, 95% CI: 1.31-3.13, P = .001) and is a rough line between high clone burden and low clone burden, while 40% is an exact cutoff point (HR = 2.11, 95% CI: 1.26-3.55, P < .0001) to guide diagnosis and treatment. Beyond the traditional binary classification of gene mutation, we aimed to find a way to divide mutant molecular markers more specifically by VAF to provide clinical therapeutic values. Our meta-analysis indicates that a high VAF is an independent, adverse prognostic factor for OS in TP53 mutant MDS patients. Patients with mediate/low-frequency parts who could be treated like wide-type patients have relatively better survival and may choose allogeneic hematopoietic stem cell transplantation as conditions permitting. Further prospective studies are needed in the future, and a large subgroup analysis of the same cutoff point subgroups is needed to obtain a more reliable basis for the impact of other mutant gene VAFs on the prognosis of MDS.

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“…Further validation is needed with a large sample study. In addition, some studies have shown that the mutation load of TET2 and TP53 has an effect on the overall survival time 24 – 26 . At present, few studies have reported that the mutation load of U2AF1 has an effect on the prognosis.…”

Section: Discussionmentioning

confidence: 99%

Differential U2AF1 mutation sites, burden and co-mutation genes can predict prognosis in patients with myelodysplastic syndrome

Wang

Guo

Dong

et al. 2020

Sci Rep

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To investigate the U2AF1 gene mutation site, mutation load and co-mutations genes in patients with myelodysplastic syndrome (MDS) and their effects on prognosis. Gene mutation detection by next-generation sequence and related clinical data of 234 MDS patients were retrospectively collected and analyzed for the relationship between the clinical characteristics, treatment efficacy and prognosis of U2AF1 gene mutation. Among the 234 MDS patients, the U2AF1 gene mutation rate was 21.7% (51 cases), and the median variant allele frequency was 39.5%. Compared with the wild type, the U2AF1 mutant had a higher incidence of chromosome 8 aberration, and was positively correlated with the occurrence of ASXL1, RUNX1, SETBP1 gene mutation, negatively correlated with SF3B1, NPM1 genes mutation (p < 0.05). The most common mutation site of U2AF1 was S34F (32 cases), while U2AF1 Q157P site mutations had a higher incidence of chromosome 7 abnormalities (p = 0.003). The U2AF1 gene mutation more frequently coincided with signal pathway related gene mutations (p = 0.043) with a trend of shortened overall survival. Among patients with U2AF1 gene mutations, those with ASXL1 mutations were prone to develop into acute myeloid leukemia, those with RUNX1 mutations had an increased risk of relapse, and those with TET2 mutations had higher 1-year survival rate. Compared with the patient group of lower mutation load (VAF ≤ 40%), the group with higher mutation load of U2AF1 (VAF > 40%) had a significantly lower 1-year survival rate (46.1% and 80.5%, p = 0.027). The criteria of U2AF1 VAF > 40% is an independent indicator for poor prognosis of MDS patients. VAF > 40% of U2AF1 is an independent factor of short OS in MDS patients. MDS patients with a mutation in the Q157P site of U2AF1 and a higher U2AF1 mutation load suggests poor prognosis, and co-mutated genes in U2AF1 can affect disease progression and prognosis.

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Genomic context and TP53 allele frequency define clinical outcomes in TP53-mutated myelodysplastic syndromes

Cited by 96 publications

References 34 publications

Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes

Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes

The prognostic impact of variant allele frequency (VAF) in TP53 mutant patients with MDS: A systematic review and meta‐analysis

Differential U2AF1 mutation sites, burden and co-mutation genes can predict prognosis in patients with myelodysplastic syndrome

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