TP53 mutations are frequent in adult acute lymphoblastic leukemia cases negative for recurrent fusion genes and correlate with poor response to induction therapy

Chiaretti, Sabina; Brugnoletti, Fulvia; Tavolaro, Simona; Bonina, Silvia; Paoloni, Francesca; Marinelli, M; Patten, Nancy; Bonifacio, Massimiliano; Kropp, Maria Grazia; Sica, Simona; Guarini, Anna; Foà, Robin

doi:10.3324/haematol.2012.076786

Cited by 54 publications

(51 citation statements)

References 14 publications

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“…The data clearly showed that (1) TP53 mutations occur more frequently thanpreviously published (15.7% vs 2% to 3% 13 ; 8% to 9% 2,6 ), (2) TP53 mutations are predominantly associated with ALL with low hypodiploidy and MYC-translocated ALL, (3) the TP53 mutation/deletion frequency increases with age, (4) TP53 mutations are associated with short survival independent of age and specific cytogenetic alterations, and (5) the adverse impact on survival occurs only when the wt TP53 is lost. The reason why TP53 mutations were found at a higher frequency in ALL patients than in earlier studies might be due to the cohort analyzed, as previous studies mainly focused on children and our cohort includes a large variety of ALL subgroups, including, eg, Burkitt/MYC1 ALL.…”

Section: Discussioncontrasting

confidence: 46%

“…6 For TP53 mutations in adult ALL, only a few studies are available that include mostly relapsed cases and small cohorts of patients. 25,26 Thus far, the largest series of adult ALL investigated for TP53 mutations includes 98 adult patients 2 and shows TP53 mutations in 8 patients (8.2%), which is similar to the TP53 mutation frequency in AML at diagnosis and in CLL at the time of progression. 10,11 Furthermore, the results support previous findings of an increase of TP53 mutations at disease reappearance.…”

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confidence: 68%

“…23,25,26 Moreover, TP53 mutations were found to be more frequent in T-lineage ALL than in B-lineage ALL and were detected in 14% of cases negative for recurrent fusion genes. 2 As data on incidence and prognostic significance of TP53 mutations in ALL remains scarce to date, we aimed to determine the TP53 mutation frequency, the association with cytogenetic subgroups and age, as well as the impact on survival in a large cohort of 625 ALL patients.…”

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confidence: 99%

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TP53 mutations occur in 15.7% of ALL and are associated with MYC-rearrangement, low hypodiploidy, and a poor prognosis

Stengel

Schnittger

Weissmann

et al. 2014

Blood

125

104

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Key Points• TP53 mutations are detected in 15.7% of patients with ALL and are correlated to a low hypodiploid karyotype and to MYC-translocations. • Disruption of both TP53alleles is associated with adverse prognosis in ALL.TP53 is the most extensively studied gene in cancer. However, data on frequency and the prognostic impact of TP53 mutations in acute lymphoblastic leukemia (ALL) remain scarce. Thus, we aimed at identifying the mutation frequency of TP53, its association with cytogenetic subgroups, and its impact on survival in a large cohort of 625 patients with ALL. Our data revealed an overall mutation incidence of 15.7%, which increases with age. Correlation with cytogenetic subgroups showed that mutations were most frequent in ALL with low hypodiploidy or MYC-rearrangements. Furthermore, for a large number of patients, both TP53 alleles were altered, either by 2 TP53 mutations (12%) or by a TP53 mutation and a TP53 deletion in the second allele (39%). A high TP53 mutation load was correlated to low hypodiploidy, high hyperdiploidy, and a complex karyotype. Moreover, a higher mutation load was found in B-lineage ALL compared with T-lineage ALL. Similar to other cancers, the median overall survival was significantly shorter in patients with TP53 mutation compared with patients with wild-type TP53. This effect was especially pronounced when both TP53 alleles were affected, either by 2 TP53 mutations or by both a mutation and an accompanying TP53 deletion. (Blood. 2014;124(2):251-258)

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Section: Discussioncontrasting

confidence: 46%

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confidence: 68%

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confidence: 99%

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TP53 mutations occur in 15.7% of ALL and are associated with MYC-rearrangement, low hypodiploidy, and a poor prognosis

Stengel

Schnittger

Weissmann

et al. 2014

Blood

125

104

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“…4,5,7,8 Over the last years much effort has been put into understanding the molecular background of relapsed and chemotherapy-resistant ALL. [9][10][11][12] In the pediatric setting, Tzoneva et al identified mutations affecting the NT5C2 gene 13 , which appeared to be acquired at relapse and, overall, to be more frequent in T-ALL than in B-ALL; similar results were recently reported in T-ALL also by Kunz et al 14 A comprehensive description of the genetic alterations in patients with chemorefractory T-ALL has thus far been lacking. We previously reported that whole transcriptome sequencing (RNAseq) is a powerful approach for the detection of translocations, single nucleotide variants, small insertions/deletions (INDEL) and gene expression deregulation in T-ALL.…”

Section: Introductionsupporting

confidence: 58%

RNA sequencing unravels the genetics of refractory/relapsed T-cell acute lymphoblastic leukemia. Prognostic and therapeutic implications

et al. 2016

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Despite therapeutic improvements, a sizable number of patients with T-cell acute lymphoblastic leukemia still have a poor outcome. To unravel the genomic background associated with refractoriness, we evaluated the transcriptome of 19 cases of refractory/early relapsed T-cell acute lymphoblastic leukemia (discovery cohort) by performing RNA-sequencing on diagnostic material. The incidence and prognostic impact of the most frequently mutated pathways were validated by Sanger sequencing on genomic DNA from diagnostic samples of an independent cohort of 49 cases (validation cohort), including refractory, relapsed and responsive cases. Combined gene expression and fusion transcript analyses in the discovery cohort revealed the presence of known oncogenes and identified novel rearrangements inducing overexpression, as well as inactivation of tumor suppressor genes. Mutation analysis identified JAK/STAT and RAS/PTEN as the most commonly disrupted pathways in patients with chemorefractory disease or early relapse, frequently in association with NOTCH1/FBXW7 mutations. The analysis on the validation cohort documented a significantly higher risk of relapse, inferior overall survival, disease-free survival and event-free survival in patients with JAK/STAT or RAS/PTEN alterations. Conversely, a significantly better survival was observed in patients harboring only NOTCH1/FBXW7 mutations: this favorable prognostic effect was abrogated by the presence of concomitant mutations. Preliminary in vitro assays on primary cells demonstrated sensitivity to specific inhibitors. These data document the negative prognostic impact of JAK/STAT and RAS/PTEN mutations in T-cell acute lymphoblastic leukemia and suggest the potential clinical application of JAK and PI3K/mTOR inhibitors in patients harboring mutations in these pathways.

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“…The P53 plays a crucial role in cell cycle regulation and development of apoptosis after DNA damage. Moreover, its role in tumorigenesis was previously reported in solid and hematologic malignancies [16]. Since the TP53 is mutated in more than 50% of human cancers, it has attracted the interest of several researchers.…”

Section: Introductionmentioning

confidence: 99%

Adverse Effect of Mobile Phone on Tp53, Brcai Genes and Dna Fragmentation in Albino Rat Liver

Em¹,

Mk²,

Sa³

2013

Int J Genom Proteomics

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TP53 mutations are frequent in adult acute lymphoblastic leukemia cases negative for recurrent fusion genes and correlate with poor response to induction therapy

Cited by 54 publications

References 14 publications

TP53 mutations occur in 15.7% of ALL and are associated with MYC-rearrangement, low hypodiploidy, and a poor prognosis

TP53 mutations occur in 15.7% of ALL and are associated with MYC-rearrangement, low hypodiploidy, and a poor prognosis

RNA sequencing unravels the genetics of refractory/relapsed T-cell acute lymphoblastic leukemia. Prognostic and therapeutic implications

Adverse Effect of Mobile Phone on Tp53, Brcai Genes and Dna Fragmentation in Albino Rat Liver

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