Frequency, spectrum, and functional significance of TP53 mutations in patients with diffuse large B-cell lymphoma

Воропаева, Е. Н.; Поспелова, Т. И.; Воевода, М. И.; Максимов, В. Н.

doi:10.1134/s0026893316060224

Cited by 11 publications

(9 citation statements)

References 30 publications

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“…Lymphoma-focused next-generation sequencing was performed on tumor biopsies at diagnosis in 370 nonconsecutive lymphoma patients. TP53 mutations were detected in 21% (78/370) of patients, consistent with previous studies [ 13 ]. Fifty patients with mutated TP53 received anti-CD19 and anti-CD22 CAR T cocktail therapy, and 28 patients received chemotherapy.…”

Section: Resultssupporting

confidence: 91%

TP53-Mutated Circulating Tumor DNA for Disease Monitoring in Lymphoma Patients after CAR T Cell Therapy

Chen

et al. 2021

Diagnostics

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Chimeric antigen receptor T (CAR T) cell immunotherapy has shown remarkable efficacy in non-Hodgkin’s lymphoma (NHL) patients. Minimal residual disease (MRD) monitoring in NHL is essential after CAR T cell therapy, which can be achieved by monitoring circulating tumor DNA (ctDNA). The mutation of TP53 in NHL has been suggested to be associated with a poor prognosis. However, whether TP53-mutated ctDNA can be used as a biomarker remains undetermined. In this study, a total of 40 patients with mutated TP53 who received CAR T cell treatment were analyzed, and specific probes targeting 29 different TP53 mutation sites in the 40 patients were designed and verified. Then, the presence of TP53-mutated ctDNA in longitudinal plasma samples was tracked by droplet digital PCR. Patients were stratified into two groups, favorable or unfavorable, based on their highest ctDNA level using a MAF cutoff of 3.15% according to the ROC curve. The unfavorable group had significantly worse PFS than the favorable group (p < 0.001). Our results suggest that patients with mutated TP53 with a favorable ctDNA profile in the first trimester have better prognostic outcomes than patients with an unfavorable profile, and ctDNA can be a reliable predictor of the subsequent clinical outcome.

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Section: Resultssupporting

confidence: 91%

TP53-Mutated Circulating Tumor DNA for Disease Monitoring in Lymphoma Patients after CAR T Cell Therapy

Chen

et al. 2021

Diagnostics

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“…To this extent, PARP1 inhibition has proven to be successful when used in DDR deficient tumors such as BRCA1- or BRCA2-deficient breast cancer, ATM-deficient colorectal cancer [ 41 ], ATM-deficient lung cancer [ 42 ], TP53/ATM-deficient MCL [ 43 ], IGH/MYC-induced BRCA2 deficient Burkitt lymphoma [ 44 ] [and PTEN/TP53-deficient prostate cancer [ 45 ]. In DLBCL, TP53 mutations are found in 21–24% of cases and are inversely correlated with survival [ 46 , 47 ]. Moreover, PARP1 is known for its role in NF-kB activation [ 48 ] contributing to inflammation and carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Identification of relevant drugable targets in diffuse large B-cell lymphoma using a genome-wide unbiased CD20 guilt-by association approach

et al. 2018

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Forty percent of patients with diffuse large B-cell lymphoma (DLBCL) show resistant disease to standard chemotherapy (CHOP) in combination with the anti-CD20 monoclonal antibody rituximab (R). Although many new anti-cancer drugs were developed in the last years, it is unclear which of these drugs can be safely combined to improve standard therapy without antagonizing anti-CD20 efficacy. In this study, we aimed to identify rituximab compatible drug-target combinations for DLBCL. For this, we collected gene expression profiles of 1,804 DLBCL patient samples. Subsequently, we performed a guilt-by-association analysis with MS4A1 (CD20) and prioritized the 500 top-ranked CD20-associated gene probes for drug-target interactions. This analysis showed the well-known genes involved in DLBCL pathobiology, but also revealed several genes that are relatively unknown in DLBCL, such as WEE1 and PARP1. To demonstrate potential clinical relevance of these targets, we confirmed high protein expression of WEE1 and PARP1 in patient samples. Using clinically approved WEE1 and PARP1 inhibiting drugs in combination with rituximab, we demonstrated significantly improved DLBCL cell killing, also in rituximab-insensitive cell lines. In conclusion, as exemplified by WEE1 and PARP1, our CD20-based genome-wide analysis can be used as an approach to identify biological relevant drug-targets that are rituximab compatible and may be implemented in phase 1/2 clinical trials to improve DLBCL treatment.

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“…Besides, TP53 gene aberrations in B-lymphocytes leads to less effective functioning of intracellular signaling pathways that can arrest cell cycle in G1 and G2 phases; DNA repair defects; more effective cell adaptation to hypoxia and angiogenesis stimulation; reduction control under telomere structure and differentiation inhibition. For these reasons, the disturbance of programed cell death due to dysfunction p53 is a basis for development and progression of lymphoproliferative disorders (Voropaeva et al, 2017). Moreover, as the TP53 gene plays an important role in mediation of chemotherapeutic agents' action and action of target drugs, the deficit of its function leads to formation of multidrug resistance phenotype of lymphoma cells (Voropaeva et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

The rs78378222 prevalence and the copy loss of the protective allele A in the tumor tissue of diffuse large B-cell lymphoma

Воропаева

Orlov

Поспелова

et al. 2020

PeerJ

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Background Rare single nucleotide polymorphisms (SNPs) are likely to be a crucial genetic factor for human diseases, including cancer. rs78378222 is rare SNP in 3′-untranslated region (UTR) of TP53 gene leading to disturbance of 3′-end mRNA processing. The frequency of rs78378222 varies in several studied populations. The meta-analysis of 34 genome-wide association studies indicated that rs78378222 was significantly associated with an increased risk of cancer overall. Bioinformatic analysis indicates that somatic loss of the protective A allele of rs78378222 occurs in the tumor tissue of some malignant. The goal of the current study is to document the rs78378222 prevalence and evaluate the copy loss status of the protective allele A in the tumor tissue of patients with diffuse large B-cell lymphoma (DLBCL). Methods Total DNA was isolated from FFPE-samples and peripheral blood of patients with DLBCL and comparable in age and sex controls. rs78378222 genotyping was performed by the PCR-RFLP method using restriction endonuclease HindIII. Direct Sanger’s sequencing was used to confirm the presence of C allele of the rs78378222. The search for TP53 gene mutations was carried out by Sanger’s direct sequencing method, according to the IARC protocol. Results The result of genotyping of 136 DNA samples from DLBCL tumor tissue suggested that frequency of the rs78378222 was 11/136 (8.1%). Rare allele C frequency was 11/272 (4.2%). A total of 5/11 DLBCL rs78378222 heterozygous samples had the heterozygosity loss in the TP53 gene. Only one of these cases was combined with TP53 gene mutations which have proven oncogenic potential—p.Arg196Gln, other four cases have not mutations in the coding regions of gene. Conclusions At the stages of DLBCL initiation or progression a loss of the protective allele A of rs78378222 occurs. Further efforts are needed to study possible molecular mechanisms underlying somatic alterations in DLBCL in this region of the TP53 3′-UTR as well as functional studies to illustrate how the presents of rs78378222 may affect tumor progression of lymphoma.

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Frequency, spectrum, and functional significance of TP53 mutations in patients with diffuse large B-cell lymphoma

Cited by 11 publications

References 30 publications

TP53-Mutated Circulating Tumor DNA for Disease Monitoring in Lymphoma Patients after CAR T Cell Therapy

TP53-Mutated Circulating Tumor DNA for Disease Monitoring in Lymphoma Patients after CAR T Cell Therapy

Identification of relevant drugable targets in diffuse large B-cell lymphoma using a genome-wide unbiased CD20 guilt-by association approach

The rs78378222 prevalence and the copy loss of the protective allele A in the tumor tissue of diffuse large B-cell lymphoma

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