BackgroundThe knowledge about specific mechanisms generating TP53 dysfunction in diffuse large B-cell lymphoma is limited. The aim of the current study was to comprehensively explore TP53 gene variability resulting from somatic mutations, promoter methylation, and allelic imbalance in tumorous tissue of diffuse large B-cell lymphoma (DLBCL).MethodsDNA samples from 74 patients with DLBCL were used. Genomic DNA was isolated from paraffin blocks of lymph nodes or from extranodal biopsies of tumors by the phenol–chloroform extraction method with guanidine. Analysis of coding sequences of the TP53 gene was based on Sanger’s direct sequencing method. The methylation status of the TP53 promoter was analyzed using by methylation-specific PCR on bisulfite-converted DNA. Assessment of the detected mutations was carried out in the IARC TP53 Database and the TP53 UMD mutation database of human cancer.ResultsThe mutations in regions coding for the DNA-binding domain were prevalent (95%). In the analyzed sample of patients, codons 275, 155, 272, and 212 were hotspots of mutations in the TP53 gene. In addition, functionally significant intron mutations (IVS6-36G > C and IVS5 + 43G > T) were detected. Instances of TP53 promoter methylation were observed only in a few samples of diffuse large B-cell lymphoma tissue. Furthermore, loss of heterozygosity was revealed only in the subgroup of patients with altered status of the gene (mutations were detected in five patients and promoter methylation in one case).ConclusionsThus, the results suggest that there are two sequential events in the formation of diffuse large B-cell lymphoma in at least some cases. The first event is mutation or methylation of the TP53 promoter, leading to appearance of a cell with increased risk of malignant transformation. The second event is the loss of an intact allele of the gene; this change is necessary for tumorigenesis. We identified TP53 mutation patterns in a Russian cohort of patients with de novo DLBCL who were treated with R-CHOP and R-CHOP-like regimens and confirmed that TP53 mutation status is a valuable prognostic biomarker.
SummaryThis study aimed to clarify the association between the TP53 rs1625895 polymorphism and the efficiency of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) therapy in 106 patients with diffuse large B cell lymphoma (DLBCL). All patients received six to eight courses of R-CHOP therapy as a first-line treatment. The rs1625895 polymorphism was genotyped by polymerase chain reaction with restriction fragment length polymorphism assay. The G/G genotype of the TP53 rs1625895 polymorphism was shown to be associated with a high probability of R-CHOP therapy failure in DLBCL patients according to the probability of remission as well as 5-year overall and relapse-free survivals.
Next-Generation Sequencing-driven analysis and Systems Biology approaches commonly serve as a backdrop for a study of a tumor genome. This issue of BMC Medical Genomics SBB-2019 ("Systems Biology and Bioinformatics") presents recent works discussed at the 11th Young Scientists School "Systems Biology and Bioinformatics"-2019, held in Novosibirsk, Russia (http://conf.bionet.nsc.ru/sbb2 019/en/). Here we collated some cancer gene expression studies, some mutation profiling studies as well as some insightful case reports. The SBB school series on bioinformatics proceeds annually since 2008 under the joint steerage of the Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences and Novosibirsk State University [1, 2]. We had publications in special topic issues after the Schools before in BMC Genomics, BMC Medical Genomics and related BioMed Central family journals since 2014 [3-5]. The SBB Schools in Novosibirsk were initially conceived as satellite event for young scientists held at the same time as BGRS\SB (Bioinformatics of Genome Regulation and Structure \ Systems Biology) conference series, since 1998 taking place biannually. The recent BGRS\SB-2020 event in Novosibirsk was over at the time of the current journal issue publication (https://bgrssb.icgbio.ru/2020/). Other special issues (Supplements) to the BMC journals in the fields of genomics, genetics, bioinformatics, and medical genetics are published at BMC Genomics, BMC Genetics and three other BMC journals. The BGRS\SB-2018 conference highlights were published in 2018 [5-7], and continued the BMC Medical
Adverse prognostic ACE DD, ADRB1 AA, MTHFR TT, and eNOS 4a/4a genotypes were more frequently observed in the non-indigenous ethnic groups; the ADRA2B DD genotype was more common in the native population. Hypertension was associated with the ACE DD, МTHFR CT, and ADRB1 AA genotypes in the native ethnic group and with the ACE ID genotype in the non-indigenous population.
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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