Pre-Cancer Diagnosis via TP53 Gene Mutations Applied Ensemble Algorithms

According to current study, individuals with cancer who have a gene mutation have a bad prognosis. Young women with breast cancer had a poorer prognosis than older women, although it is unknown if the p53 gene mutation contributed to this. Due in part to the devastation of cancer, the appropriate technology may help cancer sufferers in regaining their lives. Researchers seek for mutations in cancer-causing gene sequences in order to identify the precancerous stage. While genetic testing may be used to forecast some kinds of cancer, there is presently no effective technique for identifying all cancers caused by TP53 gene mutations. It is one of the most often discovered genetic anomalies in human cancer is a malfunction in the action of the protein P53. As a consequence, the Universal Mutation Database is used to identify gene mutations (UMDCell-line2010). The issue is that, although many basic databases (for example, Excel format databases) exist that include datasets of TP53 gene mutations associated with disease (cancer), this huge database is incapable of detecting cancer. Thus, the purpose the objective of this study is to create an approach for data mining that utilizes a neural network to ascertain the pre-cancerous state. To begin, bioinformatics techniques such as BLAST, CLUSTALW, and NCBI were used to determine whether or not there were any malignant mutations; second, the proposed method was carried out in two stages: to begin, bioinformatics techniques such as BLAST, CLUSTALW, and NCBI were used to determine whether or not there were any malignant mutations; and third, the proposed method was carried out in two stages: to begin, bioinformatics techniques such as To begin, bioinformatics tools such as BLAST and CLUSTAL Vote Algorithms were utilized to classify pre-cancer by malignant mutations in the disease's early stages. The writers teach and evaluate their subjects using a variety of situations, including cross validation and percentages. This page contains a review of the algorithms discussed before.

Li–Fraumeni syndrome in adult patients with acute lymphoblastic leukemia

Background. LiFraumeni syndrome (LFS) is a rare, autosomal dominant, hereditary disorder that is characterized by an increased risk for certain types of cancer, acute lymphoblastic leukemia (ALL), particularly. Germline TP53 mutations are associated with LFS. Genetic counseling and follow-up is essential for patients with LFS and their relatives. Special therapeutic approaches are needed for treatment of oncological disease in these patients. The article presents a series of clinical cases of patients with ALL and SLF, considers general issues of diagnosis and treatment of adult patients with this hereditary genetic syndrome. Aim. Describe clinical observations of patients with acute lymphoblastic leukemia (ALL) and LFS and consider general issues of diagnosis and treatment of adult patients with LFS and ALL. Materials and methods. TP53 gene mutations were screened using Sanger sequencing in 180 de novo patients with Ph-negative (B- and T-cell) and Ph-positive ALL treated by Russian multicenter protocols (ALL-2009, ALL-2012, ALL-2016) at the National Research Center for Hematology, Moscow, Russia, and at the hematology departments of regional clinics of Russia (multicenter study participants). Results. TP53 gene mutations were found in 7.8% (n=14) of de novo ALL patients. In patients, whose biological material was available TP53 gene mutational status was determined in non-tumor cells (bone marrow and peripheral blood during remission, bone marrow samples after allogeneic hematopoietic stem cells transplantation and in tissue of non-hematopoietic origin) for discriminating germline mutations. The analysis included 5 patients (out of 14 with TP53 mutations), whose non-tumor biological material was available for research. Germline status was confirmed in 4 out of 5 B-cell ALL (n=3), T-cell ALL (n=1) investigated patients. Conclusion. Practical value of the research is the observation that the greater part of TP53 gene mutations in patients with Ph-negative B-cell ALL are germinal and associated with LFS.

Genetic Lesions in Russian CLL Patients with the Most Common Stereotyped Antigen Receptors

Background: The features of the IGHV gene repertoire in CLL have been widely discussed in the last 20 years. In approximately 30% of cases of CLL, highly homologous "stereotyped" antigen receptors (SARs) are expressed, representing quasi identical amino acid sequences. Associations with age, disease severity, and cytogenetic aberrations have already been reported for certain SARs. It should be noted that the predictive value of certain SARs could be higher than that of IGHV mutation status. Several SAR subgroups have already been identified as independent prognostic factors in CLL (CLL#1, CLL#2, CLL#8 demonstrate an extremely aggressive course of the disease, CLL#4 - indolent). It was also shown that SAR subgroups may associate with distinct profiles of genetic lesions. Aim: To study the frequency of cytogenetic aberrations and mutations in the TP53, NOTCH1, and SF3B1 genes in CLL patients with the most common SARs in Russia. Methods: The study included 62 patients with CLL diagnosed and followed up from 2012 to 2020. Sequencing of the IGHV gene and SAR assignment were done according to the ERIC recommendations. NOTCH1 gene mutations (exon 34) were assessed by fragment analysis or by NGS using primers described by Campregher et al. TP53 gene mutations (exons 2-11) were determined using NGS according to Pavlova et al. SF3B1 gene mutations (exons 14-16) were studied in 26 patients by NGS. 51 patients underwent a FISH study for the presence of 17p13/TP53 deletions; 29 - additionally for 11q23/ATM and 13q14 deletions (Abbott, USA). Results: CLL#1, CLL#6, and CLL#3 are the most common SAR subsets in Russian CLL patients. Here we report data for 30 patients with CLL#1, 17 with CLL#6, and 15 with CLL#3. In CLL#1 group, 10 (33.3%) patients had mutations in the TP53 gene. In 7 cases, the mutation burden exceeded 35%, in three patients it was less than 10%. In 7 (23.3%) patients, mutations in the NOTCH1 gene were detected, in 5 - c.7544_7545delCT, in 1 - c.7558_7561delCTTC and in 1 - p.Q2444X. Simultaneous mutations in the NOTCH1 and TP53 genes were found in two patients. Deletion 17p13was found in 8 patients from 25 studied (32%). In 7 patients TP53 mutation and del17p13 were observed simultaneously. Deletion 11q23 was found in 6 out of 15 patients (40%). No cases with the simultaneous occurrence of del11q23 and del17p13 or mutations in the TP53 gene were observed. SF3B1 gene mutations in this group were not investigated. In the CLL#6 group, 6 (35.3%) patients had mutations in the TP53 gene (in two of them two clones with different TP53 mutations were observed). In one case, the mutation was less than 10%. In 4 (23.5%) patients NOTCH1 gene mutations (all c.7544_7545delCT) were detected, in two cases the mutation burden was less than 5%. Simultaneous NOTCH1 and TP53 gene mutations were found in two patients. Deletion 17p13 was found in 4 patients from 14 studied (28.5%). In 3 patients TP53 mutations and del17p13 were observed simultaneously. Deletion 11q23 was found in 1 patient out of 10. No SF3B1 gene mutations were found in this group (in 11 patients tested). In CLL#3 group, only 2 (13%) patients had mutations in the TP53 gene, with one having 2 different clones and the other having 4 (this patient also had del17p13, the only one in this group). Also, only 2 (13%) patients had c.7544_7545delCT deletion in the NOTCH1 gene. SF3B1 gene mutations were found in 8 (53.3%) patients. Conclusions: Our data show that in CLL#1, CLL#6, and CLL#3 subsets genetic lesions are much more common than in CLL patients in general. This is in part consistent with earlier European studies. However, in our sample, TP53 mutations and del17p13 are much more frequent in CLL#1 and CLL#6 groups. This may be due to a more sensitive approach (NGS) for mutation detection we used. Furthermore, our cohort included patients relapsed after the FCR treatment. The discrepancy in the detection rate of del11q23 in the CLL#1 subset can be explained by the small sample. Also, population differences in the development of the disease cannot be ruled out. Further studies of genetic lesions associated with certain SAR subgroups may improve diagnostics and therapy of CLL and impact the understanding of disease pathogenesis. Disclosures No relevant conflicts of interest to declare.

TP53 Status, Patient Sex, and the Immune Response as Determinants of Lung Cancer Patient Survival

Lung cancer poses the greatest cancer-related death risk and males have poorer outcomes than females, for unknown reasons. Patient sex is not a biological variable considered in lung cancer standard of care. Correlating patient genetics with outcomes is predicted to open avenues for improved management. Using a bioinformatics approach across non-small cell lung cancer (NSCLC) subtypes, we identified where patient sex, mutation of the major tumor suppressor gene, Tumour protein P53 (TP53), and immune signatures stratified outcomes in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), among datasets of The Cancer Genome Atlas (TCGA). We exposed sex and TP53 gene mutations as prognostic for LUAD survival. Longest survival in LUAD occurred among females with wild-type (wt) TP53 genes, high levels of immune infiltration and enrichment for pathway signatures of Interferon Gamma (INF-γ), Tumour Necrosis Factor (TNF) and macrophages-monocytes. In contrast, poor survival in men with LUAD and wt TP53 genes corresponded with enrichment of Transforming Growth Factor Beta 1 (TGFB1, hereafter TGF-β) and wound healing signatures. In LUAD with wt TP53 genes, elevated gene expression of immune checkpoint CD274 (hereafter: PD-L1) and also protein 53 (p53) negative-regulators of the Mouse Double Minute (MDM)-family predict novel avenues for combined immunotherapies. LUSC is dominated by male smokers with TP53 gene mutations, while a minor population of TCGA LC patients with wt TP53 genes unexpectedly had the poorest survival, suggestive of a separate etiology. We conclude that advanced approaches to LUAD and LUSC therapy lie in the consideration of patient sex, TP53 gene mutation status and immune signatures.

NEGATIVE IMPACT OF THE TP53 GENE MUTATIONS ON THE EFFICACY OF THE THERAPY OF MANTLE CELL LYMPHOMA. INTERIM RESULTS OF THE MCL-2016 PROTOCOL

Introduction. The prognosis of mantle cell lymphoma (MCL) is determined by both the intensification of the first-line therapy and the biological characteristics of the tumour.Aim. To assess the MCL incidence rate, as well as the survival rate of MCL patients with TP53 gene mutations.Materials and methods. The prospective study MCL-2016 aimed at identifying TP53 gene mutations was carried out among 24 MCL patients from January 2016 to December 2018. TP53 gene mutations were screened using Sanger sequencing (exons 1(2)–11). No TP53 gene mutations were identified in 20 patients (20 mutp53-), with TP53 gene mutations (4 mutp53 +) being observed in 4 patients.Results. 17 MCL patients (mut p53-) underwent two cycles of R-BAC (rituximab, bendamustine, cytarabine) and two cycles of R-HA (rituximab, cytarabine 12 g/m2 ) with the subsequent transplantation of autologous hematopoietic stem cells. Following therapy, minimum residual disease (MRD) was undetected in all 17 patients, with 3 patients still undergoing therapy. All patients, who completed the therapy, remain in complete remission with a median follow-up of 5 months following the transplantation of autologous hematopoietic stem cells (from 1 to 17 the months). The prognosis in MCL patients with TP53 gene mutations was worse. In the course of this study, two patients with TP53 gene mutations died of progressing MCL in spite of intensive therapy. In two patients with TP53 gene mutation, allogeneic hematopoietic stem cells were transplanted from unrelated completely identical donors. After undergoing the transplantation, the patients are alive and remain in complete remission (observation periods of 3 and 27 months).Conclusion. Following R-BAC/R-HA therapy, all patients from the mutp53- group reached complete clinical and MRDnegative remission, with an acceptable toxicity profile. For MCL patients with TP53 gene mutations, the transplantation of allogeneic hematopoietic stem cells constitutes the only effective treatment.