Clinical implication and prognostic significance of FLT3-ITD and ASXL1 mutations in Egyptian AML patients: A singlecenter study

2021 ◽  
pp. 1-11
Author(s):  
Huda F. Ebian ◽  
Sherin Elshorbagy ◽  
Haitham Mohamed ◽  
Ahmad Embaby ◽  
Tarek Khamis ◽  
...  
Keyword(s):  
Clinical Implication ◽  
Prognostic Significance ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Internal Tandem Duplication ◽  
Free Survival ◽  
Younger Age ◽  
Sex Comb ◽  
Risk Patients ◽  
Independent Risk Factors

BACKGROUND: Both of Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) and Additional Sex Comb-like 1 (ASXL1) mutations are frequent and early genetic alteration events in acute myeloid leukemia (AML) patients. These genetic alterations may be associated with unfavorable prognosis. OBJECTIVE: Up to our knowledge, this is the first study performed to evaluate the clinical implication and prognostic significance of FLT3-ITD and ASXL1 mutations and their coexistence on the outcome of Egyptian AML patients. METHODS: Our study included 83 patients with AML who were subjected to immunophenotyping and detection of FLT3-ITD and ASXL1 gene mutation by polymerase chain reaction (PCR) and real-time PCR, respectively. RESULTS: FLT3-ITD and ASXL1 mutations were detected in 20.5% and 18.1% of AML patients respectively. Seven patients (8.4%) had co-expression of both genes’ mutation. FLT3-ITD mutation was significantly higher in younger age, higher WBCs count and poor cytogenetic risk patients (P= 0.01, < 0.001 and 0.008 respectively). ASXL1 mutation was significantly higher in intermediate cytogenetic risk patients (P= 0.2). The mean period of survival and relapse free survival (RFS) were significantly reduced in FLT3-ITD and ASXL1 mutations compared with their non-mutant types (P= 0.01 and 0.03 respectively). Both mutations were independent risk factors for overall survival (OS) and (RFS) in univariate and multivariate analysis in AML patients. CONCLUSION: FLT3-ITD and ASXL1 gene mutations or their coexistence can predict a poor prognosis in AML patients.

scholarly journals Prognostic significance of concurrent gene mutations in intensively treated patients with IDH-mutated AML, an ALFA study

Blood ◽  
2021 ◽  
Author(s):  
Matthieu Duchmann ◽  
Jean-Baptiste Micol ◽  
Nicolas Duployez ◽  
Emmanuel Raffoux ◽  
Xavier Thomas ◽  
...  
Keyword(s):  
Prognostic Significance ◽  
Gene Mutations ◽  
Normal Karyotype ◽  
Genetic Alterations ◽  
Prognostic Impact ◽  
Hematopoietic Stem ◽  
Fully Integrated ◽  
Mutational Status ◽  
Trial Testing ◽  
Prospective Trials

IDH inhibitors are effective in AML, and trials evaluating frontline combinations with intensive chemotherapy (IC) are ongoing. Data on the prognostic significance of co-occurring genetic alterations and allogeneic hematopoietic stem cell transplantation (HSCT) are conflicting in each IDH-mutated subgroup treated by IC, while this information is important for trial design and results interpretation. We retrospectively analyzed 127 IDH1, 135 IDH2R140 and 57 IDH2R172 newly diagnosed AML patients treated with IC in three Acute Leukemia French Association (ALFA) prospective trials. We addressed in each IDH subgroup the prognostic impact of clinical and genetic covariates, and the role of HSCT in eligible patients. In IDH1 patients, presence of NPM1 mutations was the only variable predicting improved OS in multivariate analysis (p &lt; 0.0001). In IDH2R140, normal karyotype (p= 0.008) and NPM1 mutations (p = 0.01) predicted better OS. NPM1 mutations were associated with better DFS (p = 0.0009) whereas presence of DNMT3A mutations was associated with shorter DFS (p = 0.0006). In IDH2R172, platelet count was the only variable retained in the multivariate model for OS (p = 0.002). Among non-favorable ELN-2010 eligible patients, 71 (36%) achieved an HSCT in first complete remission (CR1) and had longer OS (p = 0.03) and DFS (p = 0.02) than not-transplanted patients. Future clinical trial testing frontline IDH inhibitors combined with IC may consider stratification on NPM1 mutational status, the main prognostic factor in IDH1 and IDH2R140 mutated AML. HSCT improve OS of non-favorable IDH1/2-mutated AML and should be fully integrated in the treatment strategy.

Chromosome Aberrations, Gene Mutations and Expression Changes, and Prognosis in Adult Acute Myeloid Leukemia

Hematology ◽  
2006 ◽  
Vol 2006 (1) ◽  
pp. 169-177 ◽  
Author(s):  
Krzysztof Mrózek ◽  
Clara D. Bloomfield
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Chromosome Aberrations ◽  
Myeloid Leukemia ◽  
Molecular Genetic ◽  
Prognostic Significance ◽  
Gene Mutations ◽  
Normal Karyotype ◽  
Genetic Alterations ◽  
Acute Myeloid

Abstract Pretreatment clinical features and prognosis of patients with acute myeloid leukemia (AML) are strongly influenced by acquired genetic alterations in leukemic cells, which include microscopically detectable chromosome aberrations and, increasingly, submicroscopic gene mutations and changes in gene expression. Cytogenetic findings separate AML patients into three broad prognostic categories: favorable, intermediate and adverse. The cytogenetic-risk classifications differ somewhat for younger adult patients and those aged 60 years or older. In many instances, patients with specific cytogenetic findings, e.g., those with a normal karyotype or those with either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22) [collectively referred to as core-binding factor (CBF) AML] can be further subdivided into prognostic categories based on the presence or absence of particular gene mutations or changes in gene expression. Importantly, many of these molecular genetic alterations constitute potential targets for risk-adapted therapies. In this article, we briefly review major cytogenetic prognostic categories and discuss molecular genetic findings of prognostic significance in two of the largest cytogenetic groups of patients with AML, namely AML with a normal karyotype and CBF AML.

scholarly journals Molecular Profiling of 22 Primary Atypical Meningiomas Shows the Prognostic Significance of 18q Heterozygous Loss and CDKN2A/B Homozygous Deletion on Recurrence-Free Survival

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 903
Author(s):  
Valeria Barresi ◽  
Michele Simbolo ◽  
Adele Fioravanzo ◽  
Maria Piredda ◽  
Maria Caffo ◽  
...  
Keyword(s):  
Copy Number ◽  
Prognostic Significance ◽  
Recurrence Risk ◽  
Genetic Alterations ◽  
Homozygous Deletion ◽  
Molecular Profile ◽  
Recurrence Free Survival ◽  
Free Survival ◽  
Atypical Meningiomas ◽  
Minor Criteria

The use of adjuvant therapy is controversial in atypical meningiomas with gross total resection. Predictors of recurrence risk could be useful in selecting patients for additional treatments. The aim of this study was to investigate whether molecular features are associated with recurrence risk of atypical meningiomas. According to WHO classification, the diagnosis of atypical meningioma was based on the presence of one major criteria (mitotic activity, brain invasion) or three or more minor criteria. The molecular profile of 22 cases (eight mitotically active, eight brain-invasive, and six with minor criteria) was assessed exploring the mutational status and copy number variation of 409 genes using next generation sequencing. Of the 22 patients with a median follow up of 53.5 months, 13 had recurrence of disease within 68 months. NF2 mutation was the only recurrent alteration (11/22) and was unrelated to clinical-pathological features. Recurring meningiomas featured a significantly higher proportion of copy number losses than non-recurring ones (p = 0.027). Chromosome 18q heterozygous loss or CDKN2A/B homozygous deletion was significantly associated with shorter recurrence-free survival (p = 0.008; hazard ratio: 5.3). Atypical meningiomas could be tested routinely for these genetic alterations to identify cases for adjuvant treatment.

scholarly journals A novel immune prognostic index for stratification of high-risk patients with early breast cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hannah Lee ◽  
Mi Jeong Kwon ◽  
Beom-Mo Koo ◽  
Hee Geon Park ◽  
Jinil Han ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
High Risk ◽  
Early Breast Cancer ◽  
Prognostic Significance ◽  
Prognostic Index ◽  
Low Risk ◽  
Lymph Node Status ◽  
Free Survival ◽  
Risk Patients

AbstractThe prognostic value of current multigene assays for breast cancer is limited to hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer. Despite the prognostic significance of immune response-related genes in breast cancer, immune gene signatures have not been incorporated into most multigene assays. Here, using public gene expression microarray datasets, we classified breast cancer patients into three risk groups according to clinical risk and proliferation risk. We then developed the immune prognostic index based on expression of five immune response-related genes (TRAT1, IL2RB, CTLA4, IGHM and IL21R) and lymph node status to predict the risk of recurrence in the clinical and proliferation high-risk (CPH) group. The 10-year probability of disease-free survival (DFS) or distant metastasis-free survival (DMFS) of patients classified as high risk according to the immune prognostic index was significantly lower than those of patients classified as intermediate or low risk. Multivariate analysis revealed that the index is an independent prognostic factor for DFS or DMFS. Moreover, the C-index revealed that it is superior to clinicopathological variables for predicting prognosis. Its prognostic significance was also validated in independent datasets. The immune prognostic index identified low-risk patients among patients classified as CPH, regardless of the molecular subtype of breast cancer, and may overcome the limitations of current multigene assays.

PROGNOSTIC SIGNIFICANCE OF MONORESISTANCE GENE EXPRESSION IN TUMORS OF PATIENTS WITH NON-SMALL CELL LUNG CANCER AFTER PREOPERATIVE CHEMOTHERAPY

2017 ◽  
Vol 63 (1) ◽  
pp. 122-127
Author(s):  
Yuliya Kzhyshkovska ◽  
Nadezhda Cherdyntseva ◽  
Sergey Tuzikov ◽  
Lyubov Pisareva ◽  
Marina Ibragimova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Neoadjuvant Chemotherapy ◽  
Lung Tumor ◽  
Prognostic Significance ◽  
Disease Free Survival ◽  
Genetic Alterations ◽  
Lung Tumors ◽  
Free Survival ◽  
Low Level ◽  
Disease Free

A significant role in the development of lung tumor resistance to drug therapy play so called mono resistance genes that determine resistance/sensitivity of tumor cells to distinct chemotherapeutic agents, they include BRCA1, RRM1, ERCC1, TOP1, TOP2a, TUBB3, TYMS, ABCC5 genes. It is shown that the use of these biomarkers as a criteria to appoint the adequate postoperative chemotherapy is associated with the forecast. However in the course of neoadjuvant chemotherapy change the expression profile of these genes can occur, which can lead to misinterpretation of results. In this regard perspective is the development of new relevant prognostic factors, which take into account occurred molecular genetic alterations in lung tumors after preoperative therapy. We presented the results of the combined treatment of 52 patients with NSCLC IIA - IIIB stage, based on the analysis of chemotherapy resistance/sensitivity gene expression for appointment the suitable drugs. It was found that the lack of expression of ERCC1 gene in lung tumor derived after neoadjuvant chemotherapy is associated with high rates of disease-free survival (P. = 0,00913). Low level expression of RRM1 gene (less than 0.5) is also associated with high rates of patient's survival (log-rank test P. = 0,01808), while a high level is a marker of poor prognosis. It is found that the combination of enhanced expression (>0.5) of any two or three genes: RRM1, ABCC5, TYMS, are the indicators of poor disease-free survival. We have shown that expression of ERCC1 gene is the independent prognostic factor. At zero ERCC1 expression in lung tumors, regardless of high or low level of expression of RRM1, ABCC5, TYMS genes, a high recurrence-free survival is observed. Thus, the data suggest the prognostic significance of the expression of ERCC1, TUBB3, RRM1, ABCC5 and TYMS genes in the lung tumor after neoadjuvant chemotherapy.

p53 and K-ras Gene Mutations Correlate With Tumor Aggressiveness But Are Not of Routine Prognostic Value in Colorectal Cancer

1999 ◽  
Vol 17 (5) ◽  
pp. 1375-1375 ◽  
Author(s):  
Silvia Tortola ◽  
Eugenio Marcuello ◽  
Isabel González ◽  
Germán Reyes ◽  
Rosa Arribas ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Significance ◽  
Gene Mutations ◽  
P53 Gene ◽  
Radical Resection ◽  
Genetic Alterations ◽  
Rank Test ◽  
P53 Mutations ◽  
Ras Gene ◽  
Ras Mutations

PURPOSE: p53 gene and K-ras mutations are among the most common genetic alterations present in colorectal cancer. The prognostic utility of such mutations remains controversial. The purpose of this study was to prospectively evaluate the prognostic significance of p53 and K-ras gene mutations in colorectal cancer. PATIENTS AND METHODS: One hundred forty patients were analyzed. Tumors belonging to the microsatellite mutator phenotype were excluded (n = 8). Mutations at the K-ras and p53 genes were detected and characterized by restriction fragment length polymorphism, single-strand conformation polymorphism, and sequencing, as appropriate. RESULTS: p53 mutations were detected in 66 (50%) and K-ras mutations were detected in 54 (41%) of the 132 patients. In 26 cases (20%), ras and p53 mutations coexisted; in 38 cases (29%), neither mutation was found. Multivariate analysis of the whole population analyzed (n = 132) showed that survival was strongly correlated with the presence of p53 mutations alone or in combination with K-ras mutations (P = .002; log-rank test). When only patients undergoing a radical resection were considered (R0; n = 101), p53 mutations were no longer of prognostic significance. CONCLUSION: p53 mutations alone or in combination with K-ras mutations are correlated with a worse outcome. However, the routine use of these mutations as prognostic markers in the clinical setting is not recommended.

scholarly journals Functional and Clinical Significance of ROR1 in Lung Adenocarcinoma

2020 ◽  
Author(s):  
Giovanna Schiavone ◽  
Epistolio Samantha ◽  
Martin Vittoria ◽  
Molinari Francesca ◽  
Barizzi Jessica ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Prognostic Significance ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Orphan Receptor ◽  
Entire Cohort ◽  
Molecular Alterations ◽  
Thyroid Transcription Factor 1 ◽  
Thyroid Transcription Factor ◽  
Transcription Factor 1

Abstract BACKGROUND: Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is normally detectable in embryonic tissues and absent in adult tissues. ROR1 was shown to inhibit apoptosis, potentiate EGFR signaling and reported to be overexpressed and associated with poor prognosis in several tumor models. This study aimed to assess the expression of ROR1 and verify its prognostic significance in lung adenocarcinoma (AC) patients.METHODS: We analyzed ROR1 expression by quantitative real-time PCR (qRT-PCR) in 56 histologically confirmed lung AC, stage I to IV, in addition we evaluated its association with TTF-1 (thyroid transcription factor-1) expression and the main molecular alterations involved in lung cancerogenesis.RESULTS: ROR1 overexpression was observed in 28.6% of the entire cohort, using a cut-off of 1, or in 51.8% of the cases using the median value as threshold. Among patients without any genetic alteration, ROR1 overexpression was observed in 34.8% considering a cut-off of 1 and 52.2% considering the median value. The distribution of ROR1 was homogeneous among the different molecular categories: we found no association of ROR1 expression and the presence of gene mutations/rearrangements or the expression of TTF-1. Furthermore, ROR1 expression was not correlated with overall survival (OS).CONCLUSIONS: ROR1 overexpression could constitute a potential therapeutic target because altered in a consistent number of lung AC, especially in cases without druggable genetic alterations. ROR1 expression is independent of classical lung cancer molecular alterations and not correlated, in a Caucasian cohort, to TTF-1 expression. Finally, ROR1 expression does not play a prognostic significance.

scholarly journals Prognostic impact of miR-196a/b expression in adult acute myeloid leukaemia: a single-centre, retrospective cohort study

2018 ◽  
Vol 46 (9) ◽  
pp. 3675-3683 ◽  
Author(s):  
JunYu Zhang ◽  
WeiE Liu ◽  
Jing Du ◽  
YangJin Jin ◽  
MinLei Zhao ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Cox Regression ◽  
Prognostic Significance ◽  
Prognostic Impact ◽  
Event Free Survival ◽  
Internal Tandem Duplication ◽  
Free Survival ◽  
Prognostic Effect ◽  
Acute Myeloid

Objective The prognostic effect of miR-196a/b expression in adult patients with leukaemia remains unclear. This study aimed to determine whether miR-196a/b expression can serve as a prognostic factor for patients with acute myeloid leukaemia. Methods We enrolled 124 patients with acute myeloid leukaemia. We measured miR-196a/b expression by real-time reverse transcription-polymerase chain reaction. We classified patients into high and low expression groups based on the median expression value. Cox regression analyses were carried out to assess the prognostic significance of miR-196a/b expression in the context of well-established predictors. Results Patients with high miR-196a/b expression were older in age, and had higher white blood cell and platelet counts than did patients with low miR-196a/b expression. Patients with high miR-196a/b expression were associated with the French–American–British classification M5 subtype and with the presence of nucleophosmin and FLT3 internal tandem duplication mutations, but were not associated with the favourable karyotype risk subgroup. Moreover, patients with high miR-196a/b expression had a shorter event-free survival rate compared with those with low miR-196a/b expression in univariate and multivariate analyses. Conclusion High miR-196a/b expression is associated with poor event-free survival.

Importance of FLT3 Mutations and Other Genetic Abnormalities in Normal Karyotype AML.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. sci-11-sci-11
Author(s):  
Clara D. Bloomfield ◽  
Guido Marcucci
Keyword(s):  
Gene Expression ◽  
Prognostic Significance ◽  
Gene Mutations ◽  
Normal Karyotype ◽  
Genetic Alterations ◽  
Wild Type ◽  
Term Survival ◽  
Flt3 Mutations ◽  
Cebpa Mutations

Cytogenetic findings at diagnosis are currently considered the most important prognostic factor in AML. By far, the most common cytogenetic finding, found in approximately 40–50% of patients, is a normal karyotype (defined as detection of only normal chromosomes in 20 or more marrow cells). Recent molecular analyses of leukemic blasts in cytogenetically normal AML (CN-AML) have revealed a striking heterogeneity with regard to the presence of acquired gene mutations and changes in gene expression. Multiple submicroscopic genetic alterations with prognostic significance have been discovered, including mutations of the FLT3 gene, both internal tandem duplications (ITDs) and point mutations (TKDs), partial tandem duplication (PTD) of the MLL gene, mutations in the NPM1, CEBPA, and WT1 genes, and high expression of the BAALC, ERG, and MN1 genes. Most of these abnormalities, except for mutations in NPM1 and CEBPA, have been associated with an adverse prognosis. CN-AML patients with FLT3 ITD, NPM1 wild type, or both have worse outcome in the range of 30% long-term survival, unless they also harbor CEBPA mutations. A high expression of the FLT3 ITD allele compared to the FLT3 wild type allele confers an especially poor prognosis. In contrast, CN-AML patients without a FLT3 ITD and with NPM1 mutations have a particularly good outcome in the range of 60% long-term survival, unless they present with high ERG expression. The prognostic significance of FLT3 TKD mutations is controversial, and, recently, the outcome of patients with the MLL PTD has improved when treated with induction therapy, including etoposide and post induction therapy with autologous transplantation. As a result, the 2008 World Health Organization classification of AML recommends evaluation of FLT3, NPM1, and CEBPA mutations in CN-AML. Application of gene expression profiling has also identified signatures that appear to separate CN-AML patients into prognostic subgroups, and, more recently, a microRNA expression signature was found to be associated with outcome in molecular high-risk CN-AML patients (i.e., those with FLT3 ITD, NPM1 wild type, or both). These and similar future findings are likely to have a major impact on the clinical management of CN-AML not only in prognostication, but also in selection of appropriate treatment, since many of the identified genetic alterations already constitute (e.g., FLT3 mutations for tyrosine kinase inhibitors) or will potentially become targets for specific therapeutic interventions.

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