Rel a Is a Novel Prognostic Marker in CLL That Is Independent of VH Gene Mutation Status, CD38 Expression and ZAP-70 Expression

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4153-4153
Author(s):  
Saman Hewamana ◽  
Thet Thet Lin ◽  
Clare Rowntree ◽  
Kamaraj Karunanithi ◽  
Alan Burnett ◽  
...  
Keyword(s):  
Dna Binding ◽  
Prognostic Marker ◽  
Prognostic Significance ◽  
Hazard Ratio ◽  
Response To Therapy ◽  
Mutation Status ◽  
Cd38 Expression ◽  
Binet Stage ◽  
Time To First Treatment

Abstract We recently demonstrated that the NF-kB subunit Rel A is associated with in vitro survival and clinical disease progression in CLL. We therefore hypothesized that Rel A would have prognostic significance in this disease. Rel A DNA binding was quantified in nuclear extracts derived from 131 unselected CLL patient samples using a quantitative DNA binding ELISA-based method. We tested the ability of Rel A to predict for the requirement for treatment and survival and compared our findings with other established prognostic markers. Rel A DNA binding was strongly associated with advanced Binet stage (P<0.0001) but did not correlate with IgVH mutation status (P = 0.25), CD38 expression (P = 0.87) or ZAP-70 expression (P = 0.55). It was predictive of time to first treatment (P = 0.02) and time to subsequent treatment (P = 0.0001). In addition, Rel A was the most predictive marker of survival both from date of diagnosis (hazard ratio 9.1, P = 0.01) and date of entry into the study (hazard ratio 3.9, P = 0.05) and retained prognostic significance in multivariate analysis for both time to first treatment and overall survival in the presence of Binet stage, IgVH mutation status, CD38 and ZAP-70. Take together our data shows that Rel A is an independent prognostic marker of survival in CLL and appears to have the unique capacity to predict the duration of response to therapy. Prospective assessment of Rel A as a marker of clinical outcome and as a therapeutic target is now clearly warranted.

Rel A Is an Independent Biomarker of Clinical Outcome in Chronic Lymphocytic Leukemia

2009 ◽  
Vol 27 (5) ◽  
pp. 763-769 ◽  
Author(s):  
Saman Hewamana ◽  
Thet Thet Lin ◽  
Clare Rowntree ◽  
Kamaraj Karunanithi ◽  
Guy Pratt ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Dna Binding ◽  
Clinical Outcome ◽  
Prognostic Significance ◽  
Response To Therapy ◽  
Lymphocytic Leukemia ◽  
Enzyme Linked Immunosorbent Assay ◽  
Mutation Status ◽  
Binet Stage ◽  
Time To First Treatment

Purpose We recently demonstrated the biologic importance of the nuclear factor kappa B (NF-κB) subunit Rel A in chronic lymphocytic leukemia (CLL) and hypothesized that Rel A DNA binding would have prognostic significance in this disease. Patients and Methods Rel A DNA binding was quantified in nuclear extracts derived from 131 unselected CLL patient samples using a quantitative DNA-binding enzyme-linked immunosorbent assay–based method. We then investigated the ability of Rel A to predict for the requirement for treatment and survival and compared our findings with other established prognostic markers. Results Rel A DNA binding was strongly associated with advanced Binet stage (P < .0001) but did not correlate with immunoglobulin VH (IgVH) mutation status (P = .25), CD38 expression (P = .87), or zeta-chain–associated protein kinase 70 (ZAP-70) expression (P = .55). It was predictive of time to first treatment (P = .02) and time to subsequent treatment (P = .0001). In addition, Rel A was the most predictive marker of survival both from date of diagnosis (hazard ratio [HR], 9.1; P = .01) and date of entry into the study (HR, 3.9; P = .05) and retained prognostic significance in multivariate analysis for both time to first treatment and overall survival in the presence of Binet stage, IgVH mutation status, CD38, and ZAP-70. Conclusion Rel A is an independent prognostic marker of survival in CLL and seems to have the unique capacity to predict the duration of response to therapy. Prospective assessment of Rel A as a marker of clinical outcome and as a therapeutic target are now warranted.

scholarly journals Serum Soluble TACI, a BLyS Receptor, Is a Powerful Prognostic Marker of Outcome in Chronic Lymphocytic Leukemia

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
Marie-Christine Kyrtsonis ◽  
Katerina Sarris ◽  
Efstathios Koulieris ◽  
Dimitrios Maltezas ◽  
Eftychia Nikolaou ◽  
...  
Keyword(s):  
Prognostic Marker ◽  
Prognostic Significance ◽  
Serum Levels ◽  
Lymphocytic Leukemia ◽  
Soluble Form ◽  
Free Light Chains ◽  
Binet Stage ◽  
Time To First Treatment ◽  
The Impact ◽  
First Time

BLyS is involved in CLL biology and its low soluble serum levels related to a shorter time to first treatment (TFT). TACI is a BLyS receptor and can be shed from cells’ surface and circulate in soluble form (sTACI). We investigated the impact of serum BLyS and sTACI levels at diagnosis in CLL patients and their relationship with disease parameters and patients’ outcome. Serum BLyS was determined in 73 patients, while sTACI in 60. Frozen sera drawn at diagnosis were tested by ELISA. sTACI concentrations correlated with BLyS (P=-0.000021), b2-microglobulin (P=0.005), anemia (P=-0.03), thrombocytopenia (P=0.04), Binet stage (P=0.02), and free light chains ratio (P=0.0003). Soluble BLyS levels below median and sTACI values above median were related to shorter TFT (P=0.0003and 0.007). During a ten-year followup, sTACI levels, but not BLyS, correlated with survival (P=0.048). In conclusion, we confirmed the prognostic significance of soluble BLyS levels with regard to TFT in CLL patients, and, more importantly, we showed for the first time that sTACI is a powerful prognostic marker, related to parameters of disease activity and staging and, more importantly, to TFT and OS.

High Incidence of Translocations in CLL: A New Prognostic Marker for Infavorable Survival Outcome.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 17-17 ◽  
Author(s):  
Christine Mayr ◽  
David M. Kofler ◽  
Raymund Buhmann ◽  
John Strehl ◽  
Raymonde Busch ◽  
...  
Keyword(s):  
Prognostic Marker ◽  
Chromosomal Aberrations ◽  
Cell Cycle Progression ◽  
Cd40 Ligand ◽  
Fish Analysis ◽  
Chromosome 11 ◽  
Cd38 Expression ◽  
High Incidence ◽  
13Q Deletion

Abstract BACKGROUND: Conventional metaphase cytogenetics underestimates the frequency of specific chromosome aberrations in B-CLL due to the low in vitro proliferative activity of CLL cells. We could recently show that stimulation of CLL cells with CD40 ligand (CD40L) induced cell cycle progression and increased the frequency of metaphases of CLL cells, which are then suitable for chromosome banding. In the present study we compared this new technique, CD40L-enhanced cytogenetics (CEC) with molecularcytogenetic data obtained by fluorescence in situ hybridization (FISH) on CLL cells. Methods: Blood samples were obtained from 95 CLL patients (Binet A: 31%, Binet B: 30%, Binet C: 39%) and subjected to simultaneous analysis by CEC and FISH. 56% of patients were previously untreated, while 44% of patients received at least one course of chemotherapy prior to the study. RESULTS: By FISH, 80% of analysed samples revealed aberrations like deletion of chromosome 11, 13 or 17 or trisomy 12. By CEC, chromosomal aberrations (range 0 to 14; median: 1) were detected in 90% of samples involving all chromosomes except the X chromosome. Importantly, a high incidence of balanced and unbalanced translocations were seen in 33 patients (35%) while 70% of the breakpoints involved were recurring. Median treatment-free survival (TFS) was significantly shorter for patients with translocations P< .0001). For patients with unbalanced translocations, overall survival was also significantly (decreased P= .0007). 25% of patients with 13q deletion as single aberration in FISH analysis additionally showed translocations (by CEC. These patients had a significantly shorter TFS compared to patients with 13q deletion as true sole aberration (median TFS: 36 mo vs. 132 mo; P= .0004). This was also true for patients with deletion of 11q. Patients with 11q- and translocations had a significant shorter TFS than patients with 11q- without translocations (median TFS: 13 mo vs. 48 mo; P= .011). All patients with 17p deletion showed translocations. In order to exclude the possibility that cytogenetic aberrations occurred as a possible treatment-associated secondary event, in a second analysis only patients who were untreated at the time of cytogenetic analysis were evaluated. In 22% of untreated patients translocations were detected and again they showed significantly lower TFS rates compared to patients without translocations (median TFS: 26 mo vs. 109 mo; P = .0128). In a multivariate analysis including Binet stage, presence of a complex karyotype (≥ 3 chromosomal aberrations), CD38 expression, 11q- and 17p-, the occurance of translocations proved to be the prognostic marker with the highest impact for an infavorable clinical outcome P< .001). CONCLUSION: Taken together, CEC is able to detect new chromosomal aberrations in CLL and enables a risk assessment for CLL patients based on the incidence of translocations otherwise indetectable by FISH or conventional metaphase cytogenetics.

Predictors of Survival in CLL: Multivariate Analyses Reveal Significant Correlation with IgVH Gene Mutation Status, Clinical Stage, and Cellular CD38 (but Not Zap-70) Expression.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5010-5010
Author(s):  
Alicia D. Volkheimer ◽  
Marc C. Levesque ◽  
Bethany E. Beasley ◽  
Louis Diehl ◽  
Youwei Chen ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Doubling Time ◽  
Multivariate Analyses ◽  
Medical Center ◽  
Clinical Stage ◽  
Leukemia Cell ◽  
Mutation Status ◽  
Cd38 Expression ◽  
Binet Stage ◽  
Univariate Analyses

Abstract One of the complexities of chronic lymphocytic leukemia (CLL) is that some patients die early from the disease, while others identically staged by conventional means may live more than two decades. This has led to a search for prognostic indicators that correlate better with eventual survival. Candidate markers include Rai stage, Binet stage, lymphocyte doubling time (DT), immunoglobulin heavy chain V region (IgVH) mutation status, and leukemia cell CD38 and Zap-70 expression. To determine which of these markers correlate best with survival in univariate and multivariate analyses, we examined these parameters in 150 CLL patients from a VA medical center and a university medical center. CLL cells were purified from patients not receiving active treatment with WBC &gt;20,000/uL by deleting T cells, monocytes, neutrophils, and erythrocytes using antibodies against CD2, CD3, CD16, CD36, CD56, and glycophorin A, and centrifugation over ficoll-Hypaque (CLL purity &gt; 97%). In univariate analyses, patients with advanced stage on presentation had shorter survival than those with low stage [14.0 yr for high modified Rai stage vs. 25.3 yr for low stage (p = 0.013), and 13.8 yr, 13.4, and 25.3 yr for Binet stages C, B, and A, respectively (p = 0.033)]. Patients with a lymphocyte DT &gt;3 yr survived twice as long (22.6 yr) as those with a DT &lt;3 yr (11.3 yr) (p = 0.004). There was a strong relationship of IgVH mutation status with survival (median survival 22.6 yr for mutated, 9.4 yr for unmutated; p = 0.0006). Likewise, cellular CD38 expression significantly correlated with survival (CD38 neg 25.3 yr, CD38 pos 13.4 yr, p = 0.008). Zap-70 expression determined by quantitative immunoblot [Zap-70/actin ratio (anti-Zap-70 antibody from Upstate; clone 2F3.2)] was not significantly related to survival (Zap-70 pos 20.8 yr, Zap-70 neg 22.6 yr). Other parameters found not to be related to eventual survival were WBC on presentation, maximum WBC reached before treatment, and time from diagnosis to initial treatment. IgVH mutation status was significantly related to lymphocyte DT, CD38 expression, and Zap-70 expression. In multivariate analyses using the proportional hazards model, IgVH mutation status (p = 0.001), cellular CD38 expression (p = 0.025), and Binet stage (p = 0.026) were significantly associated with survival (with p = 0.0002 overall for these three parameters in the model), but Zap-70 had no significant relationship to survival in the model. Thus, in contrast to other reports, cellular Zap-70 expression does not correlate with various parameters of disease severity (including survival) in our cohort of CLL patients. In summary, our univariate analyses show significant correlations of advanced clinical stage, short lymphocyte doubling time, high CD38 expression, and unmutated IgVH with short survival. However, multivariate analyses show that only IgVH gene mutation status, clinical stage at presentation, and cellular CD38 expression correlate significantly with survival.

Mutational and Cytogenetic Analyses Of 177 CLL Patients With Trisomy 12: A Retrospective Study Of The CLL French Intergroup

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4144-4144 ◽  
Author(s):  
Damien Roos-Weil ◽  
Florence Nguyen-Khac ◽  
Sylvie Chevret ◽  
Clémence Roux ◽  
Cyrille Touzeau ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Univariate Analysis ◽  
Poor Response ◽  
Response To Therapy ◽  
Advisory Committees ◽  
Cd38 Expression ◽  
Trisomy 12 ◽  
Study Population ◽  
Time To First Treatment ◽  
Notch1 Mutations

Abstract Background Cytogenetic abnormalities are of key importance for predicting clinical course and response to therapy in patients with chronic lymphocytic leukemia (CLL). Trisomy 12 (tri12), the third most frequent chromosomal aberration in CLL patients (10-20%), is associated with an intermediate prognostic risk but represents a clinical heterogeneous entity. Recently, next generation sequencing have revealed recurrent mutations in genes that were unknown to be involved in CLL pathogenesis, including NOTCH1, MYD88, SF3B1, XPO1 and BIRC3. In patients harboring tri12, NOTCH1 mutations have been shown to be present in up to 25% of cases and to confer unfavorable outcome explaining in part the clinical heterogeneity of tri12 patients. To better understand the genetic basis and prognosis of tri12 patients, we performed a multicenter retrospective study combining extensive mutational and cytogenetic analysis. Methods Patients carrying tri12 were identified using fluorescence in situ hybridization (FISH) and/or chromosome banding (CB). Main clinical and biological characteristics were collected and included in univariate analysis of prognostic factors, comprising age, Binet stage (A vs. B-C), splenomegaly, lymphocyte doubling time (LDT), LDH, beta2microglobulin (B2M), CD38 expression, IGHV mutational status, percentage of interphase nuclei positive (INP) for tri12, additional FISH (del13q, del11q, del17p) or chromosomal aberrations and presence of complex karyotype (> 2 CB abnormalities). Search for mutations was performed by Sanger direct sequencing for TP53 (exons 5-10), NOTCH1 (exon 34), MYD88 (exons 14-16), SF3B1 (exons 14-16) and XPO1 (exons 14-15). Primary and secondary endpoints were time to first treatment (TFT), response to therapy, time to next treatment (TNT) and overall survival (OS). Results The study population comprised a total of 177 untreated patients including 112 and 75 patients with stage A and B-C CLL, respectively. The median age at diagnosis was 62 years old (range, 31-87) and 33% of patients were female. B2M was superior to 4 mg/L in 30/92 (32%) patients and LDH elevated in 65%. CD38 expression was positive (>30%) in 58% and IGHV status was unmutated in 60%. Among the whole study population, all patients were positive for tri12 by FISH and 158/165 by CB. Tri12 was associated by CB with tri19 in 21 patients (13.2%), tri18 in 12 patients (7.5%), tri3 in 1 patient (<1%), t(14;18) in 9 patients (5.7%), t(14;19) in 3 patients (2%) and del14q in 7 patients (4.5%). Complex karyotype was present in 42 patients (26%) and tri12 was the sole abnormality observed by CB in 71 patients (45%). Out of 170 patients analysed with the four probes by FISH, tri12 was the sole abnormality in 114 patients (67%) and was associated with del13q, del11q and del17p in, respectively, 44 (26%), 8 (4%) and 10 (6%) patients. The median percentage of INP for tri12 was 58% (range, 5-100). TP53, NOTCH1, MYD88 and SF3B1 mutations were tested in 113 patients and identified in, respectively, 9 (8%), 19 (17%), 1 (<1%) and 1 (<1%) patients. No mutation of XPO1 was observed. Among the stage A population of 112 patients, 64 (57%) needed treatment with a median TFT of 45 months (range, 1-170). A shorter TFT was significantly associated with a LDT inferior to one year (P=0.0001), and the presence of TP53 (P=0.04) mutation while the presence of another trisomy (P=0.03) was associated with a significantly longer TFT. By multivariate analysis, only TP53 mutation retain prognostic significance for TFT (HR=3.9, 95%CI=1.02-15.04). Among the 75 stage B-C patients, 62 were treated, 51 evaluable for response to therapy and 28 received a second line of treatment. The only prognostic variable associated with poor response to therapy was the presence of NOTCH1 mutation (P=0.01). Finally, regarding the whole tri12 population, Binet stage (A vs. B-C), splenomegaly, lymphocytosis, LDH, B2M, the percentage of INP and the IGHV unmutated status were associated with worst OS in univariate analysis. Conclusion The most frequent molecular abnormalities observed in our tri12 cohort were TP53 and NOTCH1 mutations that occurred in, respectively, 8 and 17% of cases. NOTCH1 mutations were associated with poor response to therapy and TP53 mutations with a shorter time to first treatment. Disclosures: Leblond: Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Roche : Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau.

Absolute Monocyte Count and Serum CD14 As Prognostic Markers In Chronic Lymphocytic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5297-5297
Author(s):  
Daphne R. Friedman ◽  
Kathleen K. Harnden ◽  
Youwei Chen ◽  
Alicia D. Volkheimer ◽  
J. Brice Weinberg
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Risk Stratification ◽  
Clinical Outcomes ◽  
Prognostic Markers ◽  
Prognostic Significance ◽  
Hazard Ratio ◽  
Lymphocytic Leukemia ◽  
Monocyte Count ◽  
Interphase Cytogenetics ◽  
Mutation Status

Abstract Introduction Although chronic lymphocytic leukemia (CLL) is a generally indolent malignancy, there is a spectrum of disease aggressiveness. Clinical and molecular prognostic markers are helpful for the clinician and for the patient, in terms of disease management and life planning. Additional prognostic markers can help with further risk stratification, especially for CLL patients with “low-risk” disease. The prognostic value of absolute monocyte count (AMC) has been evaluated in various malignancies, including CLL where elevated AMC at diagnosis was shown to be associated with rapid time to first therapy (TTT), and in one series, inferior overall survival (OS). The mechanism by which elevated AMC is associated with worse treatment free survival is not known. However, CD14, which is secreted by monocytes, improves in vitro CLL cell survival, and is found at high levels in the serum of CLL patients. We hypothesized that elevated AMC at the time of CLL diagnosis is associated with inferior survival and that elevated serum CD14 is associated with high AMC and worse survival. Methods CLL patients followed at the Duke University and Durham VA Medical Centers and enrolled in an IRB approved protocol to collect clinical data and blood samples were evaluated. We selected patients for whom AMC was measured between three months prior to diagnosis to three months after diagnosis. We evaluated the correlation between AMC and TTT and OS, with AMC as a continuous and as a dichotomized variable. We also assessed the prognostic capability of AMC in relation to other clinical and molecular prognostic markers, such as Rai stage, race, interphase cytogenetics by FISH, CD38 and ZAP70 expression, and IGHV mutation status. We measured serum CD14 levels using an ELISA assay, and evaluated the correlation between CD14 levels and clinical outcomes or AMC. Cox proportional hazard models were used to evaluate time to event outcomes, Wilcoxon rank sum test and Kruskal-Wallis rank sum test were used to compare AMC to other prognostic markers, and Pearson’s correlation test was used to compare continuous variables. Results From a cohort of over 600 CLL patients, we selected 222 patients with AMC measured ± three months from the date of diagnosis. AMC ranged from 0 to 7.63 cells/mL. With a median follow up of 5.2 years (range 0.1 – 18.2), 102 patients (46%) had been treated, and 59 patients (27%) died. This was not significantly different from the entire cohort. Higher AMC was significantly correlated with shorter TTT (p = 0.002, hazard ratio 1.37, 95% CI 1.12 – 1.68) and inferior OS (p = 0.017, hazard ratio 1.39, 95% CI 1.06 – 1.83). There was no significant difference in AMC in patients stratified by Rai stage, race, interphase cytogenetics, CD38 or ZAP70 expression, or IGHV mutation status. When combined with molecular prognostic markers (IGHV mutation status, CD38 and ZAP70 expression, and interphase cytogenetics) in multivariate models, AMC retained significant prognostic power for TTT and OS. The serum soluble CD14 levels were measured in CLL patients from this cohort, with a mean CD14 level of 2.3 ug/mL. The prognostic significance of serum CD14 and correlation with AMC will be presented. Conclusions Absolute monocyte count at the time of CLL diagnosis is associated with inferior clinical outcomes – both TTT and OS. These results confirm and extend other reports evaluating the prognostic significance of circulating monocytes in CLL. Our evaluation of serum CD14, a monocyte-derived secreted protein that promotes CLL cell viability, in concert with AMC may provide a possible explanation for the associations identified in this cohort of patients. As an easily measured clinical marker, AMC can be readily used and/or combined with other prognostic markers to improve risk stratification and patient counseling at the time of diagnosis. Disclosures: No relevant conflicts of interest to declare.

FLT3-ITD but Not FLT3-TKD Mutations Have Major Prognostic Impact in Normal Karyotype AML.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3486-3486
Author(s):  
Stephanie Schneider ◽  
Friederike Schneider ◽  
Annika Dufour ◽  
Gudrun Mellert ◽  
Evelyn Zellmeier ◽  
...  
Keyword(s):  
Prognostic Significance ◽  
Observation Time ◽  
Molecular Techniques ◽  
Tyrosine Kinase Domain ◽  
Prognostic Impact ◽  
Term Survival ◽  
Clinical Prognosis ◽  
Mutation Status

Abstract Background: Approximately 45% of AML patients have a normal karyptype (NK-AML) and an intermediate clinical prognosis. As only 20–42% of these patients show long-term survival, it is important to identify prognostic markers to distinguish patients’ outcome more precisely. Mutations in the FLT3 gene such as internal tandem duplications (ITD) in the juxtamembrane domain and point mutations in the tyrosine kinase domain (TKD) are the second most common abnormalties in AML patients. For FLT3-ITD it is well known that patients have an unfavourable prognosis. Up to now there are not enough reliable data to determine the prognostic impact of FLT3-TKD mutations. Patients and Methods: We have investigated the prevalence of FLT3-TKD mutations in a cohort of 803 cytogenetically normal AML (NK-AML) patients and its possible prognostic significance. At diagnosis the mutation status of FLT3 (ITD and TKD) and the NPM1 gene were analyzed by routine molecular techniques. Results: The median age of all patients was 60 years and the median observation time of survivors 23.2 months. Results of the mutation status’ of FLT3-ITD, FLT3-TKD and NPM1 were available in 757/803 (94.3%), 683/803 (85.1%) and 696/803 (86.7%) patients, respectively. FLT3-ITD, FLT3-TKD and NPM1 mutations were found in 222 (29.3%), 46 (6.7%) and 354 (50.9%) of all analyzed patients, respectively. We could not detect any influence of the FLT3-TKD mutation on OS (p= 0.753), RFS (p= 0.229), EFS (p= 0.835), CR (p= 0.168) and on d16 blast count (p= 0.696). In most patients FLT3-ITD and TKD mutations were mutually exclusive, although a minority of 8/674 patients (1.2%) carried both mutations. FLT3-TKD mutations were more frequently found in patients with NPM1 mutations compared to NPM1-negative patients (9.04% vs. 3.74%; p= 0.008). In contrast to FLT3-ITD mutations FLT3-TKD mutation had no prognostic impact in NPM1 positive AML cases. Conclusions: In our study in a large cohort of 803 NK-AML patients we could not detect any prognostic impact of FLT3-TKD mutations. Although FLT3-ITD and TKD mutations have both transforming potential in vitro and in vivo mouse models, the clinical impact of both mutations shows striking differences. Further studies with FLT3-PTK inhibitors will clarify the pathogenetic relevance of these mutations in AML.

scholarly journals Prognostic Significance of POLE Exonuclease Domain Mutations in High-Grade Endometrioid Endometrial Cancer on Survival and Recurrence: A Subanalysis

2016 ◽  
Vol 26 (5) ◽  
pp. 933-938 ◽  
Author(s):  
Caroline C. Billingsley ◽  
David E. Cohn ◽  
David G. Mutch ◽  
Erinn M. Hade ◽  
Paul J. Goodfellow
Keyword(s):  
Endometrial Cancer ◽  
Confidence Interval ◽  
Prognostic Significance ◽  
Hazard Ratio ◽  
High Grade ◽  
Clinicopathologic Features ◽  
Mutation Status ◽  
Risk Of Recurrence ◽  
Endometrioid Endometrial Cancer ◽  
Grade 3

ObjectivePOLE mutations in high-grade endometrioid endometrial cancer (EEC) have been associated with improved survival. We sought to investigate the prevalence of POLE tumor mutation and its prognostic significance on outcomes and clinical applications in a subanalysis of women with high-grade EEC from a previously described cohort of 544 EEC patients in which POLE mutation status and survival outcomes were assessed.MethodsPolymerase chain reaction amplification and Sanger sequencing were used to test for POLE mutations in 72 tumors. Associations between POLE mutation, demographic and clinicopathologic features, and survival were investigated with Cox proportional hazard models.ResultsPOLE mutations were identified in 7 (9.7%) of 72 grade 3 EECs. No significant differences in the clinicopathologic features between those with POLE mutations and those without were identified. Adjusted for age, a decreased risk of recurrence was suggested in patients with a POLE mutation (adjusted hazard ratio, 0.37; 95% confidence interval, 0.09–1.55), as well as decreased risk of death (adjusted hazard ratio, 0.19; 95% confidence interval, 0.03–1.42).ConclusionsPOLE mutations in tumors of women with grade 3 EEC are associated with a lower risk of recurrence and death, although not statistically significant because of high variability in these estimates. These findings, consistent with recently published combined analyses, support POLE mutation status as a noteworthy prognostic marker and may favor a change in the treatment of women with grade 3 EECs, particularly in those with early-stage disease, in which omission of adjuvant therapy and decreased surveillance could possibly be appropriate.

Comprehensive Assessment of Genetic and Molecular Features Predicting Outcome in Patients With Chronic Lymphocytic Leukemia: Results From the US Intergroup Phase III Trial E2997

2007 ◽  
Vol 25 (7) ◽  
pp. 799-804 ◽  
Author(s):  
Michael R. Grever ◽  
David M. Lucas ◽  
Gordon W. Dewald ◽  
Donna S. Neuberg ◽  
John C. Reed ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Prognostic Significance ◽  
Variable Region ◽  
Hazard Ratio ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Therapeutic Trial ◽  
Cd38 Expression ◽  
Molecular Features ◽  
Mutational Status

Purpose Genomic features including unmutated immunoglobulin variable region heavy chain (IgVH) genes, del(11q22.3), del(17p13.1), and p53 mutations have been reported to predict the clinical course and overall survival of patients with chronic lymphocytic leukemia (CLL). In addition, ZAP-70 and Bcl-2 family proteins have been explored as predictors of outcome. Patients and Methods We prospectively evaluated the prognostic significance of a comprehensive panel of laboratory factors on both response and progression-free survival (PFS) using samples and data from 235 patients enrolled onto a therapeutic trial. Patients received either fludarabine (FL; n = 113) or fludarabine plus cyclophosphamide (FC; n = 122) as part of a US Intergroup randomized trial for previously untreated CLL patients. Results Complete response (CR) rates were 24.6% for patients receiving FC and 5.3% for patients receiving FL (P = .00004). PFS was statistically significantly longer in patients receiving FC (median, 33.5 months for patients receiving FC and 19.9 months for patients receiving FL; P < .0001). The occurrence of del(17p13.1) (hazard ratio, 3.428; P = .0002) or del(11q22.3) (hazard ratio, 1.904; P = .006) was associated with reduced PFS. CR and overall response rates were not significantly different based on cytogenetics, IgVH mutational status, CD38 expression, or p53 mutational status. Expression of ZAP-70, Bcl-2, Bax, Mcl-1, XIAP, Caspase-3, and Traf-1 was not associated with either clinical response or PFS. Conclusion These results support the use of interphase cytogenetic analysis, but not IgVH, CD38 expression, or ZAP-70 status, to predict outcome of FL-based chemotherapy. Patients with high-risk cytogenetic features should be considered for alternative therapies.

LAMC2 as a prognostic marker that promotes metastasis of lung adenocarcinoma through epithelial-mensenchymal transition (EMT).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11034-11034
Author(s):  
Yongwha Moon ◽  
Kang-seo Park ◽  
John Kim ◽  
Sami Sarfaraz ◽  
Donna Voeller ◽  
...  
Keyword(s):  
High Risk ◽  
Lung Adenocarcinoma ◽  
Prognostic Marker ◽  
Microarray Data ◽  
A549 Cells ◽  
Hazard Ratio ◽  
Basement Membranes ◽  
Risk Of Recurrence

11034 Background: Metastasis is the main cause of death in non-small cell lung cancer (NSCLC) patients. Genes responsible for NSCLC metastasis are unknown. LAMC2 is one of the 3 chains (α3, β3, γ2) of laminin 332, an important component of basement membranes, and LAMC2 involvement in metastasis is unclear. Methods: We have established a metastasis model in nude mice by repeated intracardiac injection of A549 lung adenocarcinoma cells. After 3-4 rounds of intracardiac injections, 100% metastasis penetrance was obtained. Microarray analysis was performed to identify genes differentially expressed between parental (A549P) and round-3 (A549R3) cells. In vitro migration/invasion and in vivo metastasis assays were performed in LAMC2-overexpressed A549P, LAMC2-knockdown A549R4, PC9, H358, and H322 cells. Public RNA microarray data of human NSCLC (GSE8894, GSE3141; n=249) and LAMC2 immunohistochemistry (IHC) of stage I NSCLC TMA samples (n=250) were analyzed to correlate LAMC2 and prognosis. Results: We identified LAMC2 as a putative metastasis marker of NSCLC through gene expression profiling of A549 cells enriched for metastasis in mice. Ectopic LAMC2 expression increased migration/invasion, whereas LAMC2 knockdown decreased migration/invasion in vitro. Conditioned media containing secreted LAMC2 promoted cell migration/invasion, which were blocked by LAMC2 knockdown or LAMC2 neutralizing antibody. Ectopic LAMC2 expression induced mesenchymal but decreased epithelial markers, indicating EMT, whereas LAMC2 knockdown elicited the opposite. A549R4 LAMC2 knockdown cells showed less metastatic activity than A549R4shRNA control cells in mice. In public microarray data high LAMC2 mRNA predicted high risk of recurrence (GSE8894, P=0.022; GSE3141, P=0.029) in adenocarcinoma (AC) but not squamous carcinoma (SC). Our IHC study showed that high LAMC2 predicted high risk of recurrence (hazard ratio =1.8; P=0.040) and death (hazard ratio=1.9; P=0.028) in AC but not SC by multivariate analysis. Conclusions: LAMC2 promotes metastasis through activation of EMT pathways, and is a potential prognostic marker and therapeutic target of metastasis in lung adenocarcinoma.

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