Impact Of Clinical and Biological Factors On Outcome In a Cohort Of Unselected Chronic Lymphocytic Leukemia (CLL) Patients

Abstract Introduction Chronic Lymphocytic Leukemia (CLL) is a heterogeneous disease with a variable clinical course. Therapeutic decisions are based mainly on clinical grounds. Several prognostic markers based on genetic, phenotypic and molecular lesions have emerged in the past decade as relevant, alone or in combination with each other, in order to predict the clinical course and the best treatment option for CLL patients. Among these, NOTCH1 and TP53 mutation, have been described as new prognostic markers and predictive of survival in CLL. In this study, a real-life cohort of 165 CLL patients from Sardinia (Italy), was retrospectively analyzed for clinical, laboratory data (including NOTCH-1, TP53 mutation), first line treatment and followed up for survival. Methods Patients (99 males, 66 females, age ranged 31-89 y, 24% <55 y, Binet A 60%, Binet B/C 40%) were diagnosed with CLL between 1988-2012 by standard criteria. First-line treatment: 34% patients received no therapy, 30% fludarabine based regimens (+/-Rituximab), 32% alkylating agents based regimens (+/- Rituximab), 4% other regimens. Cytogenetic analysis was performed on peripheral blood cultured in the presence of the immunostimulatory CpG-oligonucleotide DSP30/Interleukin-2. FISH analysis on interphase nuclei was done using conventional 4-probe panel. The presence of NOTCH1 c.7544_7545delCT was investigated by ARMS PCR approach. The TP53 exons 4-11 were amplified in 33 patients and direct sequenced. Data from chromosome banding analysis (n=73), CD38 expression (n=133), IGHV mutation status (n=110) were also available. Categorical variables were compared by chi-squared test and Fisher exact test when appropriate. Statistical significance was defined as P value= 0,05. Kaplan-Meier curves and log rank test were used to determine overall survival and Cox regression analysis to calculate hazardous ratios using the R statistical program. Results Survival curve for the entire cohort ofpatients showed a median survival time of 195 months (95% CI 185-303). Patient stratification based on 1st line-treatment regimens did not show any significant difference in clinical outcome. FISH analysis detected trisomy 12 in 16% (24/154) patients, 13q14 deletion in 45/154 (29%), 17p deletion in 6% (10/154) and 11q deletion in 3%(5/154). Abnormal karyotype was present in 37% (27/73) of samples including 6 cases which resulted negative at the FISH test. Presence of 17p deletion was associated with the worse overall survival in univariate analysis (81 months, 95%CI 56-117, p value=0.0001). NOTCH1 c.7544_7545delCT was present in 8% (7/99), in 21% of trisomy 12 cases and in 16,6% of patients with no other genetic prognostic markers. The presence of NOTCH1 mutation had no impact on outcome. Comparing baseline characteristics between patients with or without mutations, no significant differences were found for age, sex, stage, B symptoms, blood cell counts, LDH, ß2-microglobulin. TP53 mutations were found in 2 out of 33 patients (6%). TP53p.R181P and p.249_251del10ins3 were present in two cases with 17p deletion detected by FISH. Thirtynine patients (35%) displayed an unmutated IGHV status, 68 cases (61%) had a mutated IGHV gene while 4 cases had a borderline IGHV mutation status. Unmutated IGHV status was an indipendent prognostic factor for worse overall survival (median survival 110 months 95%CI 85-303, p value= 0,02). The IGHV gene family usage within the mutated group was VH4>VH3>VH2>VH1>VH7, whereas IGHV 3 was the most frequently used in the unmutated group, being expressed in 13 patients. IGHV 1-69 genes were present in 3 CLL patients overall (2 unmutated). Correlation between cytogenetic categories and mutation status showed that the poor prognostic marker 17p deletion was present in 4/36 (11,0%) of unmutated CLLs and in 2/55 (3,6%) of mutated cases while 13q14 deletion was statistically associated with the 45% of mutated cases (p=0.0089). Conclusion In our cohort of unselected patients NOTCH1 mutation didn’t affect outcome of CLL patients, while TP53 deletion/mutation and IGHV mutational status maintain a strong prognostic negative impact. Treatment heterogeneity is likely the reason of absence of difference in outcome in our study. In current clinical practice prognostic markers need yet to be validated in large clinical trials, not biased by stringent selection criteria. Disclosures: No relevant conflicts of interest to declare.

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CD23 Receptor Positivity Has No Prognostic Implication in Chronic Lymphocytic Leukemia.

Blood ◽

10.1182/blood.v114.22.4397.4397 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4397-4397

Author(s):

Jahan Aghalar ◽

Charles Chu ◽

Rajendra N Damle ◽

Che-Kai Tsao ◽

Nina Kohn ◽

...

Keyword(s):

Flow Cytometry ◽

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Prognostic Markers ◽

Conflicts Of Interest ◽

Prognostic Significance ◽

Lymphocytic Leukemia ◽

Mutation Status ◽

Percent Positivity ◽

Cd23 Expression

Abstract Abstract 4397 BACKGROUND Chronic Lymphocytic Leukemia (CLL) phenotypically expresses CD23, although the percentage of positive cells measured by flow cytometry is variable. We sought to analyze whether the percent of CD23 positive cells in the CLL clone correlates with time to treat (TTT), overall survival (OS) and prognostic markers CD38, ZAP-70, and IGHV mutation status. METHODS We retrospectively analyzed the flow cytometry data of 332 CLL patients on the gated population of cells that were CD5 and CD19 positive. Percentage positivity for CD23, CD38, and ZAP-70 was noted. CD38 and ZAP-70 were considered positive at cut-offs of >= 30% and >=20%, respectively. CD23 was considered negative at <30% and positive at >= 30%. IGHV sequence was determined from cDNA and then compared to germline to assess mutation status using IMGT/V-QUEST. The distributions of time from diagnosis until start of treatment and overall survival were stratified by CD23 positivity, estimated using the product limit method, and compared using the log rank test. Those who had expired without treatment or were alive and not treated at this time point were censored in the TTT analysis. Those who were still alive were censored in the OS analysis. Associations of CD23 positivity with IGHV mutation status, ZAP-70, and CD38 positivity were examined using the chi-square test. RESULTS Out of 332 patients, 25 had diminished CD23 expression (<30%) whereas 307 had normal CD23 expression (>30%). There was no difference in time until start of treatment or overall survival based on CD23 %positivity. CD23 %positivity showed no associations with IGHV mutation status, ZAP-70 or CD38 positivity. CONCLUSION CD23 percent positivity has no prognostic significance in CLL. There is no correlation between CD23 percent positivity and poor prognostic markers such as CD38, ZAP-70, or IGHV mutation status. Disclosures: No relevant conflicts of interest to declare.

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Lack of Prognostic Significance of the Conventional and Novel Prognostic Markers in Trisomy 12 Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v128.22.4354.4354 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4354-4354

Author(s):

Valter Gattei ◽

Riccardo Bomben ◽

Michele Dal Bo ◽

Antonella Zucchetto ◽

Francesca Rossi ◽

...

Keyword(s):

Flow Cytometry ◽

Research Funding ◽

Prognostic Markers ◽

Lymphocytic Leukemia ◽

Cytogenetic Abnormality ◽

Mutational Status ◽

Ighv Gene ◽

Trisomy 12 ◽

Gene Status

Abstract Background. Trisomy 12 (tris12) is a recurrent cytogenetic abnormality in chronic lymphocytic leukemia (CLL), occurring in approximately 15-20% of cases, often as the unique cytogenetic alteration, that is usually considered a clonal driver lesion occurring early in CLL evolution. In the Dohner hierarchical categorization, tris12 CLL are identified as having an intermediate prognostic risk, although recent reports suggest a more complex and heterogeneous clinical behavior. Compared to CLL lacking this cytogenetic abnormality, tris12 CLL show more atypical morphology and immunophenotype, more frequent expression of the negative prognostic markers CD49d and CD38, and presence of NOTCH1 mutations and an unmutated (UM) IGHV gene status. The increased fraction of tris12 CLL carrying adverse prognostic features is in contrast to the intermediate clinical behavior associated with most tris12 CLL cases. Aim. To perform a comprehensive evaluation of the clinical impact of the major genetic, immunogenetic and immunophenotypic prognostic markers in tris12 CLL. Methods. The study was based on a multicenter series of tris12 CLL defined according to Dohner (n=283, including 73 cases also bearing del13q), and a comparison group (control) of 553 cases with either del13q (n=308) or without any cytogenetic abnormality (no del17p, del11q, tris12, del13q, n=245). Median follow-up of patients in the tris12 and control groups were 4 years (range 0-22) and 7 years (range 0-28), with 54% and 57% treated patients, and 18% and 15% deaths, respectively. Patient characterization included modified Rai stage, CD49d (CD49dhigh, ≥30% positive cells by flow cytometry), CD38 (CD38high, ≥30% positive cells by flow cytometry) and ZAP-70 (ZAP-70high, ≥20% positive cells by flow cytometry) expression, and IGHV mutational status (mutated, M, or UM according to the 2% cutoff). TP53, BIRC3, NOTCH1 andSF3B1 mutations were screened either at diagnosis or before therapy by NGS with at least 1000X coverage and 1% of sensitivity. Groups were compared by chi-square test; overall survival (OS) was computed from diagnosis to death or censored at last observation, and analyzed by Cox regression analysis. Results. Comparing the tris12 and the control groups, median age was 64 years (range 30-92) vs 66 years (range 33-92), male gender 55% vs 56% (p=0.86), the modified Rai stage was early in 52% vs 54%, intermediate in 41% vs 42% and advanced in 7% vs 4% (p=0.20). As previously reported, tris12 CLL were characterized by a higher prevalence of cases expressing CD49d (85% vs 31%) and CD38 (62% vs 17%; all p<0.0001), and of UM IGHV cases (55% vs 25%, p<0.0001). Analysis of recurrent mutations highlighted a higher prevalence of NOTCH1 mutations (26% vs 8%, p<0.0001) and of BIRC3 mutations (21% vs 1%, p<0.0001) in tris12 vs control group CLL. Conversely, no differences were found in the fraction of cases with TP53 mutations (3% vs 4%, p=0.38) or SF3B1 mutations (7% vs 7%, p=0.89), and in cases expressing ZAP-70 (62% vs 52%, p=0.09). The impact of these features on OS was tested by univariate analysis: in tris12 CLL, only the UM IGHV gene status predicted shorter OS (HR=2.37, p=0.0063), while none of the other characteristics reaching statistical significance as OS predictors (CD49d HR=1.36, p=0.36; CD38 HR=0.42, p=0.052; ZAP-70 HR=3.12, p=0.07; TP53 HR=2.33, p=0.25; NOTCH1 HR=1.40, p=0.22; SF3B1 HR=2.05, p=0.17; BIRC3 HR=1.22, p=0.61). On the other hand, in the control cohort, a significantly higher HR was found for CD49d (HR 3.11, p<0.0001) and CD38 (HR 3.45, p<0.0001) expression, TP53 (HR 2.88, p=0.0026), NOTCH1 (HR 3.57, p<0.0001), and SF3B1 (HR 2.57, p=0.0038) mutations, as well as for the UM IGHV gene status (HR=2.81, p<0.0001), but not for ZAP-70 expression and BIRC3 mutations (HR=1.74 and HR=1.91, p=0.15 and p=0.37, respectively). Conclusions. Mutational status of IGHV genes was the sole prognostic factor able to stratify OS in tris12 CLL. Despite the high frequency of NOTCH1 and BIRC3 mutations, as well as of CD49d and CD38 overexpression, these markers failed to convey a prognostic risk in tris12 CLL. The lack of a significant clinical impact for TP53 and SF3B1 mutations might be partly explained by the low number of mutated cases combined with a relative short follow up in our tris12 cohort. These findings are in keeping with the hypothesis of a different patho-biological mechanism occurring in tris12 CLL, which however remains to be fully elucidated. Disclosures D'Arena: Janssen-Cilag: Honoraria. Rossi:Gilead: Honoraria, Research Funding; Abbvie: Honoraria; Janseen: Honoraria. Gaidano:Janssen: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Shanafelt:Genentech: Research Funding; Janssen: Research Funding; Celgene: Research Funding; GlaxoSmithkKine: Research Funding; Pharmacyclics: Research Funding; Cephalon: Research Funding; Hospira: Research Funding.

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Karyotype-specific microRNA signature in chronic lymphocytic leukemia

Blood ◽

10.1182/blood-2009-06-229211 ◽

2009 ◽

Vol 114 (18) ◽

pp. 3872-3879 ◽

Cited By ~ 132

Author(s):

Rosa Visone ◽

Laura Z. Rassenti ◽

Angelo Veronese ◽

Cristian Taccioli ◽

Stefan Costinean ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Chromosomal Abnormalities ◽

Variable Region ◽

Normal Karyotype ◽

Lymphocytic Leukemia ◽

High Expression ◽

Mutation Status ◽

Ighv Gene ◽

Trisomy 12 ◽

Disease Initiation

Abstract Chromosomal abnormalities, immunoglobulin heavy chain variable–region (IGHV) gene mutation status, and ζ-associated protein 70 (ZAP-70) expression levels have independent prognostic relevance in chronic lymphocytic leukemia (CLL); however, their concordance is variable. Because deregulation of microRNAs has been linked to disease initiation and progression in CLL, we studied the value of the microRNAs as a signature for CLL patients with specific chromosomal abnormalities. We identified 32 microRNAs able to discriminate the 11q deletion, 17p deletion, trisomy 12, 13q deletion, and normal karyotype cytogenetic subgroups. The expression values of 9 among the 32 microRNAs (miR-151-3p, miR-34a, miR-29c, miR-29b, miR-155, miR-148a, miR-146a, miR-146b5p, and miR-640) were correlated with gene expression data from the same samples to assess their biologic impact on CLL. In this study we also found that IGHV unmutated, high expression of ZAP-70 protein, and low expression of the miR-223, miR-29c, miR-29b, and miR-181 family were strongly associated with disease progression in CLL cases harboring 17p deletion, whereas in those harboring trisomy 12 only high expression of the miR-181a, among the analyzed parameters, suggested more aggressive disease. Thus, the use of the microRNA-based classifications may yield clinically useful biomarkers of tumor behavior in CLL.

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Double IGHV Gene Rearrangements in Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v124.21.5631.5631 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5631-5631

Author(s):

Benjamin M Heyman ◽

Alicia D. Volkheimer ◽

J. Brice Weinberg ◽

Mark Lanasa

Keyword(s):

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Clinical Outcomes ◽

Heavy Chain ◽

Statistical Difference ◽

Lymphocytic Leukemia ◽

P Value ◽

Gene Rearrangements ◽

Time To Treatment ◽

Ighv Gene

Abstract Background: Chronic lymphocytic leukemia (CLL) is an incurable cancer of mature B-lymphocytes that infiltrate the bone marrow, secondary lymphoid organs, and blood. Much progress has been made during the past decade in understanding the pathogenesis and prognosis in CLL. Patients with unmutated immunoglobulin gene heavy chain variable region (IGHV) genes have inferior clinical outcomes when compared to patients with mutated IGHV. While there is robust data regarding clinical outcomes in patients with single IGHV rearrangements in CLL, there is limited data regarding double IGHV rearrangements. Thus, we investigated the prevalence of double IGHV rearrangements in our institutional cohort to determine molecular features and the prognostic significance of CLL cases with double IGHV rearrangements. Methods: Patients with CLL receiving care at Duke University and Durham Veterans Affairs (VA) Medical Centers were enrolled into a longitudinal cohort study between 1999 and 2014. IGHV mutation analysis was performed on DNA from all study patients. Patients were followed clinically for disease progression, need for treatment, and overall survival. The primary end points were time to treatment (TTT) or overall survival (OS). Survival curves were estimated using Kaplan-Meier method. Statistical differences were tested using proportional hazards tests for a clinical significance of p < 0.05. CLL cell isolation and IGHV mutational analysis were done as we have previously described (BLOOD 109:1559-1567, 2007). Statistical analysis was performed using SAS enterprise guide 5.1 and JMP Pro 11. Results: A total of 489 CLL patients were studied. Of these, 420 had one IGVH gene rearrangement (single IGHV; 86%). In 69 patients (14%), we amplified two IGHV rearrangements, indicating likely biallelic IGHV. The median TTT for the single IGHV group was 5.4 years, and the median OS for the single IGHV group was 15.3 years. For the double IGHV group, the mean TTT was 6.5 years (p = 0.44), and the median OS was 15.8 years (p = 0.73). Patients with single mutated IGHV (m) had better survival (median OS = 20.1 years) than those with single unmutated IGHV (u) (median OS = 11.3 yrs; p <0.001). There can be three possible combinations in the double IGHV group: double mutated (mm), mutated-unmutated (mu), and double unmutated (uu). The Table displays the differences in TTT and OS for the groups. In our cohort, the median TTT for those with a mutated double IGHV was longer (16.3 years) than for those with an unmutated double IGHV [median = 3.2 years; p < 0.01)]. Similarly, the median OS for those with mutated double IGHV was 33.6 years, while for those without a mutation it was 9.6 years (p < 0.01). In general, the TTT and OS were longer in those patients that had a mutated IGHV versus those without. The number of mutated genes did not make a statistical difference in the patient outcomes. Similarly, when comparing the uu and u groups, there was no statistical difference in survival. Conclusions: This is the largest single center study to date that examines double IGHV gene rearrangements and patient prognosis in CLL. The mutational status of the immunoglobulin heavy chain was a very important predictor of TTT and OS, mutated longer than ummutated. There was no significant survival difference between patients with single or double rearrangements in their IGHV chains. Our data demonstrates that the presence of at least one mutated IGHV gene confers a better prognosis for patients diagnosed with CLL. Thus, patients who have double IGHV rearrangements with at least one that is mutated, should be counseled as if they have a mutated rearrangement. Table: Statistical Analyses for Mutated and Unmutated IGHV for Time to Treatment and Overall Survival Time to Treatment TTT (years) m mu u uu p value (comparison between groups) mm 18.5 0.156 0.168 <.0001 <.0001 m 9.4 0.603 <.0001 0.0001 mu 7.9 0.061 0.007 u 3.0 0.285 uu 3.2 Overall Survival OS (years) m mu u uu p value (comparison between groups) mm 33.6 0.4899 0.623 0.007 0.016 m 20.1 0.612 <.0001 0.001 mu 20.8 0.096 0.053 u 11.3 0.099 uu 9.6 Figure 1 Figure 1. Disclosures Lanasa: MedImmune: Employment.

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P04.16 TP53 mutations in codon 273 is predictive of overall survival in astrocytoma patients

Neuro-Oncology ◽

10.1093/neuonc/noz126.111 ◽

2019 ◽

Vol 21 (Supplement_3) ◽

pp. iii32-iii32

Author(s):

H Noor ◽

R Rapkins ◽

K McDonald

Keyword(s):

Overall Survival ◽

Tp53 Mutation ◽

Progression Free Survival ◽

Low Grade Glioma ◽

Low Grade ◽

Wild Type ◽

Mutation Status ◽

Free Survival ◽

Tp53 Mutations ◽

Fresh Frozen

Abstract BACKGROUND Tumour Protein 53 (TP53) is a tumour suppressor gene that is mutated in at least 50% of human malignancies. The prevalence of TP53 mutation is much higher in astrocytomas with reports of up to 75% TP53 mutant cases. Rare cases of TP53 mutation also exist in oligodendroglial tumours (10–13%). P53 pathway is therefore an important factor in low-grade glioma tumorigenesis. Although the prognostic impact of TP53 mutations has been studied previously, no concrete concordance were reached between the studies. In this study, we investigated the prognostic effects of TP53 mutation in astrocytoma and oligodendroglioma. MATERIAL AND METHODS A cohort of 65 matched primary and recurrent fresh frozen tumours were sequenced to identify hotspot exons of TP53 mutation. Exons 1 to 10 were sequenced and pathogenic mutations were mostly predominant between Exons 4 and 8. The cohort was further expanded with 78 low grade glioma fresh frozen tissues and hotspot exons were sequenced. Selecting only the primary tumour from 65 matched tumours, a total of 50 Astrocytoma cases and 51 oligodendroglioma cases were analysed for prognostic effects of TP53. Only pathogenic TP53 mutations confirmed through COSMIC and NCBI databases were included in the over survival and progression-free survival analysis. RESULTS 62% (31/50) of astrocytomas and 16% (8/51) of oligodendrogliomas harboured pathogenic TP53 mutations. Pathogenic hotspot mutations in codon 273 (c.817 C>T and c.818 G>A) was prevalent in astrocytoma with 58% (18/31) of tumours with these mutations. TP53 mutation status was maintained between primary and recurrent tumours in 93% of cases. In astrocytoma, overall survival of TP53 mutant patients was longer compared to TP53 wild-type patients (p<0.01) but was not significant after adjusting for age, gender, grade and IDH1 mutation status. In contrast, astrocytoma patients with specific TP53 mutation in codon 273 showed significantly better survival compared to other TP53 mutant and TP53 wild-type patients combined (p<0.01) in our multivariate analysis. Time to first recurrence (progression-free survival) of TP53 mutant patients was significantly longer than TP53 wild-type patients (p<0.01) after adjustments were made, while TP53 mutation in codon 273 was not prognostic for progression-free survival. In oligodendroglioma patients, TP53 mutations did not significantly affect overall survival and progression-free survival. CONCLUSION In agreement with others, TP53 mutation is more prevalent in Astrocytoma and mutations in codon 273 are significantly associated with longer survival.

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Prognostic Impact of NOTCH1 Hotspot Mutation in TP53-Mutated Patients with Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v124.21.3283.3283 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3283-3283

Author(s):

Barbara Kantorova ◽

Jitka Malcikova ◽

Veronika Navrkalova ◽

Jana Smardova ◽

Kamila Brazdilova ◽

...

Keyword(s):

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Tp53 Mutation ◽

Direct Sequencing ◽

Lymphocytic Leukemia ◽

The Other ◽

Wild Type ◽

Tp53 Mutations ◽

Time To First Treatment ◽

Hotspot Mutation

Abstract Introduction A presence of activating mutations in NOTCH1 gene has been recently associated with reduced survival and chemo-immunotherapy resistance in chronic lymphocytic leukemia (CLL). However, a prognostic significance of the NOTCH1 mutations with respect to TP53mutation status has not been fully explained yet. Methods An examined cohort included 409 patients with CLL enriched for high risk cases; in 121 patients consecutive samples were investigated. To determine the TP53 mutation status, a functional analysis of separated alleles in yeast (FASAY, exons 4-10) combined with direct sequencing was performed; the ambiguous cases were retested using an ultra-deep next generation sequencing (MiSeq platform; Illumina). The presence of NOTCH1 hotspot mutation (c.7544_7545delCT) was analyzed using direct sequencing complemented by allele-specific PCR in the selected samples. In several patients harboring concurrent NOTCH1 and TP53 mutations, single separated cancer cells were examined using multiplex PCR followed by direct sequencing. A correlation between mutation presence and patient overall survival, time to first treatment and other molecular and cytogenetic prognostic markers was assessed using Log-rank (Mantel-cox) test and Fisher's exact test, respectively. Results The NOTCH1 and TP53 mutations were detected in 16% (65/409) and 27% (110/409) of the examined patients, respectively; a coexistence of these mutations in the same blood samples was observed in 11% (19/175) of the mutated patients. The detected increased mutation frequency attributes to more unfavorable profile of the analyzed cohort; in the TP53-mutated patients missense substitutions predominated (75% of TP53 mutations). As expected, a significantly reduced overall survival in comparison to the wild-type cases (147 months) was observed in the NOTCH1-mutated (115 months; P = 0.0018), TP53-mutated (79 months; P < 0.0001) and NOTCH1-TP53-mutated patients (101 months; P = 0.0282). Since both NOTCH1 and TP53 mutations were strongly associated with an unmutated IGHV gene status (P < 0.0001 and P = 0.0007), we reanalyzed the IGHV-unmutated patients only and interestingly, the impact of simultaneous NOTCH1 and TP53 mutation presence on patient survival was missed in this case (P = 0.1478). On the other hand, in the NOTCH1 and/or TP53-mutated patients significantly reduced time to first treatment was identified as compared to the wild-type cases (41 months vs. 25 months in NOTCH1-mutated, P = 0.0075; 17 months in TP53-mutated, P < 0.0001; and 18 months in NOTCH1-TP53-mutated patients, P = 0.0003). The similar results were observed also in the subgroup of the IGHV-unmutated patients, with the exception of patients carrying sole NOTCH1 mutation (P = 0.2969). Moreover, in the NOTCH1-TP53-mutated patients an increased frequency of del(17p)(13.1) was found in comparison to the TP53-mutated patients only (72% vs. 56%); this cytogenetic defect was not detected in the patients with sole NOTCH1 mutation. Our results might indicate, that NOTCH1 mutation could preferentially co-selected with particular, less prognostic negative type of TP53 defects. Notably, in our cohort the NOTCH1 mutation predominated in the patients harboring truncating TP53 mutations localized in a C-terminal part of the TP53 gene behind the DNA-binding domain (P = 0.0128). Moreover, in one of the NOTCH1-TP53-mutated patients the analysis of separated cancer cells revealed a simultaneous presence of NOTCH1 mutation and TP53 in-frame deletion in the same CLL cell. In contrast, in the other examined NOTCH1-TP53-mutated patient the concurrent NOTCH1 mutation and TP53 missense substitution (with presumed negative impact on patient prognosis) were found in different CLL cells. Conclusions The parallel presence of NOTCH1 hotspot mutation might be detected in a significant proportion of TP53-mutated patients and it seems to be associated with less prognostic unfavorable TP53 mutations. Nevertheless, these preliminary data should be further confirmed in a large cohort of patients. This study was supported by projects VaVPI MSMT CR CZ.1.05/1.1.00/02.0068 of CEITEC, IGA MZ CR NT13493-4/2012, NT13519-4/2012 and CZ.1.07/2.3.00/30.0009. Disclosures Brychtova: Roche: Travel grants Other. Doubek:Roche: Travel grants Other.

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Determination of Both TP53 Mutation Status and the Amount of p53 Protein Has Limited Diagnostic Importance for Patients with Ovarian Cancer

Current Medicinal Chemistry ◽

10.2174/0929867329666220112141211 ◽

2022 ◽

Vol 29 ◽

Author(s):

Sebastian M. Klein ◽

Maria Bozko ◽

Astrid Toennießen ◽

Nisar P. Malek ◽

Przemyslaw Bozko

Keyword(s):

Ovarian Cancer ◽

Overall Survival ◽

Cancer Patients ◽

Tp53 Mutation ◽

P53 Protein ◽

Mutation Status ◽

Tumor Tissues ◽

Tp53 Status ◽

Diagnostic Importance

Background: Ovarian cancer is one of the most aggressive types of gynecologic cancers. Many patients have a relapse within two years after diagnosis and subsequent therapy. Among different genetic changes generally believed to be important for the development of cancer, TP53 is the most common mutation in the case of ovarian tumors. Objective: Our work aims to compare the outcomes of different comparisons based on the overall survival of ovarian cancer patients, determination of TP53 status, and amount of p53 protein in tumor tissues. Methods: We analyzed and compared a collective of 436 ovarian patient’s data. Extracted data include TP53 mutation status, p53 protein level, and information on the overall survival. Values for p53 protein level in dependence of TP53 mutation status were compared using the Independent-Samples t-Test. Survival analyses were displayed by Kaplan-Meier plots, using the log-rank test to check for statistical significance. Results: We have not found any statistically significant correlations between determination of TP53 status, amount of p53 protein in tumor tissues, and overall survival of ovarian cancer patients. Conclusion: In ovarian tumors both determination of TP53 status as well as p53 protein amount has only limited diagnostic importance.

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Recent progress of prognostic biomarkers and risk scoring systems in chronic lymphocytic leukemia

Biomarker Research ◽

10.1186/s40364-020-00222-3 ◽

2020 ◽

Vol 8 (1) ◽

Author(s):

Xiaoya Yun ◽

Ya Zhang ◽

Xin Wang

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Tp53 Mutation ◽

Scoring Systems ◽

Lymphocytic Leukemia ◽

Prognostic Biomarkers ◽

Novel Agents ◽

Prognostic Models ◽

Predictive Values ◽

Mutation Status ◽

Staging Systems

Abstract Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia with high heterogeneity in the western world. Thus, investigators identified a number of prognostic biomarkers and scoring systems to guide treatment decisions and validated them in the context of immunochemotherapy. A better understanding of prognostic biomarkers, including serum markers, flow cytometry outcomes, IGHV mutation status, microRNAs, chromosome aberrations and gene mutations, have contributed to prognosis in CLL. Del17p/ TP53 mutation, NOTCH1 mutation, CD49d, IGHV mutation status, complex karyotypes and microRNAs were reported to be of predictive values to guide clinical decisions. Based on the biomarkers above, classic prognostic models, such as the Rai and Binet staging systems, MDACC nomogram, GCLLSG model and CLL-IPI, were developed to improve risk stratification and tailor treatment intensity. Considering the presence of novel agents, many investigators validated the conventional prognostic biomarkers in the setting of novel agents and only TP53 mutation status/del 17p and CD49d expression were reported to be of prognostic value. Whether other prognostic indicators and models can be used in the context of novel agents, further studies are required.

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The mutational landscape of chronic lymphocytic leukemia and its impact on prognosis and treatment

Hematology ◽

10.1182/asheducation-2017.1.329 ◽

2017 ◽

Vol 2017 (1) ◽

pp. 329-337 ◽

Cited By ~ 19

Author(s):

Gianluca Gaidano ◽

Davide Rossi

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Predictive Biomarkers ◽

Predictive Biomarker ◽

Treatment Choice ◽

Lymphocytic Leukemia ◽

Prognostic Scores ◽

Mutation Status ◽

Biological Variables ◽

Trisomy 12 ◽

Innovative Drugs

Abstract The typical genome of chronic lymphocytic leukemia (CLL) carries ∼2000 molecular lesions. Few mutations recur across patients at a frequency >5%, whereas a large number of biologically and clinically uncharacterized genes are mutated at lower frequency. Approximately 80% of CLL patients carry at least 1 of 4 common chromosomal alterations, namely deletion 13q14, deletion 11q22-23, deletion 17p12, and trisomy 12. Knowledge of the CLL genome has translated into the availability of molecular biomarkers for prognosis and treatment prediction. Prognostic biomarkers do not affect treatment choice, and can be integrated into prognostic scores that are based on both clinical and biological variables. Molecular predictive biomarkers affect treatment choice, and currently include TP53 disruption by mutation and/or deletion and IGHV mutation status. TP53 disruption by gene mutation and/or deletion associates with chemoimmunotherapy failure and mandates treatment with innovative drugs, including ibrutinib, idelalisib, or venetoclax. The mutation status of IGHV genes represents a predictive biomarker for identifying patients that may benefit the most from chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. Assessment of these biomarkers at the time of treatment requirement is recommended by most current guidelines for CLL management. Other molecular predictors are under investigation, but their application in clinical practice is premature.

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Mutation Status and Immunoglobulin Gene Rearrangements in Patients from Northwest and Central Region of Spain with Chronic Lymphocytic Leukemia

BioMed Research International ◽

10.1155/2014/257517 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 4

Author(s):

I. González-Gascón y Marín ◽

J. A. Hernández ◽

A. Martín ◽

M. Alcoceba ◽

M. E. Sarasquete ◽

...

Keyword(s):

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Central Region ◽

Lymphocytic Leukemia ◽

Gene Rearrangements ◽

Immunoglobulin Gene ◽

Mutation Status ◽

Almost All ◽

Time To First Treatment ◽

Immunoglobulin Gene Rearrangements

The aim of this study was to investigate the frequency and mutation status of the immunoglobulin heavy variable chain (IGHV) in a cohort of 224 patients from northwest and central region of Spain diagnosed with chronic lymphocytic leukemia (CLL), and to correlate it with cytogenetic abnormalities, overall survival (OS) and time to first treatment (TTFT). 125 patients had mutated IGHV, while 99 had unmutated IGHV. The most frequently used IGHV family was IGHV3, followed by IGHV1 and IGHV4. The regions IGHV3-30, IGHV1-69, IGHV3-23, and IGHV4-34 were the most commonly used. Only 3.1% of the patients belonged to the subfamily IGHV3-21 and we failed to demonstrate a worse clinical outcome in this subgroup. The IGHV4 family appeared more frequently with mutated pattern, similar to IGHV3-23 and IGHV3-74. By contrast, IGHV1-69 was expressed at a higher frequency in unmutated CLL patients. All the cases from IGHV3-11 and almost all from IGHV5-51 subfamily belonged to the group of unmutated CLL.

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