In CLL with Complex Aberrant Karyotype Distinct Entities Can Be Deciphered by Molecular Genetic and Cytogenetic Parameters

Abstract Metaphase cytogenetics have recently defined important prognostic subgroups in CLL. In addition to the poor prognosis FISH markers del(17p) and del(11q), the presence of translocations and a complex aberrant karyotype, defined by chromosome banding analyses, have been associated with shorter overall survival in a retrospective analysis. Thus far, a complex aberrant karyotype is defined by a number of three or more chromosomal aberrations, therefore, we aimed at characterizing an unselected CLL cohort of 92 patients with complex aberrant karyotype in more detail with molecular genetic, cytogenetic, and immunophenotypic parameters. Median age at diagnosis was 62.5 years (range: 33.4–83.3 years), the male/female ratio was 2.8. An unmutated IgVH status (<= 2% mutations) was detected in 51 (60.7%) of 84 analyzed samples. A positive CD38 expression (>= 30% CD38 positive cells) was detected in 55 (64%) of 86 samples and TP53 gene mutations by denaturing high performance liquid chromatography of exons 4–9 of TP53 in 29 (36.7%) of 79 samples. As the main approach for prognostication in CLL uses FISH for del(17p), del(11q), +12, del(13q) sole and normal, we related our cohort with complex aberrant karyotype into these different FISH categories. The poor prognosis markers del(17p) and del(11q) were detected with frequencies of 39.1% (n=36) and 22.8% (n=21), respectively, accounting for almost two third of all samples (n=57, 61.9%). An overlap between del(17p) and del(11q) was detected in 5 of the 36 del(17p) cases. The intermediate risk FISH marker +12 and low risk FISH markers del(13q) as sole abnormality and “normal karyotype” appeared with an incidence of 8.7% (n=8), 21.7% (n=20) and 7.6% (n=7), respectively. The high incidence of del(11q) and del(17p) in complex karyotype seems likely, as genes implicated in sensing DNA damage and in regulating apoptosis, ATM and TP53, are candidate genes in these deleted regions. As TP53 mutations have been suggested as independent poor prognostic markers, we also added TP53 gene mutation analysis to the FISH stratification. Del(17p) was associated with TP53 mutation in 26 (86.7%) of 30 analyzed cases, whereas the three residual TP53 mutations were associated with del(11q) (n=1) and del(13q) as sole abnormality (n=2). Therefore, we chose to merge samples with high risk features within the complex karyotype into one group (n=59), i.e., samples with del(17p), del(11q) or TP53 mutation, and compared these samples to the remaining samples (n=33). Effectively, the high risk group compared to the other cohort was significantly associated with an unmutated IgVH (p=0.02, Fisher’s exact test) and with an increased, median amount of cytogenetic aberrations (4.9 vs. 3.7 aberrations, p=0.005, t-test). However, no significant difference between the two groups regarding a CD38 positive status was detected (p=0.257). The prognostic impact of high risk features (del(17p), del(11q) and TP53 mutation) within the group defined above vs the lower risk group was analyzed with log-rank statistics with respect to time from diagnosis of CLL to initial treatment (TTT). 34 patients from the high risk group and 18 patients from the low risk group were available for analysis. The high risk features within the complex karyotype were significantly associated with a higher risk of early treatment in log-rank statistics with a median TTT of 12.2 month in the higher risk group compared to 70.1 month in the lower risk group (p=0.005). In conclusion, based on poor risk cytogenetic and molecular genetic features within the group of CLL with complex aberrant karyotype, we characterized patients with a higher risk of early treatment initiation. This group includes samples with del(17p), del(11q) and TP53 mutations.

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Modified IMPROVE VTE Risk Score and Elevated D-Dimer Identify a High Venous Thromboembolism Risk in Acutely Ill Medical Population for Extended Thromboprophylaxis

TH Open ◽

10.1055/s-0040-1705137 ◽

2020 ◽

Vol 04 (01) ◽

pp. e59-e65 ◽

Cited By ~ 30

Author(s):

Alex C. Spyropoulos ◽

Concetta Lipardi ◽

Jianfeng Xu ◽

Colleen Peluso ◽

Theodore E. Spiro ◽

...

Keyword(s):

Venous Thromboembolism ◽

High Risk ◽

Risk Score ◽

Lower Risk ◽

Risk Group ◽

High Risk Group ◽

Cutoff Score ◽

Risk Of Bleeding ◽

Increased Risk ◽

D Dimer

AbstractAn individualized approach to identify acutely ill medical patients at increased risk of venous thromboembolism (VTE) and a low risk of bleeding to optimize the benefit and risk of extended thromboprophylaxis (ET) is needed. The International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) VTE risk score has undergone extensive external validation in medically ill patients for in-hospital use and a modified model was used in the MARINER trial of ET also incorporating an elevated D-dimer. The MAGELLAN study demonstrated efficacy with rivaroxaban but had excess bleeding. This retrospective analysis investigated whether the modified IMPROVE VTE model with an elevated D-dimer could identify a high VTE risk subgroup of patients for ET from a subpopulation of the MAGELLAN study, which was previously identified as having a lower risk of bleeding. We incorporated the modified IMPROVE VTE score using a cutoff score of 4 or more or 2 and 3 with an elevated D-dimer (>2 times the upper limit of normal) to the MAGELLAN subpopulation. In total, 56% of the patients met the high-risk criteria. In the placebo group, the total VTE event rate at Day 35 was 7.94% in the high-risk group and 2.83% for patients in the lower-risk group. A reduction in VTE was observed with rivaroxaban in the high-risk group (relative risk [RR]: 0.68, 95% confidence interval [CI]: 0.51–0.91, p = 0.008) and in the lower-risk group (RR: 0.69, 95% CI: 0.40 -1.20, p = 0.187). The modified IMPROVE VTE score with an elevated D-dimer identified a nearly threefold higher VTE risk subpopulation of patients where a significant benefit exists for ET using rivaroxaban.

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Mutations of the TP53 Gene Occur in 13.4% of Acute Myeloid Leukemia and Are Strongly Associated with a Complex Aberrant Karyotype.

Blood ◽

10.1182/blood.v108.11.1913.1913 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1913-1913

Author(s):

Claudia Schoch ◽

Frank Dicker ◽

Hannes Herholz ◽

Susanne Schnittger ◽

Wolfgang Kern ◽

...

Keyword(s):

Tp53 Mutation ◽

Fusion Gene ◽

Direct Sequencing ◽

Mutation Screening ◽

Molecular Genetic ◽

Treatment Strategies ◽

Normal Karyotype ◽

Tp53 Gene ◽

Trisomy 8 ◽

Tp53 Mutations

Abstract The TP53 gene is the most frequently mutated gene in human tumors identified so far. In a prior study we demonstrated that 78% of AML with complex aberrant karyotype show a mutation of the TP53 gene. The aim of this study was to determine the frequency of TP53 mutations in an unselected cohort of AML and to analyze the relation to cytogenetic and molecular genetic aberrations. In total 149 AML cases were examined by chromosome banding analysis and screened for FLT3-length mutations (FLT3-LM), MLL partial tandem duplication (MLL-PTD), NPM1 mutations, and TP53 mutations. The cohort included cases with t(8;21) (n=10), t(15;17) (n=6), inv(16) (n=4), 11q23/MLL-rearrangement (n=6), trisomy 8 sole (n=13), AML with normal karyotype (n=46), AML with complex aberrant karyotype defined as showing 3 and more clonal abnormalities but no balanced rearrangement leading to a leukemia specific fusion gene (n=26), and AML with other abnormalities (n=38). FLT3-LM were observed in 21, MLL-PTD in 4, and NPM1-Mutations in 26 cases. TP53 mutation screening of exons 3–9 was performed by denaturing high performance liquid chromatography (DHPLC). All mutations detected were verified by direct sequencing. Overall, TP53 mutations were detected in 20 of the 149 cases (13.4%). Within this cohort of TP53 mutated cases, coincidences of FLT3-LM and MLL-PTD, respectively, with TP53 mutation were detected in one case each. A complex aberrant karyotype was present in 17 of 20 cases (85%) with TP53 mutation. The remaining 3 cases with TP53 mutation showed a normal karyotype, a trisomy 8, and t(8;21) as the sole abnormality, respectively. Therefore, we confirmed a high incidence of TP53 mutations in AML with complex aberrant karyotype (17/26, 65.4%). On the other hand TP53 mutations are very rare in AML without a complex aberrant karyotype (3/123, 2.4%). Furthermore, we divided AML with complex aberrant karyotype into two subgroups:AML with “typical” complex aberrant karyotype showing a deletion of at least one of the following regions: 5q31, 7q31, 17p13 (definition according to Schoch et al. GCC, 2005) andAML with “untypical” complex aberrant karyotype comprizing all others. Interestingly, the frequency of TP53 mutations within the “typical” complex aberrant karyotype group was 75% (15/20) while in the “untypical” group it was 33% (2/6) (p=0.138). In conclusion, the overall incidence of TP53 mutations is low in AML. TP53 mutations are highly associated with AML and complex aberrant karyotype and occur very infrequently in all other cytogenetic subgroups (p<0.001). They occur frequently in particular in the subgroup showing a typical pattern of chromosomal deletions (5q, 7q, 17p). TP53 mutations might explain in part the chemoresistance of AML with complex aberrant karyotype. In addition to cytogenetics a rapid diagnostic screening for TP53 mutations could be a valuable tool to identify a subgroup of AML with poor prognosis. This would allow the early assignment of patients to alternative treatment strategies using also options targeting the TP53 pathway.

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The Impact of Comorbidities on Clinical Outcome of Patients with Myelodysplastic Syndromes: A Real-Life Survey

Blood ◽

10.1182/blood.v124.21.4668.4668 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4668-4668

Author(s):

Enrico Balleari ◽

Chiara Salvetti ◽

Andrea Bacigalupo ◽

Gianluca Forni ◽

Marco Gobbi ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Lower Risk ◽

Risk Group ◽

Real Life ◽

High Risk Group ◽

Low Risk ◽

Survival Analyses ◽

Intermediate Group ◽

Comorbidity Index

Abstract Introduction: Myelodysplastic syndromes (MDS) are a highly heterogeneous group of clonal disorders, with very different prognosis in given individuals, overall survival (OS) ranging from more than 10 years (y) for the more indolent conditions to only few months (m) for the forms approaching AML; beside of the well-established disease-related prognostic systems (classical IPSS or its revised form [IPSS-R], the prognostic implication of comorbidities is emerging as a relevant patient-related factor influencing clinical outcome. Aim of our study was to evaluate the clinical impact of comorbidities in a series of MDS patients whatever treated in a “real-life” setting. Methods: this retrospective cohort study involved the MDS patients consecutively registered between Jan 2011 and Dec 2013 into the Registro Ligure delle Mielodisplasie database, a regional registry established within the framework of the Italian Network of regional MDS registries. Data of 318 patients (pts) with available complete assessment of comorbidities at diagnosis were included into the study. The clinical characteristics and comorbidities were all considered into the analysis. Comorbidities were evaluated according to both hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and MDS-specific comorbidity index (MDS-CI). All survival analyses were made from the date of diagnosis to last follow-up, death, or progression to AML. Unless specified, survival analyses were Cox models using continuous variables accounting for interactions. Results: Our cohort mainly consisted of older (median age 75y (range 40-98) “lower-risk” MDS pts: according to IPSS stratification, 151 (54.7%) pts were classified as low-risk, 86 (31.2%) as intermediate-1, 32 (11.6%) as intermediate-2 and 7 (2.5%) were in the high-risk group. One or more comorbidity of any grade of severity was seen in 177 (55.7%) pts at diagnosis. The more common comorbidity was cardiac (26.5%). At least a single comorbidity was present in 61.2% of pts older than 75y and in 50.6% of younger pts (p=0.07). Cardiovascular disorders were more frequent among older (32.9% for >75y vs 15.1% for ≤ 75y, p<0.001), and among males (28.7% vs 17.1% for females, p=0.02). According to HCT-CI risk stratification, 141pts (44.3%) were in the low-risk group, 94 (29.6%) in the intermediate-risk group, and 83 (26.1%) in the high-risk group, while according to MDS-CI, 197 (61.9%) pts had a low-risk score, 99 (31.1%) were intermediate, and 22 (6.9%) were in the high-risk group. MDS-CI score was higher among males (43.8% vs 30.7% for females, p=0.02). It was also higher among subjects >75 y (48% vs. 28.9% for < 75 y (p=0.001). A lower comorbidity score impacted on the clinical choice for active forms of therapy, while pts with an higher burden of comorbidities were preferentially treated with supportive care, even if difference did not reach significance (p=0.07). Overall survival and risk of non-leukemic death (NLD) were analyzed (median f.u. 26.9 m (range 1-220). HCT-CI did not significantly correlated with OS nor NLD (p= 0.1 and p= 0.07, respectively), while MDS-CI was found to be of prognostic significance both for OS (mean 136.6 (95%CI 116-157) m for the low-risk group, 81.3 (95%CI 61-102) m for the intermediate group and 48.1 (95%CI 30-66) m for the high-risk group, p=0.001) and for NLD (mean 159.6 (95%CI 139-180) m for the low-risk group, 96.5 (95%CI 72-121) m for the intermediate group and 49 (95%CI 31-67) m for the high-risk group (p<0.001). The correlation was significant (p<0.001) in IPSS or IPSS-R “lower-risk” (low and intermediate-1 risk or very-low, low and intermediate groups, respectively) but not in IPSS nor IPSS-R “higher-risk” (intermediate-2 and high or high and very-high groups, respectively) pts. In multivariate analysis, the prognostic impact of MDS-CI remained independent of baseline IPSS (p=0.01) or IPSS-R (p=0.03). Conclusions: a comprehensive evaluation of comorbidities according to a tailored tool such is MDS-CI helps to predict survival in patients with MDS and should be incorporate to current prognostic scores in order to better define clinical management of these patients. Disclosures No relevant conflicts of interest to declare.

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Prognostic Value of TP53 Gene Mutations in Higher Risk MDS Treated with Azacitidine

Blood ◽

10.1182/blood.v120.21.1706.1706 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1706-1706

Author(s):

Cecile Bally ◽

Lionel Ades ◽

Aline Renneville ◽

Claude Preudhomme ◽

Marie-Joelle Mozziconacci ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Value ◽

Tp53 Mutation ◽

Conflicts Of Interest ◽

Gene Mutations ◽

Tp53 Gene ◽

Chromosome 17 ◽

Complex Karyotype ◽

Tp53 Mutations ◽

Tp53 Gene Mutations

Abstract Abstract 1706 Background: TP53 gene mutations in MDS and AML are, with the exception of cases of isolated del 5q, generally associated with complex karyotype, often including del (17p) (with loss of the remaining TP53 allele) and with poor overall outcome (Fenaux, BJH, 1992; Bejar, NEJM, 2011). They are, in MDS and AML, more specifically generally associated with resistance to chemotherapy, including anthracycline-Ara C combinations and low-dose AraC (Wattel, Blood, 1994), but their correlation with treatment outcome with hypomethylating agents has not been studied. Our aim was to assess the prognostic value of TP53 mutations for response to Azacitidine (AZA) in higher risk MDS, AML with 20–30% blasts or advanced CMML (corresponding to the EU label for AZA). Methods: Patients were treated with AZA (75 mg/m2/d, generally during 7 days every 4 weeks) in 2 centers of the Groupe Francophone des Myélodysplasies. TP53 mutations were detected by the functional FASAY technique, which assesses the transcriptional activity of p53 by co-transfecting an open gap repair plasmid with the product of amplification of TP53 from patients in yeasts whose growth is dependent on the functionality of p53. The detection limit of this technique is around 10–15% (Flaman et al, PNAS 1995). The presence of mutations was subsequently confirmed by direct sequencing using the Sanger method and, more recently, by a Next-Generation Sequencing (NGS) assay using pyrosequencing (GS Junior System, Roche with the IRON II plate design). Results: 72 pts treated with AZA (median n° of cycles of AZA received 4, range 1–7) were analyzed, including 34 MDS according to WHO classification (IPSS high: 9, int2: 13, int1: 6, undetermined: 6), 33 AML with 20–30% blasts and 5 advanced CMML. According to IPSS, karyotype was favorable in 27%, intermediate in 13% and unfavorable in 60% of the pts, including 47% of complex karyotypes. Response to AZA (according to IWG 2006 criteria) was observed overall in 51% of the pts, including 34% CR, 6% PR, 4% marrow CR, 7% stable disease with HI. Median overall survival (OS) from onset of AZA was 15.6 months, possibly explained by the 47% of complex karyotypes. 29 (40%) patients had a TP53 mutation, detected by FASAY technique and subsequently confirmed by Sanger sequencing or NGS (no false positive with FASAY technique was observed). 22 of the 34 (67%) patients with complex karyotype had a TP53 mutation. In the 7 patients with TP53 mutation without complex karyotype, 3 pts had isolated del(5q), 2 had del (17p) (isolated in 1 pt, with del (20q) in 1 pt), 1 had pentasomy 11 and 1 had +8, del(20q). Ten (77%) of the 13 cases with chromosome 17 rearrangement leading to del (17p) were TP53 mutated. Overall Response to AZA (41% vs 57%, p= 0.227) and CR rate (21% vs 42%, p= 0.073) did not significantly differ between TP53 mutated and wild-type patients. Nevertheless, OS was negatively influenced by the presence of TP53 mutation (median 13 vs 21 months, p= 0.0022, figure 1), complex cytogenetics (median 14 vs 18 months, p=0.0120), WHO AML diagnosis (median 13 vs 21 months for WHO-MDS or CMML, p= 0.0014). By multivariate analysis, marrow blast % (HR 1.03 (1.01–1.05) (p<10-4)) and TP53 mutational status (HR 2.29 (1.06–4.97) p=0.035) were the only 2 factors retaining statistical significance for OS. When the analysis was restricted to WHO MDS and CMML patients, only the presence of TP53 mutation was associated with worse OS in multivariate analysis (HR=4.08 (1.31– 12.7), p=0.015)). Conclusion: In higher risk MDS (and AML with 20–30% blasts and advanced CMML) patients treated with AZA, the presence of TP53 mutation appears to constitute an independent prognostic parameter of poorer survival. Disclosures: No relevant conflicts of interest to declare.

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Miller–Payne Grading and 70-Gene Signature Are Associated With Prognosis of Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Early-Stage Breast Cancer After Neoadjuvant Chemotherapy

Frontiers in Oncology ◽

10.3389/fonc.2021.735670 ◽

2021 ◽

Vol 11 ◽

Author(s):

Liye Wang ◽

Rongzhen Luo ◽

Qianyi Lu ◽

Kuikui Jiang ◽

Ruoxi Hong ◽

...

Keyword(s):

Breast Cancer ◽

High Risk ◽

Neoadjuvant Chemotherapy ◽

Tumor Size ◽

Risk Group ◽

Poor Response ◽

Gene Signature ◽

High Risk Group ◽

Low Risk ◽

The Poor

IntroductionHR+/HER2− breast cancer (BC) has a much lower pathological complete response (pCR) rate to neoadjuvant chemotherapy (NAC). Therefore, to better stratify the relapse risk for HR+/HER2− non-pCR populations, it is essential to accurate identification new prognostic markers.Materials and MethodsThe study retrospectively analyzed 105 stage II–III patients who were diagnosed with HR+/HER2− BC and received NAC followed by breast and axilla surgery between 2013 and 2019 in Sun Yat-Sen University Cancer Center. The Miller–Payne (MP) grading system was used to evaluate pathological responses to NAC. The 70-gene signature was used to classify the prognosis signatures.ResultsAmong the 105 patients, the study demonstrated that larger tumor size and lower progesterone receptor level at baseline and larger tumor size postoperative were statistically significantly associated with worse disease-free survival (DFS) (p = 0.004, p = 0.021, and p = 0.001, respectively). Among 54 patients who underwent the 70-gene assays, 26 (48.1%) had a low-risk signature; 28 (51.9%) patients had a high-risk signature. Patients with poor response (MP grades 1–2) were more likely to with a high-risk 70-gene signature than those with good response (MP grades 4–5). The final analysis showed that DFS was longer in the low-risk group than in the high-risk group [52.4 vs. 36.1 months of the median DFS, hazard ratio (HR) for recurrence, 0.29; 95% confidence interval (CI), 0.10–0.80; p = 0.018]. DFS was longer in the good response (MP grades 3–4) group than in the poor response (MP grades 1–2) group (94.7% vs. 60% of the patients free from recurrence; HR, 0.16; 95% CI, 0.05–0.47; p = 0.037). When stratified by MP grades combined with the 70-gene signature, subgroup analyses showed the good-response low-risk group with the best DFS, whereas the poor-response high-risk group showed the worst DFS (p = 0.048). Due to the short median follow-up time of 34.5 months (5.9–75.1 months), MP grades and the 70-gene signature did not show significant prognostic value for overall survival.ConclusionThe study showed that analysis of MP grades combined with the 70-gene signature with residual NAC-resistant breast samples has a significant correlation with DFS.

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Mutations Based on Next-Generation Sequencing May be Complementally to Prognostic Risk in Myelodysplastic Syndromes

Blood ◽

10.1182/blood-2020-140977 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 42-43

Author(s):

Jing Wang ◽

Jinsong Jia ◽

Xiaohong Liu ◽

Lizhong Gong ◽

Shengye Lu ◽

...

Keyword(s):

High Risk ◽

Lower Risk ◽

Tp53 Mutation ◽

Somatic Mutations ◽

Risk Group ◽

Idh1 Mutation ◽

Factors Associated ◽

Runx1 Mutation ◽

Idh2 Mutation

Objective: Established the value of somatic mutations based on next-generation sequencing (NGS) and explore factors associated with prognosis in myelodysplastic syndromes (MDS). Methods: From March 2012 to September 2019, 90 newly diagnosed MDS patients were treated and analysed by a sensitive NGS assay for mutations in 87 candidate genes and target regions. IPSSR higher risk include IPSS-R Intermediate, High, Very High subgroups (risk score >3.5), and IPSSR lower risk include IPSSR risk score ≤3.5. Results: A total of 90 MDS patients were recruited for this study (median age: 51.5 years; range: 16-70 years). Eighty-two (91.1%) patients harbored at least one mutation (median, 3 per patient; range, 0-11), and the most common mutations were found successively in the ASXL1 (28.9%), TP53 (21.1%), TET2 (18.9%), U2AF1 (17.8%), RUNX1 (15.6%), SETBP1 (13.3%), DNMT3A (13.3%), IDH1 (12.2%), NRAS (12.2%), KMT2D (11.1%), CBL (11.1%) and PTPN11 (11.1%) genes. The median follow-up was 32 months (range: 10-96 months). Thirty-seven (92.5%) had at least one point mutation in 40 patients with normal karyotype. ASXL1 and U2AF1 mutations had more frequently platelet levels of <50×109/L (P=0.047, P=0.023; respectively) and hemoglobin concentrations at <80 g/L (P=0.048, P=0.042; respectively). Compared with the lower risk MDS, more TP53 mutations (28% vs. 12.5%, P=0.048), RUNX1 mutations (22% vs. 7.5%, P=0.039), IDH1 mutations (18% vs. 5%, P=0.041), and IDH2 mutations (8% vs. 0, P=0.047) were found in the higher risk MDS. During the follow-up period, 37 (41.4%) patients translate to AML at a median follow-up of 24.5 months (range: 2-96 months). The median time of progress to AML from MDS diagnosis was 46 (2-96) months in MLD, 21 (2-37) months in EB1, and 18.5 (2-73) months in EB2. At 3-year follow-up, the probability of overall survival (OS) and cumulative incidence of AML transformation (CIAT) were 72.3% (95%CI 67.2%-77.8%) and 36.2% (95%CI 30.9%-41.5%), respectively. The univariate analysis results showed that ≥50 years old, IPSSR higher risk, ASXL1mutation, TP53 mutation, TET2 mutation, U2AF1 mutation, RUNX1 mutation, IDH1 mutation, IDH2 mutation, and ≥3 molecular mutations were poor factors for OS. The univariate analysis results associated with CIAT showed that IPSSR higher risk, TP53 mutation, RUNX1 mutation, IDH1 mutation, and IDH2 mutation were poor factors for CIAT.Multivariate adjust analysis showed that IPSSR higher risk, ASXL1 mutation, TP53 mutation, and RUNX1 mutation were independent prognosis factors associated with OS (HR=0.113, 95% CI: 0.093-0.199, P=0.003; HR=0.215, 95% CI: 0.103-0.623, P=0.025; HR=0.147, 95% CI: 0.084-0.506, P=0.012; HR=0.317, 95% CI: 0.122-0.661, P=0.013; respectively), and IPSSR higher risk, TP53 mutation, RUNX1 mutation, IDH1 mutation, and IDH2 mutation were independent prognosis factors associated with CIAT (HR=2.905, 95% CI: 1.155-6.312, P=0.023; HR=2.636, 95% CI: 1.024-5.023, P=0.004; HR=2.350, 95% CI: 1.043-5.789, P=0.024; HR=2.061, 95% CI: 1.036-4.078, P=0.003; HR=2.814, 95% CI: 1.073-5.359, P=0.005; respectively). Patients with mutations in one or more of the three independent survival prognostic genes (TP53, RUNX1, or ASXL1) defined as "mutation high risk" (n=48) and those without anyone of the three prognostic genes defined as "mutation low risk" (n=42). OS were significantly longer in the IPSSR both lower risk and higher risk patients with mutations low risk cohort than IPSSR lower risk patients with mutations high risk cohort (3-year OS, 95.7% vs. 47.1%, P=0.001; 79.9% vs. 47.1%, P=0.045; respectively). In the IPSSR lower risk with mutations high risk group, OS was significantly improved in the allo-HSCT cohort (3-year OS, 75.0% vs. 30.0%, P=0.042). In the IPSSR higher risk with mutations low risk group, no significant difference existed between the transplant and non-transplant arms for the probabilities of OS (3-year OS, 83.3% vs. 75.8%, P=0.972). Conclusions: Somatic mutations are common in MDS and are associated with prognosis. Mutation high risk may be complementally to IPSSR prognostic risk in MDS patients, and allo-HSCT can improved the survival in the IPSSR lower risk with mutations high risk group. Key words: myelodysplastic syndromes; somatic mutations; Prognostic dichotomization based on 3.5 of the revised international prognostic scoring system; overall survival; allogeneic stem cell transplantation. Disclosures No relevant conflicts of interest to declare.

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Incidence and Prognostic Value of TP53 Mutations in Lower Risk MDS with Del 5q.

Blood ◽

10.1182/blood.v120.21.2809.2809 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2809-2809

Author(s):

Cecile Bally ◽

Lionel Ades ◽

Aline Renneville ◽

Sophie Raynaud ◽

Virginie Eclache ◽

...

Keyword(s):

Early Phase ◽

Lower Risk ◽

Prognostic Value ◽

Tp53 Mutation ◽

Cytogenetic Response ◽

Complex Karyotype ◽

Early Disease ◽

Tp53 Mutations ◽

Erythroid Response ◽

Significant Difference

Abstract Abstract 2809 Background: TP53 gene mutations, frequent in AML and MDS with complex karyotype, have recently been found in about 20% of lower risk MDS with del 5q, where they possibly conferred resistance to lenalidomide (LEN), and a higher risk of AML progression (Jadersten, JCO, 2011). We assessed the incidence and prognostic value of TP53 mutations in 79 lower risk MDS with del 5q, treated or not with LEN, and analysed in early disease phase or after progression to higher risk MDS or AML. Methods: IPSS low and int 1 (Lower) risk MDS with del 5q were analysed at diagnosis or onset of LEN (“early phase”) and/or after progression to IPSS high or int 2 (higher) risk MDS or AML. LEN was administered at 5 or 10 mg/d during 16 weeks, and continued in erythroid responders until relapse or disease progression. TP53 mutations were detected by the functional FASAY technique, assessing the transcriptional activity of p53 by co-transfecting an open gap repair plasmid with the product of amplification of TP53 from patients in yeasts whose growth is dependent on p53 functionality. The detection limit of this technique is around 10–15% (Flaman, PNAS 1995). Mutations found by FASAY were confirmed by direct sequencing, using Sanger method and /or (more recently) high sensitivity (1%) Next Generation Sequencing (NGS) by pyrosequencing (GS Junior System-Roche, with the IRON II plate design). Results: 79 lower risk MDS with del 5q from 6 French centers of the GFM were analyzed, including 62 at diagnosis or onset of LEN (“early phase”), and 17 after progression to higher risk MDS or AML (5 of the latter were also retrospectively analysed on early phase samples). Overall, 28 (35%) of the 79 patients had TP53 mutation, including 16 (26%) of the 62 pts analyzed at early phase and 12 (70%) of the 17 evaluated after higher risk MDS or AML progression (p= 0.001). The 62 early phase pts had marrow blasts <5% and 5–9% in 91 and 9% of the cases, isolated del 5q, del 5q+1 and del5q+>1 (complex karyotype) in 84, 14 and 2% of the cases, and IPSS low and int 1 in 80 and 20% of the cases, respectively. No significant difference was found between mutated and non mutated cases for baseline characteristics including gender, age, WHO classification, cytogenetic complexity and IPSS. In the 5 pts analysed after progression where early phase samples were available, who all had received LEN, 4 had TP53 mutation at progression. In all of them, TP53 mutation was already detectable during early phase. However, the percentage of mutated colonies found by FASAY increased with progression, from 18 to 75%, 26 to 55%, 12 to 87% and 13 to 23%, respectively, showing an increase of the size of the mutated clone at progression. Among the 43 pts analyzed in early phase who received LEN (we excluded the 5 pts analysed after progression where early phase samples were available, to avoid bias), 36 (84 %) had isolated del 5q, 6 (14%) del 5q+1, and 1 (2%) had complex karyotype. IPSS was low in 73% and int-1 in 27%. 12/43 (28%) had TP53 mutation. 63% of the 43 pts achieved erythroid response, and 9 (47%) of the 19 pts evaluable at erythroid response achieved cytogenetic response. Erythroid response was seen in 45% mutated vs 71% non mutated cases (p= 0.258). Cytogenetic response was seen in 1/8(12%) mutated vs 8/11 (73%) non mutated cases (p=0.020). In those 43 pts who received LEN, the cumulative incidence (CI) of AML evolution, with death as a competitive event, did not significantly differ between patients with or without TP53 mutation (3 year CI of 35% vs 30%, p=0.33). Finally, in those pts, TP53 mutational status had no significant impact on OS (median 49 months in mutated pts vs not reached in non mutated pts, p=0.48, figure 1). Conclusion: We confirm the presence of TP53 mutations in about 25 % of lower risk MDS with del 5q analysed in early disease phase. TP53 mutations, in those patients, were not correlated with other baseline parameters. When treated with LEN, mutated cases had similar hematological response, lower cytogenetic response but no significant difference in progression to higher risk MDS or AML and survival compared to non mutated cases. The high incidence of TP 53 mutations at progression to higher risk MDS/AML (70%), and the increase in the TP53 mutated clone size observed during progression in pts with a baseline mutation support the pathophysiological importance of TP53 mutations in disease progression in lower risk MDS with del 5q. Disclosures: No relevant conflicts of interest to declare.

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TP53 Mutational Status-Based Genomic Signature for Prognosis and Predicting Therapeutic Response in Pancreatic Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.665265 ◽

2021 ◽

Vol 9 ◽

Author(s):

Feng Zhang ◽

Wenhui Zhong ◽

Honghao Li ◽

Kaijun Huang ◽

Min Yu ◽

...

Keyword(s):

Pancreatic Cancer ◽

High Risk ◽

Tp53 Mutation ◽

Therapeutic Response ◽

Risk Group ◽

High Risk Group ◽

Driver Mutation ◽

Mutational Status ◽

Prognostic Stratification ◽

Tp53 Mutational Status

TP53 mutation is a critical driver mutation that affects the carcinogenesis and prognosis of patients with pancreatic cancer (PC). Currently, there is no driver mutation-derived signature based on TP53 mutational status for prognosis and predicting therapeutic response in PC. In the present study, we characterized the TP53 mutational phenotypes in multiple patient cohorts and developed a prognostic TP53-associated signature based on differentially expressed genes between PC samples with mutated TP53 and wild-type TP53. Comprehensive investigations were carried out in prognostic stratification, genetic variation, immune cell infiltration, and efficacy prediction of chemotherapy and targeted therapy. We found that TP53 mutation commonly occurred as a survival-related driver mutation in PC. In total, 1,154 differentially expressed genes were found between two distinct TP53 mutational phenotypes. A five-gene TP53-associated signature was constructed in The Cancer Genome Atlas (TCGA) cohort by least absolute shrinkage and selection operator (LASSO)–Cox analysis and proven to be a robust prognostic predictor, which performed well in three independent Gene Expression Omnibus (GEO) validating cohorts. Remarkably, patients in the low-risk group were characterized with decreased tumor mutation burden and activity of immunity, with favorable prognosis. Higher fractions of macrophages M0 and impaired CD8 + T cells were observed in patients in the high-risk group, suggesting immunosuppression with poor survival. Patients in the high-risk group also demonstrated enhanced response to specific chemotherapeutic agents, including gemcitabine and paclitaxel. Several targeted inhibitors, like histamine receptor inhibitor, were screened out as promising drugs for PC treatment. Collectively, the TP53-associated signature is a novel prognostic biomarker and predictive indicator of PC. The signature could contribute to optimizing prognostic stratification and guide effective PC treatments.

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