Association of TP53 mutation status and GATA6 amplification with clinical outcome of pancreatic cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16224-e16224
Author(s):  
Jung-In Yang ◽  
Taehoon Ha ◽  
Edward Zhou ◽  
Chris Tzanavaris ◽  
Craig E. Devoe ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Retrospective Analysis ◽  
Tp53 Mutation ◽  
Progression Free Survival ◽  
Tp53 Gene ◽  
Genetic Alterations ◽  
Cancer Prognosis ◽  
General Belief ◽  
Genetic Changes ◽  
Survival Estimate

e16224 Background: Recent advances in pancreatic adenocarcinoma (PDAC) research unveiled that molecular subtypes reflect cancer prognosis and chemosensitivity. Here, we examined the possible use of genomic profiling of PDAC in the clinic by assessing retrospective clinical outcomes and treatment responsiveness based on genetic alterations. Methods: All patients treated for PDAC with Next-Generation Sequencing (NGS) data available between 2014 to 2020 at Northwell Health Cancer Institute were included in a retrospective analysis. Patients were subdivided into resectable and unresectable cancer. Genetic findings frequently reported in NGS were used to compare progression-free survival (PFS) and overall survival (OS) within subgroups. Survival probability was compared using Peto-Peto’s modified survival estimate followed by pairwise comparisons using Peto-Peto’s modified survival estimate. Family-wise error rate was adjusted using Benjamini & Hochberg method. Results: A total 115 patients were qualified for the evaluation. In all cases of PDAC, TP53 mutation (n = 89) was associated with poor OS compared to the wild-type TP53 gene (n = 19) (median OS 20.2 months, 95% CI 10.2 to 39.7, vs. 41.1 months, 95% CI 20.9 to 81.0, HR 1.98, p = 0.028). In unresectable PDAC, tumors with GATA6 amplification (n = 11) were associated with a significantly better OS over patients whose tumors harbored a TP53 mutation (n = 57) (median OS 22.9 months, 95% CI 9.6 to 54.5, vs. 10.0 months, 95% CI 4.2 to 23.8, HR 0.48, p = 0.048) . Within the TP53 mutation group, FOLFIRINOX (n = 21) did not show improved OS compare to Gem/NabP (n = 30) (mean OS 13.8 months, 95% CI 6.8 to 28.2, vs. 8.5 months, 95% CI 4.17 to 17.4, HR 0.84, p = 0.25). Other genetic alterations were not associated with OS. There was no difference in PFS in all PDACs. Conclusions: Our retrospective analysis showed that genetic changes in TP53 and GATA6 were significantly associated with the clinical outcome for PDAC. Mutation of TP53 was associated with poor OS in general. However, in unresectable PDAC, GATA6 amplification was associated with better clinical outcome than tumors with TP53 mutation. In contrary to general belief, FOLFIRINOX did not result in better OS than Gem/NabP.

Comprehensive Genetic and Histopathologic Study Reveals Three Types of Neuroblastoma Tumors

2001 ◽  
Vol 19 (12) ◽  
pp. 3080-3090 ◽  
Author(s):  
Maria Łastowska ◽  
Catherine Cullinane ◽  
Sadick Variend ◽  
Simon Cotterill ◽  
Nick Bown ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Genetic Alterations ◽  
Good Prognosis ◽  
Mycn Amplification ◽  
Genetic Changes ◽  
Pathology Classification ◽  
Genetic Features ◽  
1P Deletion ◽  
Tumor Types ◽  
Type 3

PURPOSE: To determine the relationship between multiple genetic features, tumor morphology, and prognosis in neuroblastoma. PATIENTS AND METHODS: The genetic alterations and morphologic features that underpin three histopathologic risk classifications were analyzed in 108 neuroblastoma patients. Tumors were subdivided into four groups based on the three most frequent and prognostically significant genetic alterations (17q gain, 1p deletion, and MYCN amplification), and all other genetic, morphologic, and clinical data were analyzed with respect to these groups. RESULTS: Our analyses identify three nonoverlapping tumor types with distinct genetic and morphologic features, defined here as types 1, 2, and 3. Type 1 tumors show none of the three significant genetic alterations and have good prognosis. Both type 2 (17q gain only or 17q gain and 1p del) and type 3 (17q gain, 1p del, and MYCN amplification) tumors progress. However, these tumor types are distinguished clinically by having significantly different median age at diagnosis and median progression-free survival (PFS). Multivariate analysis indicates that 17q gain is the only independent prognostic factor among all genetic, histopathologic, and clinical factors analyzed. Among histopathologic risk systems, the International Neuroblastoma Pathology Classification was the best predictor of PFS. CONCLUSION: Our results indicate that specific combinations of genetic changes in neuroblastoma tumors contribute to distinct morphologic and clinical features. Furthermore, the identification of two genetically and morphologically distinct types of progressing tumors suggests that possibilities for different therapeutic regimens should be investigated.

Combined aCGH and Mutational Analysis of CLL Patients with 17p Deletion.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2091-2091
Author(s):  
Hannah C. Rudenko ◽  
Vasantha Brito-Babapulle ◽  
David Gonzalez ◽  
Pilar Martinez ◽  
Paola E. Leone ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Mutational Analysis ◽  
Survival Curve ◽  
Progression Free Survival ◽  
Tp53 Gene ◽  
Chromosome 9 ◽  
Research Centre ◽  
Genomic Changes ◽  
Mutational Status ◽  
Trisomy 12

Abstract We have utilised aCGH (Breakthrough Breast Cancer Research Centre 5.8K array) and mutational analysis of the TP53 gene (exons 4–10) on 74 cases of CLL to define the extent of deletion at 17p, TP53 mutational status, additional genomic changes, and how this affects clinical outcome. 17p- cases were selected by FISH (n=37, Vysis LSI P53 probe) and 37 cases were selected as being representative of the survival curve of CLL patients without 17p-. FISH identified 22 cases with TP53- in ≥ 50% of cells, 4 cases with TP53- 20–50% and 11 cases with TP53- ≤ 20%. aCGH can detect abnormalities present in >50% of cells and all of the TP53- cases greater than 50% by FISH were detected with deletion ranging between 6-20Mb in length, the majority encompassing the entire p-arm. In addition aCGH detected deletion of 17p in 5/15 cases with TP53- <50%, and 2/37 with no detectable TP53- by FISH, these deletions clustered at 17p13.3 and 17p11.2, and did not involve the TP53 gene. Cases with 17p- >20% have a poor clinical outcome (median survival 11 months, median progression free survival 3 months), the majority of these (85%) also have a mutation of TP53 whereas in cases with ≤ 20% 17p- only 10% were mutated. The 17p- group was characterised by additional recurrent deletions involving 18p, 20p and 22q, which tended to occur as single additional events. Understanding the order in which these events occur is important, 18p- was found in 6 cases, 2 of which had <50% 17p- by FISH, suggesting that 18p- is present in a higher percentage of cells and by implication occurs prior to the 17p deletion, a similar finding was also present for the 20p- cases. 18p deletion varied in length between 5.9Mb and 12Mb, with the minimally deleted region (MDR) involving a 2.5Mb region spanning 18p11.23-p11.22. 20p- was found in 8 cases of which 3 covered almost the entire p-arm, and 5 formed 2 clusters at each end of the p-arm. 22q- was found in 8 cases, with only 1 outside of the 17p- group. Out of these 8 cases with deletion, 6 covered almost the complete q-arm but a MDR was difficult to define, however if the non-17p- case is excluded the MDR covers 1.4Mb at 22q12.3. Recurrent abnormalities were also found on other chromosomes, but did not differ between the two groups. These included regions with previously identified abnormalities; trisomy 12 (n=11), loss of 6q14.1–24.3 (n=11), loss of 11q12.1–25 (n=17) and loss of 13q12.1–21.1 (n=6) as well as detection of novel abnormalities; gain of 4p16.3–16.1 (n=23), gain of 11p15.5–15.3 (n=22), gain of 22q11.21–13.33 (n=22) and deletions on chromosome 9 (n=9). These results show that deletion of TP53 and mutation of the other allele are critical adverse prognostic factors. We have also defined a genetic background (18p-, 20p- and 22q-) on which these changes arise.

Clinical Impact of TP53 Gene Mutations in Diffuse Large B-Cell Lymphoma (DLBCL): An International DLBCL Rituxan-CHOP Consortium Program Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 967-967
Author(s):  
Ken H. Young ◽  
Nancy Patten ◽  
Sim Truong ◽  
Jens Eickhoff ◽  
Gabrielle L. Rocque ◽  
...  
Keyword(s):  
Dna Binding ◽  
Clinical Outcome ◽  
B Cell ◽  
Median Survival ◽  
Tp53 Mutation ◽  
Tp53 Gene ◽  
Chop Regimen ◽  
Tp53 Mutations ◽  
Dna Binding Domains ◽  
Binding Domains

Abstract Abstract 967 Mutations of the TP53 tumor suppressor gene are associated with a poor clinical outcome in DLBCL patients treated with CHOP. The impact of TP53 mutations on clinical outcome of DLBCL patients treated with Rituxan-CHOP has not been comprehensively analyzed. The purpose of this study was to analyze the frequency and type of TP53 mutations in Rituxan-CHOP treated DLBCL patients from twenty-two medical centers, and to correlate these with clinical outcome. TP53 mutations were identified in 138/604 (22.7%) Rituxan-CHOP treated DLBCL cases and included missense (n=133), nonsense (n=16), splice site (n=9) and frameshift (n=1) mutations. The presence of any TP53 mutation correlated with poor overall survival (OS) with a median OS of 50 months in the TP53 mutation group versus 69 months in the wild-type group (wt-TP53, P=0.0042). Seventy-three of 138 cases (53%) had mutations in the DNA binding domains of the TP53 gene, which were found to be the most important predictor of poor OS (P=0.0044). In contrast, mutations in the non-DNA binding domains did not correlate with poor OS (P=0.157). Overexpression of p53 protein significantly correlated with only TP53 missense mutations (P=0.002), but not with other types of TP53 mutations, while TP53 deletion did not correlate with mutation or OS. In comparison to our previous series of patients treated only with CHOP, Rituxan-CHOP regimen improved OS in both wt-TP53 and TP53 mutated groups. The 5-year survival rate was 42% in patients with any TP53 mutation (median survival=50 months) and 41% in patients with the DNA-binding domain mutations (median survival=49 months) compared to 52% for those with wt-TP53 (median survival=69 months). The complete remission rate was 51% in patients with any TP53 mutation and 44% in patients with the DNA-binding domain mutations, compared to 77% for those with wt-TP53. However, the clinical outcome and treatment response to the Rituxan-CHOP varied in patients with mutations in different regions of the DNA-binding domains. Patients with mutations in the DNA minor binding groove motif (Loop L3, 17% of all mutations) had significantly decreased median OS (17 months) when compared to patients with Loop L2 (16% of all mutations) or loop-sheet-helix motifs (Loop L1-S10-H2, 20% of all mutations) with median OS of 49 and 50 months, respectively. In contrast to our previous CHOP series study, median survival was significantly improved for Rituxan-CHOP treated DLBCL patients with mutations in the loop-sheet-helix motifs (43 months). Multivariate analysis confirmed that TP53 mutations and activated B-cell-like (ABC)/germinal center B-cell-like (GCB) subtype classification were independent predictors of OS with a hazard ratio of 0.69 (GCB vs ABC, 95% CI 0.49-0.98) and 1.60 (TP53 vs wt-TP53, 95% CI 1.10-2.31), respectively. Similar to our previous CHOP study, the TP53 mutation profile, regardless of location, was found to stratify GCB-DLBCL, but not ABC-DLBCL, into molecularly distinct subsets with different clinical outcomes in Rituxan-CHOP treated DLBCL patients. This study demonstrates the importance of TP53 mutational profile for predicting clinical outcome. Elucidation of the roles of specific TP53 domain mutations, as documented in our study, will help in refining prognostic models for DLBCL patients treated with either the CHOP or Rituxan-CHOP regimen. These findings also provide the rationale and strategies for p53 targeted therapeutic intervention in DLBCL patients. Disclosures: Kahl: Milllennium: Consultancy, Research Funding; Cephalon: Consultancy, Research Funding.

Next Generation Sequencing (NGS) of TP53 Gene Allows to Identify a Very High Risk Group of Philadelphia Negative Acute Lymphoblastic Leukemia (ALL) Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3796-3796
Author(s):  
Silvia Salmoiraghi ◽  
Greta Ubiali ◽  
Manuela Tosi ◽  
Barbara Peruta ◽  
Marie Lorena Guinea Montalvo ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Tp53 Mutation ◽  
Lymphoblastic Leukemia ◽  
Tp53 Gene ◽  
Wild Type ◽  
Poor Clinical Outcome ◽  
Tp53 Mutations ◽  
Next Generation Sequencing Ngs ◽  
Roche Diagnostics ◽  
Generation Sequencing

Abstract Background and Aim of the Study For both childhood and adult Acute Lymphoblastic Leukemia (ALL) patients, clinical risk factors such as age, white cell count, response to steroids, time to complete remission, as well as biologic characteristics such as immunophenotype and cytogenetic at diagnosis are important but not sufficient in predicting clinical outcome. Aberrations of TP53 play a crucial role in the molecular pathogenesis of leukemias and lymphomas in which their presence is associated to disease progression and represents a strong predictor of poor clinical outcome. In childhood ALL, hereditary and acquired TP53 mutations are involved both in the pathogenesis and progression of the disease. In adult ALL, TP53 mutations are frequent in patients negative for recurrent fusion genes and correlate with poor response to induction therapy (Chiaretti S. et al, Haematologica 2013). The aim of this study was to evaluate the impact of TP53 alterations, analyzed by Next Generation Sequencing (NGS), on the outcome of a cohort of T (n= 57) and B (n= 114) precursor, Philadelphia (Ph) negative, adult ALL patients enrolled into the NILG-ALL 09/2000 clinical trial (ClinicalTrials.gov identifier: NCT00358072, Bassan R. et al, Blood 2009) in which molecular minimal residual disease was used to guide post-remissional therapy. Patients and Study design Among the 171 patients who were investigated for TP53 mutations, 16 proved also positive for t(4;11) and 3 for t(1;19). We analyzed DNA isolated from mononuclear cells obtained from bone marrow or peripheral blood samples containing at least 30% of blasts at diagnosis. The TP53 gene was sequenced using 454 ultra-deep sequencing (Roche Diagnostics) for alterations in exons 4 to 11, following the protocol developed in the IRON-II consortium. The sequencing data were analyzed by the Roche Diagnostics GS Run Browser and GS Amplicon Variant Analyzer software. The probabilities of survival were estimated using the Kaplan Meier method. The log-rank test was used to compare survival probabilities between subgroups of patients. Results and Discussion The data obtained by NGS allowed to identify 15 coding mutations detected in the DNA binding domain region (exons 5 to 8). These alterations were observed at diagnosis in 14 patients (8%), (11 B-precursor ALL and 3 T-ALL). In 12 cases these aberrations were single nucleotide changes, in 2 cases we found a duplication (one of 4 and the other of 8 nucleotides) and in one case there was an 11 base pair DNA insertion. Remarkably, all of these DNA alterations led to missense or frame-shift mutations that introduced a premature stop codon. Moreover, they were detected with a wide range of allele burden (from 5% to 97%) pointing out that TP53 mutations can be present at diagnosis in different proportions within the leukemic clones. All patients carrying a TP53 alteration reached complete remission after induction therapy but 13 out of 14 suffered an early relapse. Frequency of relapses was significantly higher in mutated than in wild-type cases (p=0.019). Relapse DNA samples were available in 3 patients and in all of them we detected the same TP53 mutation found at diagnosis, indicating the presence of a stable mutated clone. The univariate analysis enlightens a clear relationship between TP53 mutation with an increasing age (p= 0.0003) but no correlation with other clinical features such as gender, hemoglobin, white blood count, platelets, percentage of blasts and cytogenetics at diagnosis. Moreover, patients with mutated TP53 showed a Disease Free Survival (DFS) and Overall Survival (OS) dramatically shorter than wild-type patients. The 2 years DFS was 43% in the TP53 non-mutated subjects compared to 7% in the mutated (p=0.0007). Similarly, the 2 years OS was of 50% in wild-type patients and of 7% in mutated patients (p=0.0011) (Figure 1). Conclusions In adult ALL, response to induction chemotherapy is not different in patients with a wild-type or a TP53 mutated gene, but in these latter cases the leukemia relapse rate is dramatically higher. The frequency of these mutations observed at diagnosis and the poor clinical outcome indicate the need of their identification during the diagnostic work up of adult ALL to guide treatment strategies. The use of a highly sensitive deep sequencing approach is crucial to identify also minor leukemic clones carrying TP53 mutations that may lead to the rapid emergence of a treatment resistant disease. Disclosures Kohlmann: AstraZeneca: Employment.

Independent assessment of TP53 and PTEN as predictors of response to enzalutamide (ENZ) or abiraterone acetate (AA) in men with metastatic castration-resistant prostate cancer (mCRPC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 351-351
Author(s):  
Andrew W Hahn ◽  
Nityam Rathi ◽  
David Michael Gill ◽  
Sidney VanAlstine ◽  
Austin Poole ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tp53 Mutation ◽  
Salt Lake ◽  
Univariate Analysis ◽  
Single Agent ◽  
Progression Free Survival ◽  
Genetic Alterations ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistance ◽  
Pten Loss

351 Background: Alterations in androgen receptor signaling are well-established mechanisms of resistance to medical castration. Pre-clinical studies suggest that alterations to key tumor suppressor genes, such as TP53 or PTEN, may also be associated with development of androgen independence as an alternate mechanism of castration-resistance. Previous studies have shown that TP53 inactivation and PTEN loss are predictive of response to novel androgen axis inhibitors. Here, we independently assess whether TP53 and PTEN genomic alterations are predictive of response to ENZ and AA in men with mCRPC. Methods: Clinical data and samples were analyzed from a prospective prostate cancer registry at the University of Utah (Salt Lake City, UT). Next-generation sequencing (NGS) was performed on predominantly primary tumor tissue for 343 somatic and germline genetic alterations using FoundationOne. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Patients with mCRPC who were treated with any line AA or enzalutamide were included. We performed a univariate analysis to assess the predictive value of TP53 and PTEN. Only patients treated with single-agent therapy were included. Results: Of 141 men with prostate cancer and NGS available, 56 were included. Most patients were treated with abiraterone (n = 50), and only 6 with enzalutamide. 28.6% had PTEN loss and 35.7% had a TP53 mutation. OS and PFS did not differ significantly according to PTEN or TP53 status. Median OS was 40.9 months and not reached for men with and without TP53 mutation (HR 1.85, p = 0.31). Median PFS was 7.5 months and 9.5 months for men with and without TP53 mutation (HR 1.18, p = 0.60). Median PFS was 7.2 months and 9.5 months for men with and without PTEN loss (HR 1.15, p = 0.66). Median OS for PTEN was not mature enough to analyze. Conclusions: In our independent cohort, neither TP53 mutation nor PTEN loss is predictive of response to androgen-directed therapy in men with mCRPC patients. However, this is a relatively small retrospective sample with few events. These results should be considered exploratory only.

scholarly journals TERT Promoter Mutations Differently Correlate with the Clinical Outcome of MAPK Inhibitor-Treated Melanoma Patients

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 946 ◽  
Author(s):  
Paola Del Bianco ◽  
Camilla Stagni ◽  
Silvia Giunco ◽  
Alessio Fabozzi ◽  
Lisa Elefanti ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Cancer Progression ◽  
Kinase Inhibitor ◽  
Mapk Pathway ◽  
Progression Free Survival ◽  
Genetic Alterations ◽  
Mitogen Activated Protein Kinase ◽  
Melanoma Tumor ◽  
Increased Risk ◽  
Melanoma Patients

Resistance is a major challenge in the management of mitogen-activated protein kinase inhibitor (MAPKi)-treated metastatic melanoma. Tumor genetic alterations can cause MAPK pathway reactivation, leading to lack of response and poor outcome. Characterization of the mutational profile in patients with melanoma might be crucial for patient-tailored treatment choices. Mutations in the promoter region of the telomerase reverse transcriptase gene (TERTprom) lead to increased TERT expression and telomerase activity and are frequent in BRAFV600 mutant melanoma. Reportedly, TERTprom, and BRAFV600 mutations cooperate in driving cancer progression and aggressiveness. We evaluated the effect of the TERTprom status on the clinical outcome in 97 MAPKi-treated melanoma patients. We observed that patients with the c.-146C > T mutation showed a significantly worse progression-free survival (PFS) compared to those carrying the c.-124C > T mutation and a two-fold increased risk of progression (median 5.4 vs. 9.5 months; hazard ratio (HR) 1.9; 95% confidence interval (CI) 1.2–3.2; p = 0.013). This trend was also observed for the overall survival (OS); melanoma patients with the c.-146C > T mutation showed a poorer prognosis compared to those with the c.-124C > T mutation (median 13.3 vs. 25.5 months; HR 1.9, 95% CI 1.1–3.3, p = 0.023). Our results disclose a different correlation of the two TERTprom mutations with MAPKi-treated melanoma patient outcome, highlighting a different impact of the pathway blockade.

scholarly journals High TP53 Mutation Load Predicts Primary Refractory Mantle Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3995-3995 ◽  
Author(s):  
Aleš Obr ◽  
Pavel Klener ◽  
Eva Kriegova ◽  
Zuzana Zemanova ◽  
Helena Urbankova ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Tp53 Mutation ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Tp53 Gene ◽  
Disease Stage ◽  
Mutation Load ◽  
Free Survival ◽  
Mantle Cell

Introduction: Mantle cell lymphoma (MCL) is rare B-cell lymphoma subtype with usually aggressive behavior. Mutations of TP53 gene and complex karyotype (CK) were described to be poor prognostic factors (Obr A et al, 2018), but their impact on primary resistance to induction has not been investigated. Methods: We analyzed 115 MCL patients (pts) treated in two Czech university centers from 4/2006 to 10/2016. Both classical cytogenetics and next generation sequencing (NGS, MiSeq, Illumina) for TP53 mutation detection were performed on tumoral tissue (peripheral blood, bone marrow) in all patients. Cut-off for TP53 mutation was 1% variant allele frequency (VAF). CK was defined as 3 and more cytogenetic aberrations in one cell population. Pts with stable or progressive disease (SD/PD) during induction or with relapse within 6 months after induction completion were considered as primary refractory (PrR). Variables were compared by chi-squared test. T-test was used to compare the difference between means of TP53 mutation load in PrR+ and PrR- subgroup. Cut-off for TP53 mutation load (27%) was established as median VAF. Overall and progression free survival (OS, PFS) were calculated from the date of diagnosis. Results: The median age at diagnosis was 66 (40-87) years. Ninety-six percent of pts had advanced disease (III and IV). MIPI score was low, intermediate and high in 19.1%, 27.8% and 53.0% pts, respectively. Induction regimens used were as follows: R-CHOP/R-CHOP-like in 47.8%, intensive R-HDAC-containing in 38.3% and non-anthracycline regimen in 9.6% pts. Complete and partial response was achieved in 53.0% and 27.0% pts, resp. SD/PD was observed in 11.3% pts. Overall, 27 (23.5%) pts were considered as primary refractory. TP53 mutation and CK were present in 37 (32.3%) and 15 (13.0%) pts, respectively. Age, disease stage, ECOG score, MIPI, HDAC therapy and CK did not correlate with PrR status. Significantly higher TP53 mutation load was observed in the PrR+ (42%), compared to PrR- subgroup (25%, p=0.03). After median follow-up of 4.6 years, 3-year overall survival (3-y OS) and 3-year progression free survival (3-y PFS) in all pts was 65.8% and 50.9%, resp. Median OS in PrR+ and PrR- pts was 9.2 months, and 4.5 years, resp. Survival analysis stratified according to the TP53 mutation status/mutation load showed 3-y OS and 3-y PFS for wild type (TP53-WT), low mutation load (TP53-low load), high mutation load (TP53-high load) 74.2%, 47.6%, 33.3% and 56.0%, 37.0%, 27.8%, respectively (p=0.001 both). Conclusions: High TP53 mutation load (>27% VAF), but not CK, has significantly correlated with refractory disease in MCL pts. Pts with high mutation load of TP53 gene should be considered to an innovative treatment. Acknowledgement: Supported by IGA_LF_2019_001, MH CZ - DRO (FNOl, 00098892), AZV16-32339A and AZV16-31092A grants Figure Disclosures Trneny: Morphosys: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Gilead sciences: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

Cancer of the vulva: genetic aspects of pathogenesis

GYNECOLOGY ◽  
2018 ◽  
Vol 20 (4) ◽  
pp. 9-11 ◽  
Author(s):  
V V Sobolev ◽  
Z A Nevozinskaya ◽  
A G Soboleva ◽  
I M Korsunskaya
Keyword(s):  
Squamous Cell Carcinoma ◽  
Nucleotide Sequence ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Somatic Mutations ◽  
Genetic Research ◽  
Tp53 Gene ◽  
Gene Activity ◽  
Genetic Changes ◽  
Methylation Of Dna

The review is devoted to genetic research in cancer of the vulva. In genetic changes, the mutation irreversibly changes the nucleotide sequence of DNA, or the number of copies of chromosomes changes per cell. In epigenetics, the nucleotide sequence remains unchanged, but gene activity is regulated by methylation of DNA or modification of histones. Most of the studies analyzed are devoted to the study of mutations in the TP53 gene. Many studies indicate that somatic mutations are more common in HPV-negative than in HPV-positive patients. Epigenetic studies in the main devoted to hypermethylation. The gene CDKN2A is most often studied in epigenetic terms. For most of the studied genes, hypermethylation occurs more often in squamous cell carcinoma of the vulva than in the precursors.

scholarly journals TAMI-45. PHENOGENOMIC CHARACTERIZATION OF IMMUNOMODULATORY PURINERGIC SIGNALING IN GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii222-ii223
Author(s):  
Shannon Coy ◽  
Rumana Rashid ◽  
Sylwia Stopka ◽  
Jia-Ren Lin ◽  
Philipp Euskirchen ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Single Cell ◽  
Purinergic Signaling ◽  
Progression Free Survival ◽  
Tissue Imaging ◽  
Phenotypic Properties ◽  
Spatially Resolved ◽  
Therapeutic Benefits ◽  
Adenosine Concentration ◽  
Cd73 Expression

Abstract INTRODUCTION Purinergic signaling plays critical roles in the regulation of tumor growth and anti-tumor immunity via autocrine/paracrine binding of metabolites to receptors on neoplastic and non-neoplastic populations. Extracellular purine concentrations are mediated by the ectonucleotidase enzymes CD39 and CD73, which catabolize ATP to adenosine. Within tumors such as glioblastoma, neoplastic, immune, and stromal cells expressing these enzymes may co-localize to generate immunosuppressive adenosine-rich environments. However, the composition, architecture, and phenotypic properties of these tumor ecosystems and their relationship to tumor genotype are poorly characterized. METHODS We quantified CD73 expression by immunohistochemistry in a cohort of CNS tumors [meningiomas(n=222), gliomas(n=244), ependymomas(n=44), medulloblastomas(n=24), and craniopharyngiomas(n=38)]. We used publicly-available single-cell RNA-seq data and 36-marker multiplexed tissue imaging (t-CyCIF) of 139 clinically and genomically annotated glioblastoma resections to characterize CD39 and CD73-expressing populations, define the immune architecture and tumor cell-states at single cell resolution, and identify markers of clinical outcome. We used mass spectrometry imaging (MALDI-MSI) to generate spatially-resolved quantification of purine metabolite levels in glioblastoma resections (n=10). RESULTS CD73 exhibited strong expression in a subset of gliomas and meningiomas but was typically not expressed in ependymomas or medulloblastomas. CD73 expression correlated with poor progression-free-survival in IDH-wildtype glioblastoma (p=0.04). scRNA-seq and t-CyCIF in glioblastoma showed CD73 expression in tumor cells, and CD39 expression in macrophages and endothelial cells. MALDI-MSI showed significantly greater adenosine concentrations (3.5-fold;p=0.04) in glioblastomas with high CD73 expression. scRNA-seq showed direct correlations between stem-like mRNA expression, proliferation, and CD73 expression in DIPG. CD73 expression significantly correlated with EGFR amplification, interferon signaling, and PD-L1 expression in glioblastoma. CONCLUSIONS Phenogenomic analysis of purinergic immunomodulatory signaling revealed significant interplay between CD73 activity and genotype, adenosine concentration, differentiation-state, clinical outcome, and possible interaction between CD39-positive macrophages and CD73-positive neoplastic cells. Anti-CD73 therapy may provide therapeutic benefits in glioblastoma by blunting immunosuppressive and oncogenic adenosine signaling.

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

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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