scholarly journals PTENP1-AS contributes to BRAF inhibitor resistance and is associated with adverse clinical outcome in stage III melanoma

2020 ◽  
Author(s):  
Linda Vidarsdottir ◽  
Alireza Azimi ◽  
Ingibjorg Sigvaldadottir ◽  
Aldwin Suryo Rahmanto ◽  
Andreas Petri ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Transcriptional Repression ◽  
Regional Lymph Node ◽  
Braf Inhibitor ◽  
Suppressor Gene ◽  
Stage Iii ◽  
Activating Mutations ◽  
Melanoma Patients ◽  
Stage Iii Melanoma ◽  
The Impact

ABSTRACTApproximately 50% of human cutaneous melanomas carry activating mutations in the serine/threonine protein kinase BRAF. BRAF inhibitors (BRAFi) selectively target the oncogenic BRAFV600E/K and are effective in approximately 80% of patients carrying the mutation. However, resistance to BRAFi is common and emerges within a median time of 6-7 months of treatment and is prolonged to 11 months when combined with MEK inhibitors. Better characterization of the underlying molecular processes is therefore needed to further improve treatments. Inactivation of the tumor suppressor gene PTEN has been suggested to occur during melanomagenesis and drug resistance development. We recently demonstrated that transcription of PTEN is negatively regulated by an antisense RNA from the PTEN pseudogene (PTENP1-AS) and here set out to investigate the impact of this molecular pathway on the resistance to BRAFi and clinical outcome. We used a panel of BRAFi resistant A375 sublines, and observed increased levels of PTENP1-AS associated with reduced expression of PTEN. Furthermore, this loss of PTEN expression was correlated to increased recruitment of Enhancer of zeste homolog 2 (EZH2) and formation of the transcriptional repression mark H3K27me3 at the PTEN promoter in the resistant cells. We demonstrated that targeting of PTENP1-AS was able to re-activate the expression of PTEN and sensitize resistant melanoma cells to BRAFi. Finally, we showed that PTENP1-AS is a promising prognostic marker for clinical outcome in melanoma patients as high expression of PTENP1-AS in regional lymph node metastases from stage III melanoma patients correlated with poor survival.

scholarly journals PTENP1-AS contributes to BRAF inhibitor resistance and is associated with adverse clinical outcome in stage III melanoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Linda Vidarsdottir ◽  
Alireza Azimi ◽  
Ishani Das ◽  
Ingibjorg Sigvaldadottir ◽  
Aldwin Suryo Rahmanto ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Braf Inhibitor ◽  
Stage Iii ◽  
Expression Levels ◽  
Promising Target ◽  
Stage Iii Melanoma ◽  
Inhibitor Resistance ◽  
The Impact ◽  
Resistant Cells

AbstractBRAF inhibitors (BRAFi) selectively target oncogenic BRAFV600E/K and are effective in 80% of advanced cutaneous malignant melanoma cases carrying the V600 mutation. However, the development of drug resistance limits their clinical efficacy. Better characterization of the underlying molecular processes is needed to further improve treatments. We previously demonstrated that transcription of PTEN is negatively regulated by the PTEN pseudogene antisense RNA, PTENP1-AS, and here we investigated the impact of this transcript on clinical outcome and BRAFi resistance in melanoma. We observed that increased expression levels of PTENP1-AS in BRAFi resistant cells associated with enrichment of EZH2 and H3K27me3 at the PTEN promoter, consequently reducing the expression levels of PTEN. Further, we showed that targeting of the PTENP1-AS transcript sensitized resistant cells to BRAFi treatment and that high expression of PTENP1-AS in stage III melanoma correlated with poor survival. Collectively, the data presented here show that PTENP1-AS is a promising target for re-sensitizing cells to BRAFi and also a possible prognostic marker for clinical outcome in stage III melanoma.

Predicting clinical outcome through gene expression profiling in stage III melanoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8502-8502
Author(s):  
T. John ◽  
M. A. Black ◽  
T. Toro ◽  
C. A. Gedye ◽  
I. D. Davis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Outcome ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Stage Iiib ◽  
Stage Iii ◽  
Test Set ◽  
Prognostic Groups ◽  
Melanoma Patients ◽  
Stage Iii Melanoma

8502 Background: Melanoma patients with clinically involved regional lymph nodes (Stage IIIB&C) represent a prognostically heterogeneous population. Current prognostic factors cannot distinguish the 30% of patients who will achieve long term survival from those who will relapse early. We hypothesized that gene expression profiling could identify these different prognostic groups and provide a greater understanding of the genetic mechanisms involved. Methods: Lymph node sections from 29 patients with Stage IIIB & IIIC melanoma and divergent clinical outcome as defined by time to tumor progression (TTP), including 16 poor (TTP<6 months) and 13 good (TTP>28 months) prognosis patients, were subjected to molecular profiling using spotted oligonucleotide arrays containing 30,888 probes as an initial test set. The differentially expressed genes were determined using a Wilcoxon-Mann-Whitney t-test with the false discovery rate controlling method of Benjamini-Hochberg and validated using quantitative real-time RT-PCR. Using logistic regression, a predictive score algorithm was developed based on the 15 genes for which the correlation between the two platforms was the strongest. The score was then applied to two independent validation sets of 10 and 14 patient samples. Results: Supervised analysis using differentially expressed genes was able to distinguish the two prognostic groups in the test set. The score correlated directly with clinical outcome, with higher scores associated with improved TTP. When the score was then applied to two independent sets of Stage III melanoma patient samples, it predicted clinical outcome accurately in 90% of samples. Conclusions: Stage IIIB and IIIC melanoma can be prognostically sub-classified according to the expression of 15 genes. To our knowledge this is the first study focused on Stage III disease using ex vivo patient samples. These results are encouraging and this genetic signature is currently being validated on a larger cohort. This method will allow appropriate stratification of stage III melanoma patients in adjuvant clinical trials, ameliorating the inherent biological heterogeneity that can confound these studies. [Table: see text]

scholarly journals OTHR-08. PREDICTION OF RISK OF CENTRAL NERVOUS SYSTEM METASTASIS FOR AJCC 8TH EDITION STAGE III MELANOMA PATIENTS

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i19-i20
Author(s):  
Lauren Haydu ◽  
Serigne Lo ◽  
Jennifer McQuade ◽  
Isabella Glitza ◽  
Hussein Tawbi ◽  
...  
Keyword(s):  
Primary Tumor ◽  
Cumulative Incidence ◽  
Mitotic Rate ◽  
Stage Iii ◽  
Primary Tumor Site ◽  
Cns Metastasis ◽  
Melanoma Patients ◽  
Stage Iii Melanoma ◽  
The Impact ◽  
8Th Edition

Abstract Among common solid tumors, melanoma has the highest risk of CNS metastasis. Improved understanding of the incidence, risk factors, and timing of CNS metastasis is needed to inform surveillance strategies for at-risk patients. Clinical data were extracted from two institutions for AJCC 8th edition stage III melanoma patients, diagnosed from 1998–2014 who had negative baseline CNS imaging within 4 months of diagnosis. The cumulative incidence of CNS metastasis was calculated in the presence of the competing risk of death from stage III presentation, and at benchmark time points 1-, 2-, and 5-years post-diagnosis. The cohort (N=1,918) consisted of patients from major melanoma centers in the US (50.6%) and Australia (49.4%). The first site of distant metastasis was CNS only for 3.9%, CNS and extra-cranial sites (ECS) for 1.9%, and ECS only for 31.2% of patients (N=1918); 15.5% of patients who developed distant metastases (N=708) had CNS involvement at first diagnosis of stage IV disease. Cumulative incidence of CNS metastasis from stage III diagnosis was 3.7% (95% Confidence Interval (CI): 2.9–4.6) at 1-year; 9.6% (95% CI: 8.3–11.0) at 2-years; and 15.9% (95% CI: 14.2–17.7) at 5-years. In multivariable analyses, risk of CNS metastasis was significantly higher for males; younger patients; increasing AJCC stage group; scalp primary tumor site, acral melanoma subtype, and increased primary tumor mitotic rate. Conditional analyses showed that only high primary tumor mitotic rate (&gt;9 per mm2) was significantly associated with risk of subsequent CNS metastasis among patients who survived without CNS recurrence 1-, 2-, and 5-years after the diagnosis of stage III disease. Similar rates of CNS metastasis were observed between these two large, geographically-distinct stage III melanoma patient cohorts. These results provide a framework for developing evidence-based surveillance strategies and for evaluating the impact of contemporary adjuvant therapies on the risk of melanoma CNS metastasis.

scholarly journals BRAF mutation correlates with worse local–regional control following radiation therapy in patients with stage III melanoma

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Adam R. Wolfe ◽  
Priyanka Chablani ◽  
Michael R. Siedow ◽  
Eric D. Miller ◽  
Steve Walston ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Radiation Therapy ◽  
Lymph Node ◽  
Regional Lymph Node ◽  
Stage Iii ◽  
Free Survival ◽  
Regional Control ◽  
Melanoma Patients ◽  
Stage Iii Melanoma ◽  
Local Regional Control

Abstract Background In patients with stage III melanoma, the use of adjuvant radiation therapy (RT) after lymph node dissection (LND) may be currently considered in selected high-risk patients to improve tumor control. Melanomas harbor BRAF mutations (BRAF+) in 40–50% of cases, the majority of which are on the V600E residue. This study sought to compare the clinical outcomes after RT between patients with BRAF+ and BRAF− melanoma. Methods This was a retrospective review of 105 Stage III melanoma patients treated at our institution with LND followed by adjuvant RT from 2006 to 2019. BRAF mutational status was determined on the primary skin or nodal tissue samples from all patients. We compared characteristics of the BRAF+ and BRAF− groups using Fisher’s exact test and Wilcoxon rank sum test and performed univariate and multivariate analysis using Kaplan–Meier estimates, log-rank tests, and Cox proportional hazards modeling with the clinical outcomes of local–regional lymph node control, distant metastasis-free survival (DMFS), recurrence-free survival (RFS), and overall survival (OS). Results Fifty-three (50%) patients harbored a BRAF mutation (92%, pV600E). BRAF+ patients were younger and had primary tumors more commonly found in the trunk vs head and neck compared to BRAF- patients (p < 0.05). The 5 year local–regional control in the BRAF + patients was 60% compared to 81% in the BRAF- patients (HR 4.5, 95% CI 1.3–15.5, p = 0.02). There were no significant differences in 5-year DMFS, RFS, and OS rates between the two BRAF patient groups. The presence of 4 or more positive LNs remained a significant prognostic factor for local–regional lymph node control, RFS, and OS in multivariate analysis. Conclusions Stage III melanoma patients with BRAF mutation treated with adjuvant RT had > 4 times increased risk of local recurrence or regional lymph node recurrence. These results could be useful for adjuvant RT consideration in lymph node positive melanoma patients and supports other data that BRAF mutation confers radiation resistance.

PP 3 S-100B concentrations predict disease specific survival in AJCC Stage III melanoma patients

2011 ◽  
Vol 47 ◽  
pp. S21
Author(s):  
S. Kruijff ◽  
E. Bastiaannet ◽  
M. Speijers ◽  
I. Kema ◽  
R. van Ginkel ◽  
...  
Keyword(s):  
Stage Iii ◽  
Disease Specific Survival ◽  
Ajcc Stage ◽  
Melanoma Patients ◽  
Stage Iii Melanoma ◽  
Disease Specific

Improved survival in stage III melanoma patients with GM2 antibodies: a randomized trial of adjuvant vaccination with GM2 ganglioside.

1994 ◽  
Vol 12 (5) ◽  
pp. 1036-1044 ◽  
Author(s):  
P O Livingston ◽  
G Y Wong ◽  
S Adluri ◽  
Y Tao ◽  
M Padavan ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stage Iii ◽  
Disease Free Interval ◽  
Free Interval ◽  
Ajcc Stage ◽  
Melanoma Patients ◽  
Stage Iii Melanoma ◽  
Receive Treatment ◽  
To Receive ◽  
Disease Free

PURPOSE To perform a double-blind randomized trial with American Joint Commission on Cancer (AJCC) stage III melanoma patients for the following reasons: (1) to confirm our previous finding that patients with antibodies against the melanoma differentiation antigen GM2 have an improved prognosis, and (2) to demonstrate clinical benefit from GM2 antibody induction. PATIENTS AND METHODS One hundred twenty-two patients with AJCC stage III melanoma who were free of disease after surgery were randomized: 58 to receive treatment with the GM2/BCG vaccine, and 64 to receive treatment with bacille Calmette-Guèrin (BCG) alone. All patients were pretreated with low-dose cyclophosphamide (Cy). RESULTS GM2 antibody was detected in 50 of 58 patients treated with GM2/BCG and seven of 64 patients treated with BCG alone. With a minimum follow-up period of 51 months, there was a highly significant increase in the disease-free interval (P = .004) and a 17% increase in overall survival (P = .02) in these 57 antibody-positive patients, confirming our earlier experience. Exclusion of all patients with preexisting GM2 antibodies (one in the GM2/BCG group and five in the BCG group) from statistical analysis resulted in a 23% increase in disease-free interval (P = .02) and a 14% increase in overall survival (P = .15) at 51 months for patients treated with the GM2/BCG vaccine. However, when all patients in the two treatment groups were compared as randomized, these increases were 18% for disease-free interval and 11% for survival in the GM2/BCG treatment group, with neither result showing statistical significance. CONCLUSION (1) Vaccination with GM2/BCG induced immunoglobulin M (IgM) antibodies in most patients. (2) GM2 antibody production was associated with a prolonged disease-free interval and survival. (3) Comparison of the two arms of this trial as randomized fails to show a statistically significant improvement in disease-free interval or survival for patients treated with GM2/BCG vaccines.

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