Dataset Information

Molecular stratification of metastatic melanoma using gene expression profiling: Prediction of survival outcome and benefit from molecular targeted therapy.

ABSTRACT: Melanoma is currently divided on a genetic level according to mutational status. However, this classification does not optimally predict prognosis. In prior studies, we have defined gene expression phenotypes (high-immune, pigmentation, proliferative and normal-like), which are predictive of survival outcome as well as informative of biology. Herein, we employed a population-based metastatic melanoma cohort and external cohorts to determine the prognostic and predictive significance of the gene expression phenotypes. We performed expression profiling on 214 cutaneous melanoma tumors and found an increased risk of developing distant metastases in the pigmentation (HR, 1.9; 95% CI, 1.05-3.28; P=0.03) and proliferative (HR, 2.8; 95% CI, 1.43-5.57; P=0.003) groups as compared to the high-immune response group. Further genetic characterization of melanomas using targeted deep-sequencing revealed similar mutational patterns across these phenotypes. We also used publicly available expression profiling data from melanoma patients treated with targeted or vaccine therapy in order to determine if our signatures predicted therapeutic response. In patients receiving targeted therapy, melanomas resistant to targeted therapy were enriched in the MITF-low proliferative subtype as compared to pre-treatment biopsies (P=0.02). In summary, the melanoma gene expression phenotypes are highly predictive of survival outcome and can further help to discriminate patients responding to targeted therapy.

SUBMITTER: Cirenajwis H

PROVIDER: S-EPMC4494939 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Molecular stratification of metastatic melanoma using gene expression profiling: Prediction of survival outcome and benefit from molecular targeted therapy.

Cirenajwis Helena H Ekedahl Henrik H Lauss Martin M Harbst Katja K Carneiro Ana A Enoksson Jens J Rosengren Frida F Werner-Hartman Linda L Törngren Therese T Kvist Anders A Fredlund Erik E Bendahl Pär-Ola PO Jirström Karin K Lundgren Lotta L Howlin Jillian J Borg Åke Å Gruvberger-Saal Sofia K SK Saal Lao H LH Nielsen Kari K Ringnér Markus M Tsao Hensin H Olsson Håkan H Ingvar Christian C Staaf Johan J Jönsson Göran G

Oncotarget 20150501 14

Melanoma is currently divided on a genetic level according to mutational status. However, this classification does not optimally predict prognosis. In prior studies, we have defined gene expression phenotypes (high-immune, pigmentation, proliferative and normal-like), which are predictive of survival outcome as well as informative of biology. Herein, we employed a population-based metastatic melanoma cohort and external cohorts to determine the prognostic and predictive significance of the gene ...[more]

PMID: 25909218

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Project description:Objective: Recently, performing locoregional surgical treatment still remains debatable in patients with metastatic breast cancer (MBC). Current study aimed to develop prognostic nomograms for predicting the long-term survival in MBC patients with or without surgical intervention, thereby assisting clinicians in making individualized choice. Methods: The training set included 5173 patients who were diagnosed with MBC in 2010-2013 from the Surveillance, Epidemiology, and End Results Program, while the validation set comprised 2924 patients diagnosed in 2014-2015. Multivariant Cox hazard model was applied to determine the independent risk factors for overall survival (OS) and breast cancer specific survival (BCSS). Then, individualized pre- and postoperative nomograms for predicting 1- or 3-year survival probabilities were constructed accordingly. Internal and external validations were conducted to determine the accuracy of these nomograms by calculating concordance index (C-index) and plotting calibration curves. Results: The survival analysis indicated that surgical management conferred improved OS and BCSS in patients with metastatic breast cancer. Age, T stage, grade, distant metastatic site, ER, PR and HER2 status, radiation, and chemotherapy were independent risk factors for OS and BCSS both in surgery and non-surgery group. All these factors were subsequently incorporated into the nomogram which showed acceptable predictive capabilities with C-index range of 0.65-0.80 both in training set and external validation set. In addition, a preoperative nomogram incorporating variables capable of being determined before surgery was also built with C-index above 0.70 both in training and validation set. Conclusion: Surgical management in patients with metastatic breast cancer suggests a potential survival advantage. In addition, these well-validated pre- and postoperative nomograms may provide a useful tool to assist clinicians in treatment decision-making and in evaluating patients' long term prognosis.

Project description:BackgroundAcral melanoma is a rare type of melanoma that affects world populations irrespective of skin color and has worse survival than other cutaneous melanomas. It has relatively few single nucleotide mutations without the UV signature of cutaneous melanomas, but instead has a genetic landscape characterized by structural rearrangements and amplifications. BRAF mutations are less common than in other cutaneous melanomas, and knowledge about alternative therapeutic targets is incomplete.MethodsTo identify alternative therapeutic targets, we performed targeted deep-sequencing on 122 acral melanomas. We confirmed the loss of the tumor suppressors p16 and NF1 by immunohistochemistry in select cases.ResultsIn addition to BRAF (21.3%), NRAS (27.9%), and KIT (11.5%) mutations, we identified a broad array of MAPK pathway activating alterations, including fusions of BRAF (2.5%), NTRK3 (2.5%), ALK (0.8%), and PRKCA (0.8%), which can be targeted by available inhibitors. Inactivation of NF1 occurred in 18 cases (14.8%). Inactivation of the NF1 cooperating factor SPRED1 occurred in eight cases (6.6%) as an alternative mechanism of disrupting the negative regulation of RAS. Amplifications recurrently affected narrow loci containing PAK1 and GAB2 (n = 27, 22.1%), CDK4 (n = 27, 22.1%), CCND1 (n = 24, 19.7%), EP300 (n = 20, 16.4%), YAP1 (n = 15, 12.3%), MDM2 (n = 13, 10.7%), and TERT (n = 13, 10.7%) providing additional and possibly complementary therapeutic targets. Acral melanomas with BRAFV600E mutations harbored fewer genomic amplifications and were more common in patients with European ancestry.ConclusionOur findings support a new, molecularly based subclassification of acral melanoma with potential therapeutic implications: BRAFV600E mutant acral melanomas with characteristics similar to nonacral melanomas that could benefit from BRAF inhibitor therapy, and non-BRAFV600E mutant acral melanomas. Acral melanomas without BRAFV600E mutations harbor a broad array of therapeutically relevant alterations. Expanded molecular profiling would increase the detection of potentially targetable alterations for this subtype of acral melanoma.

Dataset Information

Molecular stratification of metastatic melanoma using gene expression profiling: Prediction of survival outcome and benefit from molecular targeted therapy.

Publications

Molecular stratification of metastatic melanoma using gene expression profiling: Prediction of survival outcome and benefit from molecular targeted therapy.

Similar Datasets

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