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- Betancourt, Lazaro Hiram, et al.
(författare)
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The human melanoma proteome atlas-Defining the molecular pathology
- 2021
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Ingår i: Clinical and Translational Medicine. - : Wiley. - 2001-1326. ; 11:7, s. 1-20
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Tidskriftsartikel (refereegranskat)abstract
- The MM500 study is an initiative to map the protein levels in malignant melanoma tumor samples, focused on in-depth histopathology coupled to proteome characterization. The protein levels and localization were determined for a broad spectrum of diverse, surgically isolated melanoma tumors originating from multiple body locations. More than 15,500 proteoforms were identified by mass spectrometry, from which chromosomal and subcellular localization was annotated within both primary and metastatic melanoma. The data generated by global proteomic experiments covered 72% of the proteins identified in the recently reported high stringency blueprint of the human proteome. This study contributes to the NIH Cancer Moonshot initiative combining detailed histopathological presentation with the molecular characterization for 505 melanoma tumor samples, localized in 26 organs from 232 patients.
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- Betancourt, Lazaro Hiram, et al.
(författare)
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Improved survival prognostication of node-positive malignant melanoma patients utilizing shotgun proteomics guided by histopathological characterization and genomic data
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Metastatic melanoma is one of the most common deadly cancers, and robust biomarkers are still needed, e.g. to predict survival and treatment efficiency. Here, protein expression analysis of one hundred eleven melanoma lymph node metastases using high resolution mass spectrometry is coupled with in-depth histopathology analysis, clinical data and genomics profiles. This broad view of protein expression allowed to identify novel candidate protein markers that improved prediction of survival in melanoma patients. Some of the prognostic proteins have not been reported in the context of melanoma before, and few of them exhibit unexpected relationship to survival, which likely reflects the limitations of current knowledge on melanoma and shows the potential of proteomics in clinical cancer research.
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| 7. |
- Cabrita, Rita, et al.
(författare)
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The Role of PTEN Loss in Immune Escape, Melanoma Prognosis and Therapy Response
- 2020
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 12:3
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Tidskriftsartikel (refereegranskat)abstract
- Checkpoint blockade therapies have changed the clinical management of metastatic melanoma patients considerably, showing survival benefits. Despite the clinical success, not all patients respond to treatment or they develop resistance. Although there are several treatment predictive biomarkers, understanding therapy resistance and the mechanisms of tumor immune evasion is crucial to increase the frequency of patients benefiting from treatment. The PTEN gene is thought to promote immune evasion and is frequently mutated in cancer and melanoma. Another feature of melanoma tumors that may affect the capacity of escaping T-cell recognition is melanoma cell dedifferentiation characterized by decreased expression of the microphtalmia-associated transcription factor (MITF) gene. In this study, we have explored the role of PTEN in prognosis, therapy response, and immune escape in the context of MITF expression using immunostaining and genomic data from a large cohort of metastatic melanoma. We confirmed in our cohort that PTEN alterations promote immune evasion highlighted by decreased frequency of T-cell infiltration in such tumors, resulting in a worse patient survival. More importantly, our results suggest that dedifferentiated PTEN negative melanoma tumors have poor patient outcome, no T-cell infiltration, and transcriptional properties rendering them resistant to targeted- and immuno-therapy.
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| 8. |
- Cirenajwis, Helena, et al.
(författare)
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Molecular stratification of metastatic melanoma using gene expression profiling: prediction of survival outcome and benefit from molecular targeted therapy.
- 2015
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 6:14, s. 12297-12309
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Tidskriftsartikel (refereegranskat)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.
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| 9. |
- Cirenajwis, Helena, et al.
(författare)
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NF1-mutated melanoma tumors harbor distinct clinical and biological characteristics
- 2017
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Ingår i: Molecular Oncology. - : Wiley. - 1574-7891. ; 11:4, s. 438-451
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Tidskriftsartikel (refereegranskat)abstract
- In general, melanoma can be considered as a UV-driven disease with an aggressive metastatic course and high mutational load, with only few tumors (acral, mucosal, and uveal melanomas) not induced by sunlight and possessing a lower mutational load. The most commonly activated pathway in melanoma is the mitogen-activated protein kinase (MAPK) pathway. However, the prognostic significance of mutational stratification is unclear and needs further investigation. Here, in silico we combined mutation data from 162 melanomas subjected to targeted deep sequencing with mutation data from three published studies. Tumors from 870 patients were grouped according to BRAF, RAS, NF1 mutation or triple-wild-type status and correlated with tumor and patient characteristics. We found that the NF1-mutated subtype had a higher mutational burden and strongest UV mutation signature. Searching for co-occurring mutated genes revealed the RASopathy genes PTPN11 and RASA2, as well as another RAS domain-containing gene RASSF2 enriched in the NF1 subtype after adjustment for mutational burden. We found that a larger proportion of the NF1-mutant tumors were from males and with older age at diagnosis. Importantly, we found an increased risk of death from melanoma (disease-specific survival, DSS; HR, 1.9; 95% CI, 1.21-3.10; P = 0.046) and poor overall survival (OS; HR, 2.0; 95% CI, 1.28-2.98; P = 0.01) in the NF1 subtype, which remained significant after adjustment for age, gender, and lesion type (DSS P = 0.03, OS P = 0.06, respectively). Melanoma genomic subtypes display different biological and clinical characteristics. The poor outcome observed in the NF1 subtype highlights the need for improved characterization of this group.
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| 10. |
- Ekedahl, Henrik
(författare)
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Clinical aspects of molecular profiles in metastatic malignant melanoma
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Malignant melanoma is a heterogeneous, malignant neoplastic disease, most often originating in the skin. Melanoma is characterized by a high mutational load and has a vastly variable prognosis, depending on disease stage. Genetic aberrations in the mitogen-activating protein kinase (MAPK) pathway are important in melanoma, of which mutations in BRAF and NRAS are the most common. Additionally, recurrent mutations in the promoter of TERT, the catalytic subunit of telomerase, have been associated with a poor prognosis in primary melanoma. The introduction of the first T-cell activating antibody, ipilimumab, and the first selective inhibitor of mutant BRAF, vemurafenib, marked the beginning of a new paradigm in the treatment of metastatic melanoma. The rapidly increasing number of treatment options warrants improved prognostic and predictive capability. The aim of this thesis was to examine clinical aspects, in particular prognostic and predictive values, of mutational and transcriptional profiles in metastatic melanoma.Frozen tumor samples from the Lund Melanoma Study Group molecular melanoma cohort were subjected to mutation analysis of BRAF, NRAS (paper I), and the TERT promoter (paper III), as well as global gene expressionanalysis and deep targeted sequencing (paper II). Patients with BRAF-mutant tumors not treated with BRAF inhibitor showed an inferior overall survival from stage IV disease compared with patients treated with BRAF inhibitor (hazard ratio (HR) 2.35, confidence interval (CI) 1.10-5.01). There was a trend towards better prognosis for patients with wildtype tumors compared with BRAFV600E-mutants (HR 0.64, CI 0.39-1.04). TERT promoter mutations were not associated with prognosis in non-acral cutaneous metastatic melanoma. Two hundredfourteen melanoma samples, mostly metastases, were classified into four gene expression phenotypes, reflecting distinct biological features: ‘proliferative’, ‘pigmentation’, ‘high-immune response’, and ‘normal-like’. Mutationalpatterns were similar across the phenotypes. Among patients with regional metastatic disease, the proliferative and the pigmentation phenotypes were associated with an increased risk of distant metastasis (HR 2.8, CI 1.43-5.57, and HR 1.9, CI 1.05-3.28) compared with the high-immune response phenotype. In two external datasets, the proliferative phenotype was found to be enriched in tumors progressing on MAPK inhibition. In paper IV, the one-year clinical use of a next generation sequencing-based 26-genes mutation panel in advanced melanoma was characterized in relation to given treatment. The fraction of BRAF hotspot-mutant alleles was highly heterogeneous, and patients with tumors harboring a fraction in the highest and lowest deciles progressed early on MAPK inhibition. In conclusion, metastatic melanoma displays various mutational and transcriptional profiles, relevant for prognosis and treatment prediction.
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