| 1. |
- Ingvar, Åsa M, et al.
(författare)
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Participation in a Prospective Cohort Study on Melanoma did not Affect the Incidence and Mortality of the Studied Disease
- 2020
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Ingår i: Acta Dermato-Venereologica. - : Medical Journals Sweden AB. - 1651-2057 .- 0001-5555. ; 100:1
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Tidskriftsartikel (refereegranskat)abstract
- Prospective observational studies have shown previously that study participants have lower morbidity and mortality than non-participants. The aim of the current study was to determine whether participants in a prospective cohort study on melanoma have a different incidence and mortality of melanoma compared with non-participants and the background population. Information was collected from Swedish National Registers on participants (n = 30,501) and non-participants (n = 10,499) in the "Melanoma In Southern Sweden" (MISS) study and the background population (n = 243,032). Hazard ratios were calculated for overall incidence of cancer and melanoma, and all-cause and melanoma-specific mortality, using Cox regression. Participants had a lower overall incidence of cancer and all-cause mortality than non-participants and the background population. There was no difference in incidence of melanoma or melanoma-specific characteristics between participants and the background population. In conclusion, participants in the MISS study have a slightly better general health, but are a representative sample of the population with regard to studies of melanoma risk factors.
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| 2. |
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| 3. |
- Sanna, Adriana, et al.
(författare)
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Tumor genetic heterogeneity analysis of chronic sun-damaged melanoma
- 2020
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Ingår i: Pigment Cell & Melanoma Research. - : Wiley. - 1755-148X .- 1755-1471. ; 33:3, s. 480-489
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Tidskriftsartikel (refereegranskat)abstract
- Chronic sun-damaged (CSD) melanoma represents 10%-20% of cutaneous melanomas and is characterized by infrequent BRAF V600E mutations and high mutational load. However, the order of genetic events or the extent of intra-tumor heterogeneity (ITH) in CSDhigh melanoma is still unknown. Ultra-deep targeted sequencing of 40 cancer-associated genes was performed in 72 in situ or invasive CMM, including 23 CSDhigh cases. In addition, we performed whole exome and RNA sequencing on multiple regions of primary tumor and multiple in-transit metastases from one CSDhigh melanoma patient. We found no significant difference in mutation frequency in melanoma-related genes or in mutational load between in situ and invasive CSDhigh lesions, while this difference was observed in CSDlow lesions. In addition, increased frequency of BRAF V600K, NF1, and TP53 mutations (p < .01, Fisher's exact test) was found in CSDhigh melanomas. Sequencing of multiple specimens from one CSDhigh patient revealed strikingly limited ITH with >95% shared mutations. Our results provide evidence that CSDhigh and CSDlow melanomas are distinct molecular entities that progress via different genetic routes.
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| 4. |
- Sanna, Adriana, et al.
(författare)
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Tumor genetic heterogeneity analysis of chronic sun-damaged melanoma.
- 2020
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Ingår i: Pigment cell & melanoma research. - : Wiley-Blackwell. - 1755-148X. ; 33:3, s. 480-489
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Tidskriftsartikel (refereegranskat)abstract
- Chronic sun-damaged (CSD) melanoma represents 10%-20% of cutaneous melanomas and is characterized by infrequent BRAF V600E mutations and high mutational load. However, the order of genetic events or the extent of intra-tumor heterogeneity (ITH) in CSDhigh melanoma is still unknown. Ultra-deep targeted sequencing of 40 cancer-associated genes was performed in 72 in situ or invasive CMM, including 23 CSDhigh cases. In addition, we performed whole exome and RNA sequencing on multiple regions of primary tumor and multiple in-transit metastases from one CSDhigh melanoma patient. We found no significant difference in mutation frequency in melanoma-related genes or in mutational load between in situ and invasive CSDhigh lesions, while this difference was observed in CSDlow lesions. In addition, increased frequency of BRAF V600K, NF1, and TP53 mutations (p < .01, Fisher's exact test) was found in CSDhigh melanomas. Sequencing of multiple specimens from one CSDhigh patient revealed strikingly limited ITH with >95% shared mutations. Our results provide evidence that CSDhigh and CSDlow melanomas are distinct molecular entities that progress via different genetic routes.
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| 5. |
- Berta, Judit, et al.
(författare)
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Apelin promotes blood and lymph vessel formation and the growth of melanoma lung metastasis
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Apelin, a ligand of the APJ receptor, is overexpressed in several human cancers and plays an important role in tumor angiogenesis and growth in various experimental systems. We investigated the role of apelin signaling in the malignant behavior of cutaneous melanoma. Murine B16 and human A375 melanoma cell lines were stably transfected with apelin encoding or control vectors. Apelin overexpression significantly increased melanoma cell migration and invasion in vitro, but it had no impact on its proliferation. In our in vivo experiments, apelin significantly increased the number and size of lung metastases of murine melanoma cells. Melanoma cell proliferation rates and lymph and blood microvessel densities were significantly higher in the apelin-overexpressing pulmonary metastases. APJ inhibition by the competitive APJ antagonist MM54 significantly attenuated the in vivo pro-tumorigenic effects of apelin. Additionally, we detected significantly elevated circulating apelin and VEGF levels in patients with melanoma compared to healthy controls. Our results show that apelin promotes blood and lymphatic vascularization and the growth of pulmonary metastases of skin melanoma. Further studies are warranted to validate apelin signaling as a new potential therapeutic target in this malignancy.
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| 6. |
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| 7. |
- 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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| 8. |
- Cabrita, Rita, et al.
(författare)
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Tertiary lymphoid structures improve immunotherapy and survival in melanoma
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 577:7791, s. 561-565
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Tidskriftsartikel (refereegranskat)abstract
- Checkpoint blockade therapies that reactivate tumour-associated T cells can induce durable tumour control and result in the long-term survival of patients with advanced cancers1. Current predictive biomarkers for therapy response include high levels of intratumour immunological activity, a high tumour mutational burden and specific characteristics of the gut microbiota2,3. Although the role of T cells in antitumour responses has thoroughly been studied, other immune cells remain insufficiently explored. Here we use clinical samples of metastatic melanomas to investigate the role of B cells in antitumour responses, and find that the co-occurrence of tumour-associated CD8+ T cells and CD20+ B cells is associated with improved survival, independently of other clinical variables. Immunofluorescence staining of CXCR5 and CXCL13 in combination with CD20 reveals the formation of tertiary lymphoid structures in these CD8+CD20+ tumours. We derived a gene signature associated with tertiary lymphoid structures, which predicted clinical outcomes in cohorts of patients treated with immune checkpoint blockade. Furthermore, B-cell-rich tumours were accompanied by increased levels of TCF7+ naive and/or memory T cells. This was corroborated by digital spatial-profiling data, in which T cells in tumours without tertiary lymphoid structures had a dysfunctional molecular phenotype. Our results indicate that tertiary lymphoid structures have a key role in the immune microenvironment in melanoma, by conferring distinct T cell phenotypes. Therapeutic strategies to induce the formation of tertiary lymphoid structures should be explored to improve responses to cancer immunotherapy.
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| 9. |
- Cabrita, Rita, et al.
(författare)
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Tertiary lymphoid structures improve immunotherapy and survival in melanoma.
- 2020
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Ingår i: Nature. - : Nature Publishing Group. - 1476-4687 .- 0028-0836. ; 577:7791, s. 561-565
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Tidskriftsartikel (refereegranskat)abstract
- Checkpoint blockade therapies that reactivate tumour-associated T cells can induce durable tumour control and result in the long-term survival of patients with advanced cancers1. Current predictive biomarkers for therapy response include high levels of intratumour immunological activity, a high tumour mutational burden and specific characteristics of the gut microbiota2,3. Although the role of T cells in antitumour responses has thoroughly been studied, other immune cells remain insufficiently explored. Here we use clinical samples of metastatic melanomas to investigate the role of B cells in antitumour responses, and find that the co-occurrence of tumour-associated CD8+ T cells and CD20+ B cells is associated with improved survival, independently of other clinical variables. Immunofluorescence staining of CXCR5 and CXCL13 in combination with CD20 reveals the formation of tertiary lymphoid structures in these CD8+CD20+ tumours. We derived a gene signature associated with tertiary lymphoid structures, which predicted clinical outcomes in cohorts of patients treated with immune checkpoint blockade. Furthermore, B-cell-rich tumours were accompanied by increased levels of TCF7+ naive and/or memory T cells. This was corroborated by digital spatial-profiling data, in which T cells in tumours without tertiary lymphoid structures had a dysfunctional molecular phenotype. Our results indicate that tertiary lymphoid structures have a key role in the immune microenvironment in melanoma, by conferring distinct T cell phenotypes. Therapeutic strategies to induce the formation of tertiary lymphoid structures should be explored to improve responses to cancer immunotherapy.
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| 10. |
- 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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