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- 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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- Ekblom Bak, Elin, 1981-, et al.
(författare)
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Accelerometer derived physical activity patterns in 27.890 middle‐aged adults : The SCAPIS cohort study
- 2022
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Ingår i: Scandinavian Journal of Medicine and Science in Sports. - : John Wiley & Sons. - 0905-7188 .- 1600-0838. ; 32:5, s. 866-880
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Tidskriftsartikel (refereegranskat)abstract
- The present study aims to describe accelerometer-assessed physical activity (PA) patterns and fulfillment of PA recommendations in a large sample of middle-aged men and women, and to study differences between subgroups of socio-demographic, socio-economic, and lifestyle-related variables. A total of 27 890 (92.5% of total participants, 52% women, aged 50–64 years) middle-aged men and women with at least four days of valid hip-worn accelerometer data (Actigraph GT3X+, wGT3X+ and wGT3X-BT) from the Swedish CArdioPulmonary bioImage Study, SCAPIS, were included. In total, 54.5% of daily wear time was spent sedentary, 39.1% in low, 5.4% in moderate, and only 0.1% in vigorous PA. Male sex, higher education, low financial strain, born in Sweden, and sedentary/light working situation were related to higher sedentary time, but also higher levels of vigorous PA. High BMI and having multiple chronic diseases associated strongly with higher sedentary time and less time in all three PA intensities. All-year physically active commuters had an overall more active PA pattern. The proportion fulfilling current PA recommendations varied substantially (1.4% to 92.2%) depending on data handling procedures and definition used. Twenty-eight percent was defined as having an “at-risk” behavior, which included both high sedentary time and low vigorous PA. In this large population-based sample, a majority of time was spent sedentary and only a fraction in vigorous PA, with clinically important variations between subgroups. This study provides important reference material and emphasizes the importance of a comprehensive assessment of all aspects of the individual PA pattern in future research and clinical practice.
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- Eriksson, Daniel, et al.
(författare)
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Cytokine Autoantibody Screening in the Swedish Addison Registry Identifies Patients With Undiagnosed APS1
- 2018
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 103:1, s. 179-186
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Tidskriftsartikel (refereegranskat)abstract
- Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features autoimmune Addison disease as a major component. Although APS1 accounts for only a small fraction of all patients with Addison disease, early identification of these individuals is vital to prevent the potentially lethal complications of APS1.Objective: To determine whether available serological and genetic markers are valuable screening tools for the identification of APS1 among patients diagnosed with Addison disease.Design: We systematically screened 677 patients with Addison disease enrolled in the Swedish Addison Registry for autoantibodies against interleukin-22 and interferon-α4. Autoantibody-positive patients were investigated for clinical manifestations of APS1, additional APS1-specific autoantibodies, and DNA sequence and copy number variations of AIRE.Results: In total, 17 patients (2.5%) displayed autoantibodies against interleukin-22 and/or interferon-α4, of which nine were known APS1 cases. Four patients previously undiagnosed with APS1 fulfilled clinical, genetic, and serological criteria. Hence, we identified four patients with undiagnosed APS1 with this screening procedure.Conclusion: We propose that patients with Addison disease should be routinely screened for cytokine autoantibodies. Clinical or serological support for APS1 should warrant DNA sequencing and copy number analysis of AIRE to enable early diagnosis and prevention of lethal complications.
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- Harbst, Katja, et al.
(författare)
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Multiregion whole-exome sequencing uncovers the genetic evolution and mutational heterogeneity of early-stage metastatic melanoma
- 2016
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Ingår i: Cancer Research. - 0008-5472. ; 76:16, s. 4765-4774
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Tidskriftsartikel (refereegranskat)abstract
- Cancer genome sequencing has shed light on the underlying genetic aberrations that drive tumorigenesis. However, current sequencing-based strategies, which focus on a single tumor biopsy, fail to take into account intratumoral heterogeneity. To address this challenge and elucidate the evolutionary history of melanoma, we performed whole-exome and transcriptome sequencing of 41 multiple melanoma biopsies from eight individual tumors. This approach revealed heterogeneous somatic mutations in the range of 3%-38% in individual tumors. Known mutations in melanoma drivers BRAF and NRAS were always ubiquitous events. Using RNA sequencing, we found that the majority of mutations were not expressed or were expressed at very low levels, and preferential expression of a particular mutated allele did not occur frequently. In addition, we found that the proportion of ultraviolet B (UVB) radiation-induced C>T transitions differed significantly (P <0.001) between early and late mutation acquisition, suggesting that different mutational processes operate during the evolution of metastatic melanoma. Finally, clinical history reports revealed that patients harboring a high degree of mutational heterogeneity were associated with more aggressive disease progression. In conclusion, our multiregion tumor-sequencing approach highlights the genetic evolution and non-UVB mutational signatures associated with melanoma development and progression, and may provide a more comprehensive perspective of patient outcome.
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| 8. |
- Karlsson, Anna K, et al.
(författare)
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Mutational and gene fusion analyses of primary large cell and large cell neuroendocrine lung cancer.
- 2015
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Ingår i: Oncotarget. - 1949-2553. ; 6:26, s. 22028-22037
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Tidskriftsartikel (refereegranskat)abstract
- Large cell carcinoma with or without neuroendocrine features (LCNEC and LC, respectively) constitutes 3-9% of non-small cell lung cancer but is poorly characterized at the molecular level. Herein we analyzed 41 LC and 32 LCNEC (including 15 previously reported cases) tumors using massive parallel sequencing for mutations in 26 cancer-related genes and gene fusions in ALK, RET, and ROS1. LC patients were additionally subdivided into three immunohistochemistry groups based on positive expression of TTF-1/Napsin A (adenocarcinoma-like, n = 24; 59%), CK5/P40 (squamous-like, n = 5; 12%), or no marker expression (marker-negative, n = 12; 29%). Most common alterations were TP53 (83%), KRAS (22%), MET (12%) mutations in LCs, and TP53 (88%), STK11 (16%), and PTEN (13%) mutations in LCNECs. In general, LCs showed more oncogene mutations compared to LCNECs. Immunomarker stratification of LC revealed oncogene mutations in 63% of adenocarcinoma-like cases, but only in 17% of marker-negative cases. Moreover, marker-negative LCs were associated with inferior overall survival compared with adenocarcinoma-like tumors (p = 0.007). No ALK, RET or ROS1 fusions were detected in LCs or LCNECs. Together, our molecular analyses support that LC and LCNEC tumors follow different tumorigenic paths and that LC may be stratified into molecular subgroups with potential implications for diagnosis, prognostics, and therapy decisions.
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| 9. |
- Lauss, Martin, et al.
(författare)
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Genome-Wide DNA Methylation Analysis in Melanoma Reveals the Importance of CpG Methylation in MITF Regulation.
- 2015
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 1523-1747 .- 0022-202X. ; 135:7, s. 1820-1828
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Tidskriftsartikel (refereegranskat)abstract
- The microphthalmia-associated transcription factor (MITF) is a key regulator of melanocyte development and a lineage-specific oncogene in melanoma; a highly lethal cancer known for its unpredictable clinical course. MITF is regulated by multiple intracellular signaling pathways although the exact mechanisms that determine MITF expression and activity remain incompletely understood. In this study, we obtained genome-wide DNA methylation profiles from 50 stage IV melanomas, normal melanocytes, keratinocytes and dermal fibroblasts, and utilized The Cancer Genome Atlas (TCGA) data for experimental validation. By integrating DNA methylation and gene expression data we found that hypermethylation of MITF and its co-regulated differentiation pathway genes, corresponded to decreased gene expression levels. In cell lines with a hypermethylated MITF-pathway, over-expression of MITF did not alter the expression level or methylation status of the MITF pathway genes. In contrast however, demethylation treatment of these cell lines induced MITF-pathway activity, confirming that gene-regulation was controlled via methylation. The discovery that the activity of the master regulator of pigmentation, MITF, and its downstream targets may be regulated by hypermethylation has significant implications for understanding the development and evolvement of melanoma.Journal of Investigative Dermatology accepted article preview online, 23 February 2015. doi:10.1038/jid.2015.61.
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| 10. |
- Lauss, Martin, et al.
(författare)
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Mutational and putative neoantigen load predict clinical benefit of adoptive T cell therapy in melanoma
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Adoptive T-cell therapy (ACT) is a highly intensive immunotherapy regime that has yielded remarkable response rates and many durable responses in clinical trials in melanoma; however, 50-60% of the patients have no clinical benefit. Here, we searched for predictive biomarkers to ACT in melanoma. Whole exome-and transcriptome sequencing and neoantigen prediction were applied to pre-treatment samples from 27 patients recruited to a clinical phase I/II trial of ACT in stage IV melanoma. All patients had previously progressed on other immunotherapies. We report that clinical benefit is associated with significantly higher predicted neoantigen load. High mutation and predicted neoantigen load are significantly associated with improved progression-free and overall survival. Further, clinical benefit is associated with the expression of immune activation signatures including a high MHC-I antigen processing and presentation score. These results improve our understanding of mechanisms behind clinical benefit of ACT in melanoma.
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