| 1. |
- Huvila, J., et al.
(författare)
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Combined ASRGL1 and p53 immunohistochemistry as an independent predictor of survival in endometrioid endometrial carcinoma
- 2018
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Ingår i: Gynecologic Oncology. - : Academic Press Inc.. - 0090-8258 .- 1095-6859. ; 149:1, s. 173-180
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Tidskriftsartikel (refereegranskat)abstract
- Objective: In clinical practise, prognostication of endometrial cancer is based on clinicopathological risk factors. The use of immunohistochemistry-based markers as prognostic tools is generally not recommended and a systematic analysis of their utility as a panel is lacking. We evaluated whether an immunohistochemical marker panel could reliably assess endometrioid endometrial cancer (EEC) outcome independent of clinicopathological information. Methods: A cohort of 306 EEC specimens was profiled using tissue microarray (TMA). Cost- and time-efficient immunohistochemical analysis of well-established tissue biomarkers (ER, PR, HER2, Ki-67, MLH1 and p53) and two new biomarkers (L1CAM and ASRGL1) was carried out. Statistical modelling with embedded variable selection was applied on the staining results to identify minimal prognostic panels with maximal prognostic accuracy without compromising generalizability. Results: A panel including p53 and ASRGL1 immunohistochemistry was identified as the most accurate predictor of relapse-free and disease-specific survival. Within this panel, patients were allocated into high- (5.9%), intermediate- (29.5%) and low- (64.6%) risk groups where high-risk patients had a 30-fold risk (P < 0.001) of dying of EEC compared to the low-risk group. Conclusions: P53 and ASRGL1 immunoprofiling stratifies EEC patients into three risk groups with significantly different outcomes. This simple and easily applicable panel could provide a useful tool in EEC risk stratification and guiding the allocation of treatment modalities.
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| 2. |
- Jotanovic, Jelena, et al.
(författare)
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Transcriptome Analysis Reveals Distinct Patterns Between the Invasive and Noninvasive Pituitary Neuroendocrine Tumors
- 2024
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Ingår i: Journal of the Endocrine Society. - : Oxford University Press. - 2472-1972. ; 8:5
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Tidskriftsartikel (refereegranskat)abstract
- Although most pituitary neuroendocrine tumors (PitNETs)/pituitary adenomas remain intrasellar, a significant proportion of tumors show parasellar invasive growth and 6% to 8% infiltrate the bone structures, thus affecting the prognosis. There is an unmet need to identify novel markers that can predict the parasellar growth of PitNETs. Furthermore, mechanisms that regulate bone invasiveness of PitNETs and factors related to tumor vascularization are largely unknown.We used genome-wide mRNA analysis in a cohort of 77 patients with PitNETs of different types to explore the differences in gene expression patterns between invasive and noninvasive tumors with respect to the parasellar growth and regarding the rare phenomenon of bone invasiveness. Additionally, we studied the genes correlated to the contrast enhancement quotient, a novel radiological parameter of tumor vascularization.Most of the genes differentially expressed related to the parasellar growth were genes involved in tumor invasiveness. Differentially expressed genes associated with bone invasiveness are involved in NF-κB pathway and antitumoral immune response. Lack of clear clustering regarding the parasellar and bone invasiveness may be explained by the influence of the cell lineage-related genes in this heterogeneous cohort of PitNETs.Our transcriptomics analysis revealed differences in the molecular fingerprints between invasive, including bone invasive, and noninvasive PitNETs, although without clear clustering. The contrast enhancement quotient emerged as a radiological parameter of tumor vascularization, correlating with several angiogenesis-related genes. Several of the top genes related to the PitNET invasiveness and vascularization have potential prognostic and therapeutic application requiring further research.
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| 3. |
- Djureinovic, Dijana, et al.
(författare)
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Profiling cancer testis antigens in non-small-cell lung cancer
- 2016
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Ingår i: JCI INSIGHT. - : American Society for Clinical Investigation. - 2379-3708. ; 1:10
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Tidskriftsartikel (refereegranskat)abstract
- Cancer testis antigens (CTAs) are of clinical interest as biomarkers and present valuable targets for immunotherapy. To comprehensively characterize the CTA landscape of non-small-cell lung cancer (NSCLC), we compared RNAseq data from 199 NSCLC tissues to the normal transcriptome of 142 samples from 32 different normal organs. Of 232 CTAs currently annotated in the Caner Testis Database (CTdatabase), 96 were confirmed in NSCLC. To obtain an unbiased CTA profile of NSCLC, we applied stringent criteria on our RNAseq data set and defined 90 genes as CTAs, of which 55 genes were not annotated in the CTdatabase, thus representing potential new CTAs. Cluster analysis revealed that CTA expression is histology dependent and concurrent expression is common. IHC confirmed tissue-specific protein expression of selected new CTAs (TKTL1, TGIF2LX, VCX, and CXORF67). Furthermore, methylation was identified as a regulatory mechanism of CTA expression based on independent data from The Cancer Genome Atlas. The proposed prognostic impact of CTAs in lung cancer was not confirmed, neither in our RNAseq cohort nor in an independent meta-analysis of 1,117 NSCLC cases. In summary, we defined a set of 90 reliable CTAs, including information on protein expression, methylation, and survival association. The detailed RNAseq catalog can guide biomarker studies and efforts to identify targets for immunotherapeutic strategies.
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| 4. |
- Walinder, Göran, et al.
(författare)
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Outcome and characteristics of non-measurable myeloma : A cohort study with population-based data from the Swedish Myeloma Registry
- 2020
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Ingår i: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 104:5, s. 376-382
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Tidskriftsartikel (refereegranskat)abstract
- Objective We describe survival in patients with oligo- and non-secretory multiple myeloma (MM). We refer to the whole group as non-measurable MM and compare it with secretory MM. Methods Oligo-secretory MM was defined as M protein in serum <10 g/L and M protein in urine <200 measured as mg/day, mg/liter or mg/mmol creatinine. If patients had no M protein, they were defined as non-secretory. The groups were also subdivided by Free Light Chains (SFLC) level and ratio. Results Out of 4325 patients with symptomatic MM in the Swedish Myeloma Registry during 2008-2016 eligible for the study, 389 patients (9%) had non-measurable MM. Out of these, 253 patients (6%) had oligo-secretory and 136 (3%) had non-secretory MM. Median survival for secretory MM was 42.7 months, non-measurable MM 40.2 months, oligo-secretory MM 38.6 months, and non-secretory MM 44.6 months. Difference in overall observed survival was non-significant for all groups when compared with secretory MM. Within non-secretory MM, stem cell transplantation (SCT), 95% being auto-SCT, was significant for superior survival in multivariate analysis (HR 0.048. P = .0015). Conclusion In this population-based study, we found no difference in survival between oligo- or non-secretory MM when compared with secretory MM. SCT appears to be important also for patients with non-secretory disease.
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| 5. |
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| 6. |
- Glimelius, Bengt, et al.
(författare)
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U-CAN : a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.
- 2018
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Ingår i: Acta Oncologica. - : Taylor & Francis. - 0284-186X .- 1651-226X. ; 57:2, s. 187-194
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Tidskriftsartikel (refereegranskat)abstract
- Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.
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| 7. |
- Zhang, C., et al.
(författare)
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LIPG-promoted lipid storage mediates adaptation to oxidative stress in breast cancer
- 2019
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 145:4, s. 901-915
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Tidskriftsartikel (refereegranskat)abstract
- Endothelial lipase (LIPG) is a cell surface associated lipase that displays phospholipase A1 activity towards phosphatidylcholine present in high‐density lipoproteins (HDL). LIPG was recently reported to be expressed in breast cancer and to support proliferation, tumourigenicity and metastasis. Here we show that severe oxidative stress leading to AMPK activation triggers LIPG upregulation, resulting in intracellular lipid droplet accumulation in breast cancer cells, which supports survival. Neutralizing oxidative stress abrogated LIPG upregulation and the concomitant lipid storage. In human breast cancer, high LIPG expression was observed in a limited subset of tumours and was significantly associated with shorter metastasis‐free survival in node‐negative, untreated patients. Moreover, expression of PLIN2 and TXNRD1 in these tumours indicated a link to lipid storage and oxidative stress. Altogether, our findings reveal a previously unrecognized role for LIPG in enabling oxidative stress‐induced lipid droplet accumulation in tumour cells that protects against oxidative stress, and thus supports tumour progression.
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| 8. |
- Bauer, Wolfgang, et al.
(författare)
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Plasma Proteome Fingerprints Reveal Distinctiveness and Clinical Outcome of SARS-CoV-2 Infection
- 2021
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Ingår i: Viruses. - : MDPI. - 1999-4915. ; 13:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: We evaluated how plasma proteomic signatures in patients with suspected COVID-19 can unravel the pathophysiology, and determine kinetics and clinical outcome of the infection.Methods: Plasma samples from patients presenting to the emergency department (ED) with symptoms of COVID-19 were stratified into: (1) patients with suspected COVID-19 that was not confirmed (n = 44); (2) non-hospitalized patients with confirmed COVID-19 (n = 44); (3) hospitalized patients with confirmed COVID-19 (n = 53) with variable outcome; and (4) patients presenting to the ED with minor diseases unrelated to SARS-CoV-2 infection (n = 20). Besides standard of care diagnostics, 177 circulating proteins related to inflammation and cardiovascular disease were analyzed using proximity extension assay (PEA, Olink) technology.Results: Comparative proteome analysis revealed 14 distinct proteins as highly associated with SARS-CoV-2 infection and 12 proteins with subsequent hospitalization (p < 0.001). ADM, IL-6, MCP-3, TRAIL-R2, and PD-L1 were each predictive for death (AUROC curve 0.80-0.87). The consistent increase of these markers, from hospital admission to intensive care and fatality, supported the concept that these proteins are of major clinical relevance.Conclusions: We identified distinct plasma proteins linked to the presence and course of COVID-19. These plasma proteomic findings may translate to a protein fingerprint, helping to assist clinical management decisions.
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| 9. |
- Bergman, Julia, et al.
(författare)
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The human adrenal gland proteome defined by transcriptomics and antibody-based profiling.
- 2017
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Ingår i: Endocrinology. - : Endocrine Society. - 0013-7227 .- 1945-7170. ; 158:2, s. 239-251
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Tidskriftsartikel (refereegranskat)abstract
- The adrenal gland is a composite endocrine organ with vital functions that include the synthesis and release of glucocorticoids and catecholamines. To define the molecular landscape that underlies the specific functions of the adrenal gland, we combined a genome-wide transcriptomics approach using messenger RNA sequencing of human tissues with immunohistochemistry-based protein profiling on tissue microarrays. Approximately two-thirds of all putative protein coding genes were expressed in the adrenal gland, and the analysis identified 253 genes with an elevated pattern of expression in the adrenal gland, with only 37 genes showing a markedly greater expression level (more than fivefold) in the adrenal gland compared with 31 other normal human tissue types analyzed. The analyses allowed for an assessment of the relative expression levels for well-known proteins involved in adrenal gland function but also identified previously poorly characterized proteins in the adrenal cortex, such as the FERM (4.1 protein, ezrin, radixin, moesin) domain containing 5 and the nephroblastoma overexpressed (NOV) protein homolog. We have provided a global analysis of the adrenal gland transcriptome and proteome, with a comprehensive list of genes with elevated expression in the adrenal gland and spatial information with examples of protein expression patterns for corresponding proteins. These genes and proteins constitute important starting points for an improved understanding of the normal function and pathophysiology of the adrenal glands.
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| 10. |
- Uhlén, Mathias, et al.
(författare)
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A pathology atlas of the human cancer transcriptome
- 2017
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 357:6352, s. 660-
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is one of the leading causes of death, and there is great interest in understanding the underlying molecular mechanisms involved in the pathogenesis and progression of individual tumors. We used systems-level approaches to analyze the genome-wide transcriptome of the protein-coding genes of 17 major cancer types with respect to clinical outcome. A general pattern emerged: Shorter patient survival was associated with up-regulation of genes involved in cell growth and with down-regulation of genes involved in cellular differentiation. Using genome-scale metabolic models, we show that cancer patients have widespread metabolic heterogeneity, highlighting the need for precise and personalized medicine for cancer treatment. All data are presented in an interactive open-access database (www.proteinatlas.org/pathology) to allow genome-wide exploration of the impact of individual proteins on clinical outcomes.
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