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Wang, D., Eraslan, B., Wieland, T., Hallstrom, B., Hopf, T., Zolg, D. P., . . . Kuster, B. (2019). A deep proteome and transcriptome abundance atlas of 29 healthy human tissues. Molecular Systems Biology, 15(2), Article ID e8503.
Open this publication in new window or tab >>A deep proteome and transcriptome abundance atlas of 29 healthy human tissues
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2019 (English)In: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 15, no 2, article id e8503Article in journal (Refereed) Published
Abstract [en]

Genome-, transcriptome- and proteome-wide measurements provide insights into how biological systems are regulated. However, fundamental aspects relating to which human proteins exist, where they are expressed and in which quantities are not fully understood. Therefore, we generated a quantitative proteome and transcriptome abundance atlas of 29 paired healthy human tissues from the Human Protein Atlas project representing human genes by 18,072 transcripts and 13,640 proteins including 37 without prior protein-level evidence. The analysis revealed that hundreds of proteins, particularly in testis, could not be detected even for highly expressed mRNAs, that few proteins show tissue-specific expression, that strong differences between mRNA and protein quantities within and across tissues exist and that protein expression is often more stable across tissues than that of transcripts. Only 238 of 9,848 amino acid variants found by exome sequencing could be confidently detected at the protein level showing that proteogenomics remains challenging, needs better computational methods and requires rigorous validation. Many uses of this resource can be envisaged including the study of gene/protein expression regulation and biomarker specificity evaluation.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
human proteome, human transcriptome, proteogenomics, quantitative mass spectrometry, RNA-Seq
National Category
Biochemistry and Molecular Biology Bioinformatics and Systems Biology
Identifiers
urn:nbn:se:uu:diva-379281 (URN)10.15252/msb.20188503 (DOI)000459628300002 ()30777892 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationEU, Horizon 2020
Available from: 2019-03-14 Created: 2019-03-14 Last updated: 2019-03-14Bibliographically approved
Aasebö, K. Ö., Dragomir, A., Sundström, M., Mezheyeuski, A., Edqvist, P.-H. D., Eide, G. E., . . . Sorbye, H. (2019). Consequences of a high incidence of microsatellite instability and BRAF-mutated tumors: A population-based cohort of metastatic colorectal cancer patients. Cancer Medicine, 8(7), 3623-3635
Open this publication in new window or tab >>Consequences of a high incidence of microsatellite instability and BRAF-mutated tumors: A population-based cohort of metastatic colorectal cancer patients
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2019 (English)In: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634, Vol. 8, no 7, p. 3623-3635Article in journal (Refereed) Published
Abstract [en]

Background: Immunotherapy for patients with microsatellite-instable (MSI-H) tumors or BRAF-inhibitors combination treatment for BRAF-mutated (mutBRAF) tumors in metastatic colorectal cancer (mCRC) is promising, but the frequency of these molecular changes in trial patients are low. Unselected population-based studies of these molecular changes are warranted.

Methods: A population-based cohort of 798 mCRC patients in Scandinavia was studied. Patient and molecular tumor characteristics, overall survival (OS) and progression-free survival (PFS) were estimated.

Results: Here, 40/583 (7%) tumor samples were MSI-H and 120/591 (20%) were mutBRAF; 87% of MSI-H tumors were mutBRAF (non-Lynch). Elderly (>75 years) had more often MSI-H (10% vs 6%) and MSI-H/mutBRAF (9% vs 4%) tumors. Response rate (5% vs 44%), PFS (4 vs 8 months), and OS (9 vs 18 months) after first-line chemotherapy was all significantly lower in patients with MSI-H compared to patients with microsatellite stable tumors. MSI-H and mutBRAF were both independent poor prognostic predictors for OS (P = 0.049, P < 0.001) and PFS (P = 0.045, P = 0.005) after first-line chemotherapy. Patients with MSI-H tumors received less second-line chemotherapy (15% vs 37%, P = 0.005).

Conclusions: In unselected mCRC patients, MSI-H and mutBRAF cases were more common than previously reported. Patients with MSI-H tumors had worse survival, less benefit from chemotherapy, and they differed considerably from recent third-line immunotherapy trial patients as they were older and most had mutBRAF tumor (non-Lynch).

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
colorectal neoplasm, microsatellite instability, proto-oncogene proteins, B-raf, prognosis, neoplasm metastasis, KRAS protein
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-391954 (URN)10.1002/cam4.2205 (DOI)000477017100030 ()31070306 (PubMedID)
Funder
Erik, Karin och Gösta Selanders FoundationSwedish Cancer Society
Available from: 2019-08-27 Created: 2019-08-27 Last updated: 2019-08-27Bibliographically approved
Cadenas, C., Vosbeck, S., Edlund, K., Grgas, K., Madjar, K., Hellwig, B., . . . Hengstler, J. G. (2019). LIPG-promoted lipid storage mediates adaptation to oxidative stress in breast cancer. International Journal of Cancer, 145(4), 901-915
Open this publication in new window or tab >>LIPG-promoted lipid storage mediates adaptation to oxidative stress in breast cancer
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2019 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, no 4, p. 901-915Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
LIPG, PLIN2, TXNRD1, breast cancer, endothelial lipase, lipid droplets, oxidative stress
National Category
Clinical Laboratory Medicine Cancer and Oncology
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-380591 (URN)10.1002/ijc.32138 (DOI)000472571300005 ()30653260 (PubMedID)
Available from: 2019-03-29 Created: 2019-03-29 Last updated: 2019-08-16Bibliographically approved
Edlund, K., Madjar, K., Mattsson, J. S., Djureinovic, D., Lindskog, C., Brunnström, H., . . . Hengstler, J. G. (2019). Prognostic Impact of Tumor Cell Programmed Death Ligand 1 Expression and Immune Cell Infiltration in NSCLC. Journal of Thoracic Oncology, 14(4), 628-640, Article ID S1556-0864(19)30009-7.
Open this publication in new window or tab >>Prognostic Impact of Tumor Cell Programmed Death Ligand 1 Expression and Immune Cell Infiltration in NSCLC
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2019 (English)In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 14, no 4, p. 628-640, article id S1556-0864(19)30009-7Article in journal (Refereed) Published
Abstract [en]

Introduction: Infiltration of T and B/plasma cells has been linked to NSCLC prognosis, but this has not been thoroughly investigated in relation to the expression of programmed death ligand 1 (PD-L1). Here, we determine the association of lymphocytes and PD-L1 with overall survival (OS) in two retrospective cohorts of operated NSCLC patients who were not treated with checkpoint inhibitors targeting the programmed death 1/PD-L1 axis. Moreover, we evaluate how PD-L1 positivity and clinicopathologic factors affect the prognostic association of lymphocytes.

Methods: Cluster of differentiation (CD) 3 (CD3)-, CD8-, CD4-, forkhead box P3 (FOXP3)-, CD20-, CD79A-, and immunoglobulin kappa constant (IGKC)-positive immune cells, and tumor PD-L1 positivity, were determined by immunohistochemistry on tissue microarrays (n = 705). Affymetrix data was analyzed for a patient subset, and supplemented with publicly available transcriptomics data (N = 1724). Associations with OS were assessed by Kaplan-Meier plots and uni- and multivariate Cox regression.

Results: Higher levels of T and B plasma cells were associated with longer OS (p = 0.004 and p < 0.001, for CD8 and IGKC, respectively). Highly proliferative tumors with few lymphocytes had the worst outcome. No association of PD-L1 positivity with OS was observed in a nonstratified patient population; however, a significant association with shorter OS was observed in never-smokers (p = 0.009 and p = 0.002, 5% and 50% cutoff). Lymphocyte infiltration was not associated with OS in PD-L1–positive tumors (50% cutoff). The prognostic association of lymphocyte infiltration also depended on the patients’ smoking history and histologic subtype.

Conclusions: Proliferation, PD-L1 status, smoking history, and histology should be considered if lymphocyte infiltration is to be used as a prognostic biomarker.

Keywords
Adenocarcinoma, Ki67, Lymphocyte, Prognosis, Squamous cell carcinoma
National Category
Clinical Laboratory Medicine Cell and Molecular Biology
Research subject
Pathology; Pathology; Pathology; Pathology
Identifiers
urn:nbn:se:uu:diva-380592 (URN)10.1016/j.jtho.2018.12.022 (DOI)000462167700021 ()30639618 (PubMedID)
Funder
Swedish Cancer Society, 15 0831
Available from: 2019-03-29 Created: 2019-03-29 Last updated: 2019-04-17Bibliographically approved
Eraslan, B., Wang, D., Gusic, M., Prokisch, H., Hallström, B. M., Uhlen, M., . . . Gagneur, J. (2019). Quantification and discovery of sequence determinants of protein-per-mRNA amount in 29 human tissues. Molecular Systems Biology, 15(2), Article ID e8513.
Open this publication in new window or tab >>Quantification and discovery of sequence determinants of protein-per-mRNA amount in 29 human tissues
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2019 (English)In: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 15, no 2, article id e8513Article in journal (Refereed) Published
Abstract [en]

Despite their importance in determining protein abundance, a comprehensive catalogue of sequence features controlling protein-to-mRNA (PTR) ratios and a quantification of their effects are still lacking. Here, we quantified PTR ratios for 11,575 proteins across 29 human tissues using matched transcriptomes and proteomes. We estimated by regression the contribution of known sequence determinants of protein synthesis and degradation in addition to 45 mRNA and 3 protein sequence motifs that we found by association testing. While PTR ratios span more than 2 orders of magnitude, our integrative model predicts PTR ratios at a median precision of 3.2-fold. A reporter assay provided functional support for two novel UTR motifs, and an immobilized mRNA affinity competition-binding assay identified motif-specific bound proteins for one motif. Moreover, our integrative model led to a new metric of codon optimality that captures the effects of codon frequency on protein synthesis and degradation. Altogether, this study shows that a large fraction of PTR ratio variation in human tissues can be predicted from sequence, and it identifies many new candidate post-transcriptional regulatory elements.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
codon usage, mRNA sequence motifs, proteomics, transcriptomics, translational control
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-379280 (URN)10.15252/msb.20188513 (DOI)000459628300004 ()30777893 (PubMedID)
Funder
EU, Horizon 2020, 633974
Available from: 2019-03-14 Created: 2019-03-14 Last updated: 2019-03-14Bibliographically approved
Fredolini, C., Byström, S., Sanchez-Rivera, L., Ioannou, M., Tamburro, D., Pontén, F., . . . Schwenk, J. M. (2019). Systematic assessment of antibody selectivity in plasma based on a resource of enrichment profiles. Scientific Reports, 9, Article ID 8324.
Open this publication in new window or tab >>Systematic assessment of antibody selectivity in plasma based on a resource of enrichment profiles
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 8324Article in journal (Refereed) Published
Abstract [en]

There is a strong need for procedures that enable context and application dependent validation of antibodies. Here, we applied a magnetic bead assisted workflow and immunoprecipitation mass spectrometry (IP-MS/MS) to assess antibody selectivity for the detection of proteins in human plasma. A resource was built on 414 IP experiments using 157 antibodies (targeting 120 unique proteins) in assays with heat-treated or untreated EDTA plasma. For each protein we determined their antibody related degrees of enrichment using z-scores and their frequencies of identification across all IP assays. Out of 1,313 unique endogenous proteins, 426 proteins (33%) were detected in >20% of IPs, and these background components were mainly comprised of proteins from the complement system. For 45% (70/157) of the tested antibodies, the expected target proteins were enriched (z-score >= 3). Among these 70 antibodies, 59 (84%) co-enriched other proteins beside the intended target and mainly due to sequence homology or protein abundance. We also detected protein interactions in plasma, and for IGFBP2 confirmed these using several antibodies and sandwich immunoassays. The protein enrichment data with plasma provide a very useful and yet lacking resource for the assessment of antibody selectivity. Our insights will contribute to a more informed use of affinity reagents for plasma proteomics assays.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-387726 (URN)10.1038/s41598-019-43552-5 (DOI)000470243800005 ()31171813 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationSwedish Foundation for Strategic Research Swedish Research CouncilEU, FP7, Seventh Framework Programme, 115317Swedish Cancer Society
Available from: 2019-06-25 Created: 2019-06-25 Last updated: 2019-06-25Bibliographically approved
Niinivirta, M., Enblad, G., Lindskog, C., Pontén, F., Dragomir, A. & Ullenhag, G. (2019). Tumoral pyruvate kinase L/R as a predictive marker for the treatment of renal cancer patients with sunitinib and sorafenib. Journal of Cancer, 10(14), 3224-3231
Open this publication in new window or tab >>Tumoral pyruvate kinase L/R as a predictive marker for the treatment of renal cancer patients with sunitinib and sorafenib
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2019 (English)In: Journal of Cancer, ISSN 1837-9664, Vol. 10, no 14, p. 3224-3231Article in journal (Other academic) Published
Abstract [en]

Background and aims: Treatment with tyrosine kinase inhibitors (TKI) like sunitinib and sorafenib has improved the prognosis of patients with metastatic renal cell cancer (mRCC). No predictive marker is available to select patients who will gain from these treatments. Tumoral pyruvate kinase L/R (PKLR) is a membrane protein with highly specific expression in the renal tubule. We have previously shown that the tumoral expression of cubilin (CUBN) is associated with progression free survival (PFS) in mRCC patients treated with sunitinib and sorafenib. The aim of the present study was to investigate if PKLR can predict response in these patients, alone and/or in combination with CUBN.

Methods: A tissue microarray (TMA) was constructed of tumor samples from 139 mRCC patients. One hundred and thirty-six of these patients had been treated with sunitinib or sorafenib in the first or second-line setting. Thirty patients suffered from early severe toxicity leading to the termination of treatment. The remaining patients (n=106) were selected for the current study.

Results: Fifty-five (52%) of the tumors expressed membranous PKLR. Patients with PKLR tumor expression experienced a significantly longer PFS compared to patients with no expression (eight versus five months, p = 0.019). Overall survival (OS) was also significantly better for patients with PKLR expression. In addition, the combined expression of PKLR and CUBN resulted in a higher predictive value than either marker alone.

Conclusions: In this real world study we show that tumoral PKLR membrane expression is a positive predictive biomarker for sunitinib and sorafenib treatment in patients suffering from mRCC. Our results also indicate that the combined expression with cubilin more accurately than PKLR alone can select patients with no benefit from treatment.

National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:uu:diva-360611 (URN)10.7150/jca.30130 (DOI)000470088200017 ()
Funder
Knut and Alice Wallenberg Foundation
Available from: 2018-09-16 Created: 2018-09-16 Last updated: 2019-06-26Bibliographically approved
Huvila, J., Laajala, T. D., Edqvist, P.-H. D., Mardinoglu, A., Talve, L., Pontén, F., . . . Auranen, A. (2018). Combined ASRGL1 and p53 immunohistochemistry as an independent predictor of survival in endometrioid endometrial carcinoma. Gynecologic Oncology, 149(1), 173-180
Open this publication in new window or tab >>Combined ASRGL1 and p53 immunohistochemistry as an independent predictor of survival in endometrioid endometrial carcinoma
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2018 (English)In: Gynecologic Oncology, ISSN 0090-8258, E-ISSN 1095-6859, Vol. 149, no 1, p. 173-180Article in journal (Refereed) Published
Abstract [en]

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- (295%) 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.

Place, publisher, year, edition, pages
ACADEMIC PRESS INC ELSEVIER SCIENCE, 2018
Keywords
Endometrial cancer, Risk stratification, Prognostic, Modelling, ASRGL1, p53
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-352701 (URN)10.1016/j.ygyno.2018.02.016 (DOI)000430152400026 ()29486992 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationSwedish Cancer Society
Available from: 2018-06-08 Created: 2018-06-08 Last updated: 2018-06-08Bibliographically approved
Djureinovic, D., Dodig-Crnkovic, T., Hellström, C., Holgersson, G., Bergqvist, M., Mattsson, J. S., . . . Micke, P. (2018). Detection of autoantibodies against cancer-testis antigens in non-small cell lung cancer. Lung Cancer, 125, 157-163
Open this publication in new window or tab >>Detection of autoantibodies against cancer-testis antigens in non-small cell lung cancer
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2018 (English)In: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 125, p. 157-163Article in journal (Refereed) Published
Abstract [en]

Cancer testis antigens (CTAs) are defined as proteins that are specifically expressed in testis or placenta and their expression is frequently activated in cancer. Due to their ability to induce an immune response, CTAs may serve as suitable targets for immunotherapy. The aim of this study was to evaluate if there is reactivity against CTAs in the plasma of non-small cell lung cancer (NSCLC) patients through the detection of circulating antibodies. 

To comprehensively analyse auto-antibodies against CTAs the multiplexing capacities of suspension bead array technology was used. Bead arrays were created with 120 protein fragments, representing 112 CTAs. Reactivity profiles were measured in plasma samples from 133 NSCLC patients and 57 cases with benign lung diseases. Altogether reactivity against 69 antigens, representing 81 CTAs, was demonstrated in at least one of the analysed samples. Twenty-nine of the antigens (45 CTAs) demonstrated exclusive reactivity in NSCLC samples. Reactivity against CT47A genes, PAGE3, VCX, MAGEB1, LIN28B and C12orf54 were only found in NSCLC patients at a frequency of 1%-4%. The presence of autoantibodies towards these six antigens was confirmed in an independent group of 34 NSCLC patients.

In conclusion, we identified autoantibodies against CTAs in the plasma of lung cancer patients. The reactivity pattern of autoantibodies was higher in cancer patients compared to the benign group, stable over time, but low in frequency of occurrence. The findings suggest that some CTAs are immunogenic and that these properties can be utilized as immune targets.

Keywords
Lung cancer, adenocarcinoma, squamous cell cancer, cancer immunity, tumor markers, MAGE, PAGE
National Category
Medical and Health Sciences Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-347809 (URN)10.1016/j.lungcan.2018.09.012 (DOI)000450378500023 ()
Funder
Swedish Cancer Society, 2012/738Knut and Alice Wallenberg FoundationErik, Karin och Gösta Selanders Foundation
Available from: 2018-04-07 Created: 2018-04-07 Last updated: 2019-03-29Bibliographically approved
Larsson, A., Karnevi, E., Nodin, B., Sorbye, H., Dragomir, A., Pfeiffer, P., . . . Ponten, F. (2018). Expression of podocalyxin-like protein and epidermal growth factor receptor in metastatic colorectal cancer: Prognostic impact and relationship with response to cetuximab.. In: : . Paper presented at ASCO 2018.
Open this publication in new window or tab >>Expression of podocalyxin-like protein and epidermal growth factor receptor in metastatic colorectal cancer: Prognostic impact and relationship with response to cetuximab.
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2018 (English)Conference paper, Poster (with or without abstract) (Refereed)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-365898 (URN)
Conference
ASCO 2018
Available from: 2018-11-14 Created: 2018-11-14 Last updated: 2018-11-14
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-0703-3940

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