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| 2. |
- Berggrund, Malin, et al.
(författare)
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Identification of candidate plasma protein biomarkers for cervical cancer using the multiplex proximity extension assay
- 2019
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Ingår i: Molecular & Cellular Proteomics. - 1535-9476 .- 1535-9484. ; 18:4, s. 735-743
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Tidskriftsartikel (refereegranskat)abstract
- Human papillomavirus (HPV) is recommended as the primary test in cervical cancer screening, with co-testing by cytology for HPV-positive women to identify cervical lesions. Cytology has low sensitivity and there is a need to identify biomarkers that could identify dysplasia that are likely to progress to cancer. We searched for plasma proteins that could identify women with cervical cancer using the multiplex proximity extension assay (PEA). The abundance of 100 proteins were measured in plasma collected at the time of diagnosis of patients with invasive cervical cancer and in population controls using the Olink Multiplex panels CVD II, INF I, and ONC II. Eighty proteins showed increased levels in cases compared to controls. We identified a signature of 11 proteins (PTX3, ITGB1BP2, AXIN1, STAMPB, SRC, SIRT2, 4E-BP1, PAPPA, HB-EGF, NEMO and IL27) that distinguished cases and controls with a sensitivity of 0.96 at a specificity of 1.0. This signature was evaluated in a prospective replication cohort with samples collected before, at or after diagnosis and achieved a sensitivity of 0.78 and a specificity 0.56 separating samples collected at the time of diagnosis of invasive cancer from samples collected prior to diagnosis. No difference in abundance was seen between samples collected prior to diagnosis or after treatment as compared to population controls, indicating that this protein signature is mainly informative close to time of diagnosis. Further studies are needed to determine the optimal window in time prior to diagnosis for these biomarker candidates.
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| 3. |
- Borgmästars, Emmy, 1990-
(författare)
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In search of early biomarkers in pancreatic ductal adenocarcinoma using multi-omics and bioinformatics
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive malignancy with a 5-year survival of 10 %. Surgery is the only curative treatment. Unfortunately, few patients are eligible for surgery due to late detection. Thus, we need ways to detect the disease at an earlier stage and for that good screening biomarkers could be used. Previous studies have analyzed circulating analytes in prospective studies to identify early PDAC signals. One such class is microRNAs (miRNAs). MicroRNAs are non-coding RNAs of around 22 nucleotides that act as post- transcriptional regulators by interaction with messenger RNAs (mRNAs). The function of a miRNA can be elucidated by target prediction, to identify its potential targets, followed by enrichment analysis of the predicted targets. Challenges with this approach includes a lot of false positives being generated and that miRNAs can perform their role in a tissue- or disease-specific manner. Other classes of analytes that have previously been studied in prospective PDAC cohorts are metabolites and proteins. Aims: This thesis has three aims. First, to build a miRNA functional analysis pipeline with correlation support between miRNA and its predicted target genes. Second, to identify potential circulating biomarkers for early detection of PDAC using multi-omics. Third, to identify potential prognostic metabolites in a prospective PDAC cohort.Methods: We used publicly available data from the cancer genome atlas-pancreatic adenocarcinoma (TCGA-PAAD) and pre-diagnostic plasma samples from the Northern Sweden Health and Disease Study. We built a pipeline in R including miRNA, mRNA, and protein expression data from TCGA-PAAD for in silico miRNA functional analysis. Pre- diagnostic plasma samples from future PDAC patients as well as matched healthy controls were analyzed using multi- omics. Tissue polypeptide specific antigen (TPS) was analyzed by enzyme linked immunosorbent assay in 267 future PDAC samples and 320 healthy controls. Metabolomics and clinical biomarkers (carbohydrate antigen (CA) 19-9, carcinoembryonic antigen (CEA), and CA 15-3) were profiled in 100 future PDAC samples and 100 healthy controls using liquid chromatography-mass spectrometry (MS), gas chromatography-MS, and multi-plex technology. Of these, a subset of 39 future PDAC patients and 39 healthy controls were profiled for 2083 microRNAs using targeted sequencing and 644 proteins using proximity extension assays. Circulating levels of multi-omics analytes were analyzed using conditional or unconditional logistic regression. Least absolute shrinkage and selection operator (LASSO) in combination with 500 bootstrap iterations identified the most informative variables. The prognostic value of metabolites was assessed using cox regression. Multi-omics factor analysis (MOFA) and data integration analysis for biomarker discovery using latent components (DIABLO) were used for multi-omics integration analyses.Results: An automated pipeline was built consisting of 1) miRNA target prediction, 2) correlation analyses between miRNA and its targets on mRNA and protein expression levels, and 3) functional enrichment of correlated targets to identify enriched Kyoto encyclopedia of genes and genomes (KEGG) pathways and gene ontology (GO) terms for a specific miRNA. The pipeline was run for all microRNAs (~700) detected in the TCGA-PAAD cohort. These results can be downloaded from a shiny app (https://emmbor.shinyapps.io/mirfa/). TPS was not altered in pre-diagnostic PDAC patients up to 24 years prior to diagnosis, but increased at diagnosis (OR = 1.03, 95 % CI: 1.01-1.05). Internal area under curves of 0.74, 0.80, and 0.88 were achieved for five metabolites, two proteins, and two miRNAs that were selected by LASSO and bootstrap iterations, in combination with CA 19-9. Neither MOFA nor DIABLO separated well between future PDAC cases and healthy controls. Conclusions: Our bioinformatics pipeline for in silico functional analysis of microRNAs successfully identifies enriched KEGG pathways and GO terms for miRNA isoforms. The investigated plasma samples are heterogeneous, but among the analyzed variables, we identified five metabolites, two proteins, and two microRNAs with highest potential for early PDAC detection. CA 19-9 levels increased closer to diagnosis. We identified five fatty acids that could be studied in a diagnostic PDAC cohort as prognostic biomarkers.
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| 4. |
- Cui, Tao, 1982-, et al.
(författare)
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Invasive cervical tumors with high and low HPV titer represent molecular subgroups with different disease etiology
- 2019
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 40:2, s. 269-278
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Tidskriftsartikel (refereegranskat)abstract
- Invasive cervical cancer (ICC) with very low titer of high-risk human papillomavirus (HPV) has worse clinical outcome than cases with high titer, indicating a difference in molecular etiology. Fresh-frozen ICC tumors (n = 49) were classified into high- and low-HPV-titer cases using real-time PCR-based HPV genotyping. The mutation spectra were studied using the AmpliSeq Comprehensive Cancer Panel and the expression profiles using total RNA sequencing, and the results were validated using the AmpliSeq Transcriptome assay. HPV DNA genotyping and RNA sequencing showed that 16.6% of ICC tumors contained very low levels of HPV DNA and HPV transcripts. Tumors with low HPV levels had more mutations with a high allele frequency and fewer mutations with low allele frequency relative to tumors with high HPV titer. A number of genes showed significant expression differences between HPV titer groups, including genes with somatic mutations. Gene ontology and pathway analyses implicated the enrichment of genes involved in DNA replication, cell cycle control and extracellular matrix in tumors with low HPV titer. The results indicate that in low titer tumors, HPVs act as trigger of cancer development whereas somatic mutations are clonally selected and become drivers of the tumor development process. In contrast, in tumors with high HPV titer the expression of HPV oncoproteins plays a major role in tumor development and the many low frequency somatic mutations represent passengers. This putative subdivision of invasive cervical tumors may explain the higher radiosensitivity of ICC tumors with high HPV titer and thereby have consequences for clinical management.
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| 5. |
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| 6. |
- Enroth, Stefan, et al.
(författare)
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Cancer associated epigenetic transitions identified by genome-wide histone methylation binding profiles in human colorectal cancer samples and paired normal mucosa
- 2011
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Ingår i: BMC Cancer. - : BioMed Central. - 1471-2407. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Despite their well-established functional roles, histone modifications have received less attention than DNA methylation in the cancer field. In order to evaluate their importance in colorectal cancer (CRC), we generated the first genome-wide histone modification profiles in paired normal colon mucosa and tumor samples.METHODS: Chromatin immunoprecipitation and microarray hybridization (ChIP-chip) was used to identify promoters enriched for histone H3 trimethylated on lysine 4 (H3K4me3) and lysine 27 (H3K27me3) in paired normal colon mucosa and tumor samples from two CRC patients and for the CRC cell line HT29.RESULTS: By comparing histone modification patterns in normal mucosa and tumors, we found that alterations predicted to have major functional consequences were quite rare. Furthermore, when normal or tumor tissue samples were compared to HT29, high similarities were observed for H3K4me3. However, the differences found for H3K27me3, which is important in determining cellular identity, indicates that cell lines do not represent optimal tissue models. Finally, using public expression data, we uncovered previously unknown changes in CRC expression patterns. Genes positive for H3K4me3 in normal and/or tumor samples, which are typically already active in normal mucosa, became hyperactivated in tumors, while genes with H3K27me3 in normal and/or tumor samples and which are expressed at low levels in normal mucosa, became hypersilenced in tumors.CONCLUSIONS: Genome wide histone modification profiles can be used to find epigenetic aberrations in genes associated with cancer. This strategy gives further insights into the epigenetic contribution to the oncogenic process and may identify new biomarkers.
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| 7. |
- Enroth, Stefan, et al.
(författare)
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Effects of Long-Term Storage Time and Original Sampling Month on Biobank Plasma Protein Concentrations
- 2016
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Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 12, s. 309-314
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Tidskriftsartikel (refereegranskat)abstract
- The quality of clinical biobank samples is crucial to their value for life sciences research. A number of factors related to the collection and storage of samples may affect the biomolecular composition. We have studied the effect of long-time freezer storage, chronological age at sampling, season and month of the year and on the abundance levels of 108 proteins in 380 plasma samples collected from 106 Swedish women. Storage time affected 18 proteins and explained 4.8–34.9% of the observed variance. Chronological age at sample collection after adjustment for storage-time affected 70 proteins and explained 1.1–33.5% of the variance. Seasonal variation had an effect on 15 proteins and month (number of sun hours) affected 36 proteins and explained up to 4.5% of the variance after adjustment for storage-time and age. The results show that freezer storage time and collection date (month and season) exerted similar effect sizes as age on the protein abundance levels. This implies that information on the sample handling history, in particular storage time, should be regarded as equally prominent covariates as age or gender and need to be included in epidemiological studies involving protein levels.
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| 8. |
- Rada-Iglesias, A., et al.
(författare)
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Histone H3 lysine 27 trimethylation in adult differentiated colon associated to cancer DNA hypermethylation
- 2009
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Ingår i: Epigenetics. - 1559-2294. ; 4:2, s. 107-13
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Tidskriftsartikel (refereegranskat)abstract
- DNA hypermethylation of gene promoters is a common epigenetic alteration occurring in cancer cells. However, little is known about the mechanisms instructing these cancer-specific DNA hypermethylation events. Recent reports have suggested that genes bound by polycomb/Histone H3 lysine 27 trimethylation (H3K27me3) in embryonic stem (ES) cells are frequent targets for cancer-specific DNA hypermethylation. This polycomb-premarking is assumed to be restrained to ES cells, even though almost no polycomb/H3K27me3 binding profiles are available for differentiated tissues. We generated H3K27me3 profiles in human normal colon and they significantly overlapped with those of ES cells and genes hypermethylated in colorectal cancer (CRC). Moreover, colon H3K27me3 was more restricted to genes hypermethylated in CRC, while ES H3K27me3 was also common in genes hypermethylated in other tumors. Therefore, the suggested polycomb pre-marking of genes for cancer DNA hypermethylation is not necessarily limited to ES or early precursor cells but can occur later in differentiated tissues.
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| 9. |
- Sundkvist, Anneli, et al.
(författare)
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Targeted plasma proteomics identifies a novel, robust association between cornulin and Swedish moist snuff
- 2018
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Ingår i: Scientific Reports. - London : Nature Publishing Group. - 2045-2322. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Lifestyle behaviors are believed to influence the body's inflammatory state. Chronic low-grade inflammation contributes to the development of major non-communicable diseases such as diabetes, cardiovascular disease and cancer. Inflammation may thus be an important link between lifestyle and disease. We evaluated self-reported physical activity, tobacco use and alcohol consumption in relation to plasma levels of 160 validated inflammatory and cancer biomarkers. The study included 138 participants from a population-based cohort, all with repeated sampling of plasma and data ten years apart, allowing consideration of both intra- and inter-individual variation. Of 17 relationships identified, the strongest was an independent, positive association between cornulin (CRNN) and Swedish moist snuff (snus) use. We replicated the finding in a second cohort of 501 individuals, in which a dose-response relationship was also observed. Snus explained approximately one fifth of the variance in CRNN levels in both sample sets (18% and 23%). In conclusion, we identified a novel, independent, dose-dependent association between CRNN and snus use. Further study is warranted, to evaluate the performance of CRNN as a potential snus biomarker. The putative importance of lifestyle behaviors on a wide range of protein biomarkers illustrates the need for more personalized biomarker cut-offs.
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