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- Farkas, Sanja, 1983-
(författare)
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DNA methylation in the placenta and in cancerwith special reference to folate transporting genes
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- DNA methylation is an epigenetic mechanism that regulates the gene transcription. Folate is used in cellular synthesis of methyl groups, nucleic acids and amino acids. In complex diseases like cancer and neural tube defects (NTD), various genetic and epigenetic alterations can be found that disrupt the normal cell function. The main goals of this thesis were to analyze whether the genes responsible for the folate transport (FOLR1, PCFT, and RFC1) could be regulated by DNA methylation in placenta, blood leukocytes and colorectal cancer. We also addressed the genome-wide DNA methylation changes in colorectal cancer andcervical cancer.We found that changes in the methylated fraction of the RFC1 gene were dependent on the RFC1 80G>A polymorphism in placental specimens with NTDs and blood leukocytes from subjects with high homocysteine (Paper I). In colorectal cancer, the greatest difference in DNA methylation was observed in the RFC1 gene and was related to a lower protein expression (Paper II).In Paper III and IV we studied the DNA methylated fraction using a high-density array. Paper III was focused on genes in the DNA repair pathway and frequently mutated in colorectal cancer. We found that aberrant methylation in the DNA mismatch repair genes was not a frequent event in colorectal cancer and we identified five candidate biomarker genes in colorectal cancer, among them the GPC6 and DCLRE1C genes. In Paper IV, we found hypomethylation of genes involved in the immune system in cervical cancer specimens compared to healthy cervical scrapes and we identified twenty four candidate genes for further evaluation ofclinical value.In conclusion, the work of this thesis filled a relevant knowledge gap regarding the role of differential methylation of the folate transport genes in NTD and colorectal cancer. This thesis work also provided insights into the functional role of DNA methylation in cancer specific pathways and identified potential novel biomarker genes.
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| 2. |
- Isaksson, Helena, 1978-
(författare)
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Clinical studies of RNA as a prognostic and diagnostic marker for disease
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Technologies for RNA detection are evolving rapidly and gives an op-portunity for discovery of new markers for early detection of complex diseases. Today in clinical work we rely on signs and symptoms in com-bination with the measurement of protein levels for diagnosis. The quick turnaround time of mRNA synthesis may provide an earlier diagnostic signal than protein-based biomarkers assays, in acute dramatic condi-tions such as acute mesenteric ischemia (AMI), for early detection of cancer, as prognostic tool in cancer treatment and as an aid in difficult diagnosis of unknown origin.The main goals of this thesis was to apply a whole genome approach to study different complex diseases to evaluate the applicability of RNA as a diagnostic or prognostic marker for disease, preferably from an easily accessible source such as peripheral blood. This was investigated in an animal model with induced AMI, a cohort of ovarian cancer patients and in a single-patient study of a girl with a severe inflammatory syn-drome.Through this thesis we have gained insight into how gene expression is regulated in ischemic intestinal tissue.We found that a peripheral blood test can distinguish between ovarian cancer patients with or without residual tumour mass after surgery with the help of expression analysis of six genes. We also found that gene expressions of three genes can predict overall survival in peripheral whole blood from ovarian cancer patients. And that gene expression profiles indeed can significantly distinguish between two groups of high and low risk ovarian cancer. In the single-patient study, we tried but failed to device a successful treatment before it was too late. Neverthe-less, the things we learned and the case studies that were published may serve as a diagnostic tool for clinicians facing similar syndromes.
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| 3. |
- Lindqvist, Breezy Malakkaran, 1978-
(författare)
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Biological signature of HER2-positive breast cancer
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Human epidermal growth factor receptor 2 (HER2) overexpressing breast cancers (HER2+ breast cancer) are associated with an aggressive disease course. This thesis is focused on improving the understanding of the biological signature of HER2+ breast cancer.In Paper I, we identified a common deletion spanning the SLC25A43 gene which codes for a mitochondrial transport protein. Loss of heterozygosity in this gene was confirmed in an extended cohort of HER2+ breast cancer and in other types of cancers. Protein expression analysis of SLC25A43using immunohistochemistry (IHC) in HER2+ breast cancers showed that tumours with negative or low expression of SLC25A43 had lower S-phase fraction compared to tumours with medium or high expression, indicating its possible role in cell proliferation. Absence of mutations in this gene in HER2+ breast cancers led to Paper II where DNA methylation in the SLC25A43 gene was interrogated using Pyrosequencing. HER2+ breast cancer with no deletion in the SLC25A43 gene showed higher methylation in the CpG island (CGI), suggesting methylation in the CGI as an alternate mechanism for SLC25A43 gene inactivation. Methylation in the CGI and in the adjacent shores of the SLC25A43 gene was associated with negative oestrogen receptor status and positive lymph node status. In Paper III, genome-wide DNA methylation analysis of HER2+ breast cancer and normal breast tissue revealed hypermethylation in HER2+ breast cancer affecting particularly the homeobox gene family when compared to normal. We identified a total of 73 candidate genes showing differential methylation in HER2+ breast cancer and external validation of gene expression in a selected group of these genes revealed lowered mean expression in HER2+ breast cancer, warranting future clinical studies of these candidate genes. In Paper IV, we investigated expression and localisation of phosphorylated (p) Akt and FOXO3a and FOXG1 in HER2+ breast cancer using IHC. Cytoplasmic expression of pFOXO3a was associated with sentinel node metastasis while cytoplasmic expression of FOXG1 was correlated to negative progesterone receptor status. This indicates the biological and prognostic value of these proteins in HER2+ breast cancer.Thus, this thesis identified changes at the genetic, epigenetic and protein levels which add new information and improve our understanding of HER2+ breast cancer.
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| 4. |
- Pettersson-Pablo, Paul, 1986-
(författare)
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Biomarkers of vascular function and structure in young healthy adults
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Atherosclerosis is a disease affecting the blood vessels in the body. Its pathophysiologic mechanisms involve infiltration of the vessel walls by fatty matter and immune cells. This process is slow, starting in childhood but typically not manifesting as symptomatic disease until late adulthood (after 60 years of age). The identification of younger individuals with a high risk for early intervention has a higher potential of preventing morbidity and mortality.In this thesis, part of the Lifestyle, Biomarkers and Atherosclerosis study (LBA), the earliest stages of vascular dysfunction have been examined in a population of young, healthy, non-smoking subjects. Vascularfunction and structure measurements predict a future risk of cardiovascular disease (CVD). The measurements were analyzed in relation to clinical chemistry analyses of various biomarkers in serum and plasma that have been associated with inflammation or cardiovascular risk. A secondary aim was to examine estrogen containing contraceptive use and its relation to the CVD biomarkers.In Paper I and Paper II of the thesis, the association between inflammatory biomarkers, body fat percentage and vascular function and structure measurements was examined in multivariable linear regression models. A higher body fat percentage predicted an increased serum concentration of C-reactive protein (CRP) and orosomucoid. In Paper II, a higher body fat percentage and a higher CRP were associated with a more unfavorable vascular function and structure.In Paper III and Paper IV, we employed two multiplex proteomics panels to analyze inflammatory proteins and proteins previously implicated in CVD. In multivariable linear regression models, proteins implicated in hemostasis, inflammatory signaling and chemoattraction correlated with different vascular function and structure measurements. InPaper IV, insulin-like growth factor-binding protein 1 (IGFBP1) and IGFBP2 were independently predictive of an increased vascular stiffness.In conclusion, even in young, healthy individuals, altered concentrations of serum biomarkers can be detected in subjects with increased body fat and unfavorable vascular function and structure.
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