| 1. |
- Klaff, Rami, 1971-
(författare)
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Disease-Specific Survival in Prostate Cancer Patients : Results from the Scandinavian Prostate Cancer Group (SPCG) Trial No. 5 and Regional Cancer Register Data
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- IntroductionProstate cancer (PCa) is the most common cancer among men in Sweden. The clinical course varies considerably, which makes it difficult to predict the prognosis in the individual case. In order to explore the early as well as the late course of the disease, large study groups and population-based cohorts are necessary.AimsTo explore factors that influence the long-term outcome of men with low-risk tumours in a population-based register, to predict the long-term course, and to assess the mortality rate for men with prostate cancer (Paper I)To analyse long-term outcome and to investigate factors associated with long-term survival in patients with metastases to the skeleton (Paper II)To analyse early androgen deprivation treatment (ADT) failure and to define clinical predictors associated with short survival due to early ADT failure in prostate cancer patients with bone metastases (Paper III)To analyse the prognostic significance of the extent of bone metastases in relation to other pretreatment variables in prostate cancer patients, and to explore the impact of bone metastases on quality-of-life (Paper IV)Material and methodsThe study groups were assembled from The South East Region Prostate Cancer Register (SERPCR), and The Scandinavian Prostate Cancer Group (SPCG) Trial No. 5. In the first study, prognostic factors and long-term disease-specific mortality rates of low-risk prostate cancer patients from the early PSA era were analysed. In the second study, patient-related factors, quality-of-life (QoL) and long-term survival in 915 PCa patients with bone metastases (M1b) under ADT, were analysed. In Study III factors predicting primary failure to respond to ADT were identified. Study IV explored the impact of the extent of bone metastases on survival and QoL for these men.Result and conclusionsThe long-term disease-specific mortality of low-risk localised PCa is low, but the annual mortality rate gradually increases. This indicates that some tumours slowly develop into lethal cancer, particularly in men 70 years or older and with a PSA level ≥ 4 μg/L. From the SPCG Trial No. 5, a subgroup of patients with M1b disease and favourable set of predictive factors survived more than 10 years under ADT with an acceptable QoL. Independent predictors of long-term survival were identified as performance status (PS) < 2, limited extent of bone metastases, and a PSA level < 231 μg/L at the time of enrolment in the trial. However, four independent clinical predictors of early ADT failure could be defined. Men exhibiting these features should be considered for an alternative treatment. Patient grouping based on three categories of extent of bone metastases related to PS, haemoglobin, and QoL at presentation, as independent predictors of mortality, may provide improved accuracy of prognosis.
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| 2. |
- Slind Olsen, Renate
(författare)
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Circulating and genetic factors in colorectal cancer : Potential factors for establishing prognosis?
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Colorectal cancer (CRC) is defined as a cancer appearing in the colon or in the rectum. In Sweden, ~ 6300 individuals were diagnosed with the disease in 2014 and ~ 2550 individuals diagnosed with CRC die each year due to their cancer. Surgery is the main treatment option of CRC and a survival rate of ~ 10 % is estimated if distant metastases have developed. It is therefore of importance to find factors that may be useful together with tumour, node, metastasis (TNM) stage to establish early CRC diagnosis, prognosis and follow-up of CRC patients. The aim of this thesis was to study the possible association of CD93, PLA2G4C, PDGF-D and inflammatory cytokines with CRC disease progression.In a prospective study approach CD93 and PLA2G4C single nucleotide polymorphisms (SNPs) were of potential importance in CRC prognosis.The T/T genotype of CD93 was associated with an increased CD93 expression in CRC tissue. Further, CRC patients carrying this genotype were associated with disseminated CRC at diagnosis and a lower recurrence-free survival after surgery. The A allele of a SNP of PLA2G4C was a stronger predictor for CRC-specific mortality than the conventional risk factors used in the clinic for selection of TNM stage II patients for adjuvant treatment. This indicates that the T/T genotype of CD93 and the A allele of PLA2G4C may be potential genetic factors related to disease severity and spread. Furthermore, they distinguish CRC patients that may benefit from a more comprehensive follow-up and adjuvant treatment.To study the putative involvement of PDGF-D in CRC the effects of PDGF-D signalling was studied in vitro. PDGF-D signalling altered the expression of genes of importance in CRC carcinogenesis and proliferation which was blocked by imatinib, a tyrosine kinase inhibitor. This indicates that PDGF-D signalling may be an important pathway in CRC progression and a potential target in CRC treatment.The analysis of various inflammatory cytokines in plasma at diagnosis showed an association between high levels and increased total- or CRC-specific mortality two years after surgery. High levels of CCL1 and CCL24 was the only cytokines strongly correlated with a worse CRC prognosis after statistical adjustments and may be of interest for further evaluation.In conclusion, this thesis presents circulating and genetic factors such as CD93, PLA2G4C, PDGF-D, CCL1 and CCL24 that may be of importance in CRC progression and may be of clinical value together with TNM stage in establishing prognosis.
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| 3. |
- Aljabery, Firas
(författare)
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Staging and tumor biological mechanisms of lymph node metastasis in invasive urinary bladder cancer
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Aim: To study the possibility of detecting lymph node metastasis in locally advanced urinary bladder cancer (UBC) treated with radical cystectomy (RC) by using preoperative positron emission tomography/computed tomography (PET/CT) and peroperative sentinel node biopsy (SNB) technique. We also investigate the clinical significance of macrophage traits expression by cancer cells, M2-macrophage infiltration (MI) in tumor stroma and the immunohistochemical expression of biomarkers in cancer cells in relation to clinicopathologic data.Patients and Methods: We studied prospectively 122 patients with UBC, pathological stage pT1–pT4 treated with RC and pelvic lymph node dissection (PLND) during 2005–2011 at the Department of Urology, Linköping University Hospital. In the first study, we compared the results of preoperative PET/CT and conventional CT with the findings of postoperative histopathological evaluation of lymph nodes (LNs). In the second study we investigated the value of SNB technique for detecting pathological LNs during RC in patients with UBC. W also examined the significance of the primary tumor location in the bladder in predicting the site of LN metastases, and the prognostic significance of lympho-vascular invasion (LVI) and lymph node metastasis density (LNMD) on survival. In the third study, we investigate the clinical significance of macrophage infiltration (MI) in tumor stroma and macrophage-traits expression by tumor cells. In the fourth study, we investigate the cell cycle suppression proteins p53, p21, pRb, p16, p14 ARF as well as tumors proliferative protein Ki67 and DNA repair protein ERCC1 expression in cancer cells. The results were compared with clinical and pathological characteristics and outcome.Results: Prior to RC, PET/CT was used to detect LN metastasis in 54 patients. PET/CT had 41% sensitivity, 86% specificity, 58% PPV, and 76% NPV, whereas the corresponding figures for conventional CT were 41%, 89%, 64%, and 77%. SNB was performed during RC in 103 patients. A median number of 29 (range 7–68) nodes per patient were examined. SNs were detected in 83 out of 103 patients (81%). The sensitivity and specificity for detecting metastatic disease by SNB varied among LN stations, with average values of 67% -90%. LNMD or ≥8% and LVI were significantly related to shorter survival. In 103 patients, MI was high in 33% of cases, while moderate and low infiltration occurred in 42% and 25% of tumors respectively. Patients with tumors containing high and moderate compared to low MI had low rate of LN metastases (P=0.06) and improved survival (P=0.06), although not at significant level. The expression of different tumor suppression proteins was altered in 47-91% of the patients. There were no significant association between cancer specific survival (CSS) and any of the studied biomarkers. In case of altered p14ARF, ERCC1 or p21, CSS was low in case of low p53 immunostaining but increased in case of p53 accumulation, although not at a significant level, indicating a possible protective effect of p53 accumulation in these cases.Conclusion: PET/ CT provided no improvement over conventional CT in detection and localization of regional LN metastases in bladder cancer. It is possible to detect the SN but the technique is not a reliable for perioperative localization of LN metastases; however, LVI and LNMD at a cut-off level of 8% had significant prognostic values. MI in the tumor microenvironment but not CD163 expression in tumor cells seems to be synergistic with the immune response against urinary bladder cancer. Our results further indicate that altered p53 might have protective effect on survival in case of altered p14ARF, p21, or ERCC1 indicating an interaction between these biomarkers.
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| 4. |
- Loftås, Per, 1964-
(författare)
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Response to neoadjuvant treatment in rectal cancer surgery
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Rectal cancer is one of the three most common malignancies in Sweden with an annual incidence of about 2000 cases. Current treatment consists of surgical resection of the rectum including the loco-regional lymph nodes in the mesorectum. In advanced cases, neoadjuvant chemo-radiotherapy (CRT) prior to the operative treatment reduces local recurrences and enables surgery. The neoadjuvant treatment can also eradicate the tumour completely, i.e. complete response. This research project was designed to investigate the effects of preoperative radiotherapy/ CRT and analyze methods to predict response to CRT.Study I investigated the expression of the FXYD-3 protein with immunohistochemistry in rectal cancer, with or without preoperative radiotherapy. The results from the total cohort showed that, strong FXYD-3 expression was correlated to infiltrative tumour growth (p = 0.02). In the radiotherapy group, strong FXYD-3 expression was related to an unfavourable prognosis (p = 0.02). Tumours with strong FXYD-3 expression had less tumour necrosis (p = 0.02) after radiotherapy. FXYD-3 expression in the primary tumour was increased compared to normal mucosa (p=0.008). We concluded that FXYD-3 expression was a prognostic factor in patients receiving preoperative radiotherapy for rectal cancer.Study II investigated FXYD-3 expression in tumours that developed local recurrences following surgery and compared this with expression in tumours that did not develop local recurrences. There was no difference in the expression of FXYD-3 between the group that developed local recurrences and the group that did not develop local recurrences. There was no difference in survival between those with strong or weak FXYD-3 expression. We concluded that this study could not confirm the findings from study 1 i.e. that FXYD-3 expression has prognostic significance in rectal cancer.Study III was a register-based study on the incidence and effects of complete response to neoadjuvant treatment. Eight per cent of the patients with adequate CRT to achieve complete response also had a complete histological response of the luminal tumor in the resected bowel. Sixteen per cent of that group had remaining lymph node metastases in the operative specimen. Chemotherapy together with radiotherapy doubled the chance of complete response in the luminal tumour. Patients with remaining lymph node metastases had a lower survival rate compared to those without. We concluded that residual nodal involvement after neoadjuvant treatment was an important factor for reduced survival after complete response in the luminal tumour.Study IV followed up the results from the previous study by re-evaluating magnetic resonance imaging (MRI)- images in patients with complete tumour response. Two experienced MRI radiologists performed blinded re-staging of post CRT MR- images from patients with complete response in the luminal tumour. One group with lymph node metastases and another one without were studied and the results compared with the pathology reports. The sensitivity, specificity, and positive and negative predicted values for correct staging of positive lymph nodes was 37%, 84%, 70% and 57%. The size of the largest lymph node (4.5 mm, p=0.04) seemed to indicate presence of a tumour positive lymph node. We concluded that MRI couldn’t correctly stage patients for lymph node metastases in patients with complete response to CRT in the luminal tumour.
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| 5. |
- Söderquist, Fanny
(författare)
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Melatonin in the gastrointestinal tract
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Melatonin is recognised as the pineal hormone regulating sleep and circadian rhythm. It has also been identified in peripheral tissues (mainly in animals) and thought to display a variety of actions, including anti-inflammatory properties, regulation of gastrointestinal (GI) functions, glucose homeostasis and beneficial effects in different tumour types. Patients with irritable bowel disorder commonly exhibit psychiatric co-morbidity and disturbances of the gut-brain axis have been proposed to play a role in these disorders. The focus of this thesis was to study melatonin and melatonin receptors in the normal human GI tract, the pancreas and small intestinal neuroendocrine tumours. The thesis also explores the complex relationship between GI symptoms and underlying psychiatric traits in the context of elevated levels of peripheral melatonin during waking hours.In paper I-II, tissue samples from the normal human GI tract and pancreas and tumour tissue from small intestinal neuroendocrine tumours were analysed for expression of melatonin and melatonin receptors using immunohistochemistry. For tumour patients, melatonin was also analysed in plasma and set in relation to symptoms and outcome. In paper III-IV, a cohort of young adults (18-25 years) seeking psychiatric care was examined for GI symptoms, melatonin levels in saliva, depressive symptoms and anxiety traits. Psychiatric assessments were performed using structured or semi structured interviews. Depressive symptoms were measured using the self-rating version of the Montgomery-Åsberg Depression Rating Scale; GI symptoms were measured using the Gastrointestinal Symptoms Rating Scale for Irritable Bowel Syndrome; and personality traits were evaluated using the Swedish Universities Scales of Personality.Melatonin and melatonin receptors were widely expressed in the normal human gut and pancreas (paper I) but even in small intestinal neuroendocrine tumours known to produce serotonin (paper II). The intensity of the melatonin immunoreactivity in tumour tissue was found to correlate with lower proliferation index. After treatment, plasma levels of melatonin were reduced in tumour patients. Young adult patients seeking psychiatric care reported more GI symptoms than healthy controls, regardless of the currently active psychotropic medication. The level of GI symptoms was associated with severity of depressive symptoms and trait anxiety (paper III). Higher postprandial levels of melatonin were associated with the GI symptoms of bloating and pain (paper IV).In summary, these findings demonstrate the widespread presence of melatonin in the human gut and confirm a link between melatonin, psychiatric health and GI symptoms.
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| 6. |
- Latini, Francesco, M.D. 1982-
(författare)
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Significance of white matter anatomy in interpreting features and behaviour of low-grade gliomas and implications for surgical treatment
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Diffuse gliomas are extremely heterogeneous tumours characterized by slow growth but extensive infiltration. Their kinetic features reflect the complex interaction over time with the surrounding brain, influencing treatment planning and outcome. Indeed, resection of diffuse gliomas present a surgical challenge due to their invasiveness and the preferential location in eloquent regions. White matter bundles are the main eloquent limit to surgical resection, but this anatomical-functional information cannot be predicted preoperatively on the individual level. The incomplete description of the human brain connectome, the complex application of pathological/lesion model to the brain connectomic organization, and the underestimated role of white matter anatomy in radiological classification systems are among the major limitations for the comprehension of the glioma/white matter interaction. The overall aim of this thesis was to explore a new approach and new techniques to study the glioma/white matter interaction. A combination of white matter dissection and diffusion tensor tractography (DTT) was used to describe the connectomic organization of two major temporo-occipital connections, the inferior and the middle longitudinal fasciculus. This information was applied to patients with diffuse gliomas, demonstrating how white matter analysis was important to decode patient specific cognitive and language impairment. A new classification system for diffuse gliomas, the Brain-Grid, was created, merging local radiological anatomy with a DTT atlas for infiltration analysis. This standardized radiological tool provided information on subcortical extension (tumour invasiveness), speed, and preferential direction of glioma progression. Applied to a larger cohort of patients, differences were detected between diffuse gliomas subtypes. Tumour invasiveness and the preferential location, type, and extent of white matter involvement differed, impacting overall survival. Regional differences in white matter infiltration were detected among five major white matter bundles, and possible favourable morphological and diffusion features were investigated with transmission electron microscopy and DTT. Fibre diameter, myelin thickness, and the organization of the white matter fibres were different in regions with high infiltration frequency, providing a possible link to the preferential location of diffuse gliomas. Finally, the white matter connectivity, tumour-induced neuroplasticity, clinical and demographic information, preoperative assessment (neuropsychological and language evaluation) were compared with intraoperative findings during awake surgery. Neuropsychological impairment was associated with more invasive tumours and a higher risk of the intraoperative finding of eloquent tumour. The pattern of early cortical neuroplasticity seemed exhausted at the time of diagnosis, with age as a factor predicting the neuroplasticity potential. The combined use of these new techniques revealed new insights into the glioma/white matter interaction. The results provided in this thesis, describe a new way to structure the multidisciplinary perioperative management of these patients. This new information may improve the functional outcome at the individual level, resulting in prolonged survival for adults with diffuse gliomas.
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| 7. |
- Wilms, Torben, 1973-
(författare)
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Squamous cell carcinoma of the head and neck, focusing on Epstein-Barr-virus, programmed cell death ligand 1 and serum lipoproteins
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Squamous cell carcinoma of the head and neck (SCCHN)comprises a large group of tumours including the oral cavity and nasopharyngealarea, and typically affects older males in association with alcohol/tobacco usage.Within the oral cavity, the mobile tongue is the most common site for tumourdevelopment. The incidence of squamous cell carcinoma of the oral tongue(SCCOT) is increasing in younger people, which has been suggested to associatewith other than the traditional risk factors for this disease. Two common humanoncogenic viruses, human papillomavirus (HPV) and Epstein-Barr virus (EBV)are connected to certain types of SCCHN, in oropharynx and nasopharynxrespectively. The receptor programmed cell death 1 (PD)-1 and its ligandprogrammed cell death ligand 1 (PD-L1) are particularly relevant in immunecheckpoint control, and elevated levels have been seen in various cancer types. Alink between hyperlipidemia and cancer risk has previously been suggested. Theaim of this thesis was to investigate risk factors and prognostic features forSCCHN, by focusing on EBV, PD-L1 and serum lipoproteins.Materials and methods: Ninety-eight cases of SCCOT and 15 cases of tonsillarsquamous cell carcinoma were examined for the presence of EBV-encodedribonucleic acids (EBERs), EBV deoxyribonucleic acid (DNA) and the proteinEBV-encoded nuclear antigen-1 (EBNA-1), using in situ hybridisation,polymerase chain reaction (PCR) and immunohistochemistry respectively. Onehundred and one cases of SCCOT were examined for expression of PD-L1 intumour and surrounding immune cells using Ventana SP263immunohistochemistry assay and a QuickScore (QS) method. An estimation oftumour-infiltrating immune cells was also performed in 25 of the patients.Circulating levels of PD-L1 were measured using an electrochemiluminescenceassay platform in serum from 30 patients. Finally, serum samples from 106patients and 28 healthy controls were investigated for levels of total cholesterol,low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides andlipoprotein(a).Results: In the first study, using an in situ hybridisation kit no EBER transcriptswere detected. No EBV DNA was identified with PCR analysis, andimmunohistochemistry for EBNA-1 was also negative. In the second study, highertumour cell PD-L1 levels were found in females than males (p = 0.019). Forpatients with low PD-L1 in tumour cells, better survival was shown in males thanfemales (overall survival p = 0.021, disease-free survival p = 0.020). Tumourinfiltrating natural killer (NK) T cells, immature dendritic cells (DCs) and M1macrophages correlated positively with tumour cell PD-L1 (p < 0.05). In the laststudy, the only lipoprotein showing significant difference in concentration iiibetween healthy controls and patients was HDL (p = 0.012). Kaplan-Meiersurvival curves showed that patients with high levels of total cholesterol or LDLhad better survival than patients with normal levels (p = 0.028 and p = 0.007respectively). Adjusting for the effects of age at diagnosis, TNM stage and weightchange, multivariate Cox regression models showed LDL to be an independentprognostic factor for both overall (p = 0.010) and disease-free survival (p =0.018).Conclusion: We excluded EBV as a potential player in SCCOT in both old andyoung patients and highlight the importance of appropriate controls for EBVencoded RNA in-situ hybridization (EBER-ISH) when investigating EBV inhuman diseases. Regarding PD-L1, our data supported the significance of genderon tumour cell PD-L1 expression and demonstrated combined effects of genderand PD-L1 levels on clinical outcome in patients with SCCOT. Data also indicatedthe involvement of specific immune cell types in PD-L1-regulated immuneevasion. Looking at serum lipoproteins, we found high LDL levels to be beneficialfor survival outcome in patients with SCCHN. Furthermore, the use of cholesterollowering medicine for prevention or management of SCCHN needs to be carefullyevaluated.
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| 8. |
- Haider, Zahra, 1988-
(författare)
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DNA methylation signatures in precursor lymphoid neoplasms : with focus on clinical implications & the biology behind
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Precursor lymphoid neoplasms, namely acute lymphoblastic leukemias (ALL) and lymphoblastic lymphomas (LBL), are characterized by an aggressive proliferation of malignant progenitor B- or T-cells. To improve risk classification at diagnosis, better prognostic and treatment stratifying biomarkers are needed. Altered DNA methylation pattern is a hallmark of neoplastic transformation, and has been employed as a molecular prognostic and predictive marker in various cancers, including hematological malignancies. Our research group previously identified a CpG island methylator phenotype (CIMP) panel that classified pediatric T-ALL patients into prognostic subgroups.The aim of this thesis was to evaluate distinct DNA methylation signatures in precursor lymphoid neoplasms, and to validate the prognostic value of CIMP classification in separate patient cohorts. Additionally, the biological mechanisms underlying the distinct CIMP methylation signatures in these malignancies were investigated.The prognostic relevance of CIMP classification was validated in an independent Nordic cohort of pediatric T-ALL patients. Combination of CIMP status with minimal residual disease (MRD) status, could further dissect the high-risk MRD positive T-ALL patients into two CIMP subgroups with significantly distinct outcomes. Furthermore, CIMP classification at diagnosis was shown to predict overall survival in relapsed BCP-ALL patients. CIMP methylation signatures were also identified in T-LBL patients, indicating a broader relevance of CIMP based classification in lymphoid malignancies. Investigating the biology behind CIMP methylation signatures showed the association of CIMP status with the proliferative history of the leukemic cells. A differential transcriptomic analysis revealed a correlation of CIMP subgroups with known T-ALL drivers, as well as with novel genes in T-ALL biology. Finally, we identified distinct DNA methylation patterns and genetic aberrations in T-ALL and T-LBL that might contribute to the different clinical presentation of these two diseases. In conclusion, we validated the prognostic significance of CIMP methylation signature in precursor lymphoid malignancies and identified transcriptomic profiles that associated with the subgroups. DNA methylation is a strong candidate for further risk classification in lymphoid neoplasms and our findings can contribute to the identification of new potential targets for treatment.
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| 9. |
- Kozlowski, Piotr, 1969-
(författare)
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Prognostic factors, treatment and outcome in adult acute lymphoblastic leukemia : Population-based studies in Sweden
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Acute lymphoblastic leukemia (ALL) has poor prognosis in older/elderly adults and in high-risk/relapsed disease. Recommended treatment of ALL was evaluated (study I-IV). Data was obtained from the Swedish Acute Leukemia registries and from patient records.I. We assessed ALL relapse treatment and outcome in 76 patients aged 15-65 years (y). Complete remission (CR) was achieved in 50/71 patients (70%). Of them, 29 underwent allogeneic hematopoietic stem cell transplantation (hSCT). Five year overall survival (OS) was 15%, but close to 50% in 19 patients <35y after hSCT.II. We studied outcome of treatment with the Hyper-CVAD protocol in 19 of 24 patients with T-ALL aged 18-72y. CR was reached in 89%, but 5y leukemia-free survival was only 29%, and 20% in 15 patients not transplanted in CR1. Six patients received hSCT in CR2. Finally, 5y OS in all 19 patients was 47%. The only negative prognostic factor found was age ≥35y.III. We evaluated minimal residual disease (MRD) monitoring in 35 patients with Philadelphia (Ph) negative B-ALL aged 46-79y and treated with the ABCDV protocol. The CR rate was 91%. MRD was measured by flow cytometry in 73% in CR1 (MRD1) and omitted in those >70y or with high-risk ALL. Five patients received hSCT (only one due to MRD). Five year OS in the whole cohort was 47%. Continuous CR but not OS was improved in patients with MRD1 <0.1 %.IV. We studied 155 patients with ALL (Ph+ in 35%) aged 55-85y and treated with remission induction/palliation (124/31). Both, intensive, and palliative treatment resulted in the CR rates of 70/83/16% and 3y OS of 26/32/3%. OS was negatively influenced by age and platelet count ≤35×109/L (but not Ph+). OS was not enhanced by introduction of an age-adapted protocol.We concluded that intensive treatment with subsequent allogeneic hSCT is the most reasonable option in younger patients with ALL recurrence (I). Hyper-CVAD has low relapse-preventing efficacy (II). MRD guided intensification is probably feasible in only a minority of older patients (III). Prognosis in elderly ALL is poor, but no longer impaired by Ph+ (IV).
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| 10. |
- Nordlund, Jessica
(författare)
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Gene Expression and DNA Methylation in Acute Lymphoblastic Leukemia
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Pediatric acute lymphoblastic leukemia (ALL) is the most common malignancy in children, which results from the malignant transformation of progenitor cells in the bone marrow into leukemic cells. The precise mechanisms for this transformation are not well defined, however recent studies suggest that aberrant regulation of gene expression or DNA methylation may play an important role. Hence, the aim of this thesis was to use novel methods to investigate genome-wide gene expression and DNA methylation patterns in a large collection of primary ALL cells from pediatric patients. With these studies, we aimed to increase the understanding of factors that regulate gene expression and DNA methylation in ALL.In the first study of the thesis we found that data obtained from genome-wide digital gene expression analysis enabled excellent cytogenetic subtype-specific classification of ALL cells and revealed new features of gene expression within the disease, such as prevalent antisense transcription and alternative polyadenylation. In the second study we used technology developed for large-scale single nucleotide polymorphism (SNP) genotyping for quantitative analysis of allele-specific gene expression (ASE), revealing widespread ASE in ALL cells. Analysis of DNA methylation in promoter regions of the genes displaying ASE using DNA-microarrays revealed frequent regulation of gene expression by DNA methylation. In the third study, using the same DNA methylation array, we identified differences in the DNA methylation patterns in ALL cells at diagnosis compared to healthy mononuclear cells from the bone marrow of the same children at remission. In the fourth study we measured the DNA methylation of >450,000 CpG sites across the genome in a large collection of ALL samples and non-leukemic control cells. We found that ALL cells displayed highly divergent DNA methylation patterns depending on their cytogenetic subtype and widespread regions of differential methylation were enriched for repressive histone marks. DNA methylation levels at distinct regions in the genome were substantially increased at relapse compared to matched cells from diagnosis.Collectively, the results presented in this thesis provide new insights into the patterns of gene expression and epigenetic changes in ALL and further increase our understanding of the development and progression of the disease, which will hopefully lead to better treatment options in the future.
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