| 1. |
- Cederquist, Kristina, 1971-
(författare)
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Genetic and epidemiological studies of hereditary colorectal cancer
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer, HNPCC) is the most common hereditary syndrome predisposing to colorectal cancer, accounting for 1-3% of all colorectal cancer. This multi-organ cancer predisposition syndrome is caused by mutations in the mismatch repair (MMR) genes, especially MLH1 and MSH2, and to lesser extents MSH6 and PMS2, which lead to widespread genetic instability and thus microsatellite instability (MSI). Hereditary cancer often manifests in two or more tumours in a single individual; 35-40% of Lynch syndrome patients have synchronous or metachronous tumours of the two major Lynch syndrome-related cancers: colorectal and endometrial. The main purposes of the work underlying this thesis were to identify persons at risk of Lynch syndrome or other types of hereditary colorectal cancer, to estimate the cancer risks associated with these predispositions and to identify the underlying genetic causes. A population-based cohort of 78 persons with double primary colorectal or colorectal and endometrial cancer was identified. Cancer risks in their 649 first-degree relatives were estimated in relation to tumour MSI status (positive or negative) and age at diagnosis (before or after 50 years of age) in the probands. The overall standardised incidence ratio was 1.69 (95% CI; 1.39-2.03). The highest risks for Lynch syndrome-associated cancers: (colorectal, endometrial, ovarian and gastric) were found in families with young MSI-positive probands, likely representing Lynch syndrome families. Importantly, no overall risk was found in families with old probands, irrespective of MSI status. Blood samples were available from 24 MSI-positive patients for mutation screening of MLH1, MSH2 and MSH6. Sequence variants or rearrangements predicted to affect protein function were found in 16 patients. Six novel variants were found: two large rearrangements, two truncating and two missense mutations. The missense mutations were found to segregate in the families. Studies of allele frequencies, MSI and loss of immunostaning in tumours from family members further supports the hypothesis that these missense changes play a role in Lynch syndrome, as do the non-conservative nature and evolutionary conservation of the amino acid exchanges. Five families had mutations in MLH1, five in MSH2, and six in MSH6. The unexpectedly large impact of MSH6 was in genealogical studies shown to be due to a founder effect. Cumulative risk studies showed that the MSH6 families, despite their late age of onset, have a high lifetime risk for all Lynch syndrome-related cancers, significantly higher in women (89% by age 80 years) than in men (69%). The gender differences are in part due to high endometrial (70%) and ovarian cancer risk (33%) in addition to the high colorectal cancer risk (60%). These findings are of great importance for counselling and surveillance of families with MSH6 mutations. Finally, in a large family with MSI-negative hereditary colorectal cancer for which the MMR genes and APC had been excluded as possible causes, a genome-wide linkage analysis was performed, resulting in a suggested linkage to chromosome 7. Conclusions: Relatives of probands with MSI-positive, double primary colorectal and endometrial cancer diagnosed before the age of 50 years have significantly increased risks of Lynch syndrome-related cancers. MSH6 mutations, which have unusually high impact in this study population due to a founder effect, confer high cumulative risks of cancer despite the generally late age of onset.
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| 2. |
- Johansson, Mattias, 1977-
(författare)
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Prostate cancer aetiology : epidemiological studies of the IGF- and one-carbon metabolism pathways
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to investigate the involvement of the insulin-like growth factor- and the one-carbon metabolism pathways in prostate cancer aetiology, studying both circulating biomarkers and genetic variation. Papers included in the thesis were conducted within the case-control study CAncer Prostate in Sweden (CAPS), and the two prospective studies European Prospective Investigation into nutrition and Cancer (EPIC), and Northern Sweden Health and Disease Cohort (NSHDC).In paper I, we investigated the relation between genetic variants of the IGF1 gene and prostate cancer risk within the CAPS study. We found that a common haplotype within the 3’ region of the IGF1 gene is associated with increased prostate cancer risk.In paper II, we investigated if the variants of the IGF1 gene that were associated with prostate cancer risk in paper I, are also associated with circulating levels of IGF1. Circulating levels of IGF1 were analysed in controls from the CAPS study and three haplotype tagging SNPs (htSNPs) were genotyped in subjects from the NSHDC study in which circulating IGF1 had previously been analysed. The genetic variants previously associated with increased prostate cancer risk were now also found to be associated with elevated levels of circulating IGF1. We concluded that variation in the 3’ region of the IGF1 gene affects prostate cancer risk by influencing circulating levels of IGF1.In paper III, we investigated if variants of the IGFBP1, IGFBP3 and IGFALS genes are associated with i) prostate cancer risk, ii) circulating concentrations of total and intact IGFBP3, and iii) prostate cancer-specific survival probability. In addition, we investigated if circulating concentrations of total and intact IGFBP3 are associated with prostate cancer-specific survival probability. No association between genetic variation and overall prostate cancer risk or survival was observed, but we found a strong association between elevated levels of intact IGFBP3 and increased risk of prostate cancer-specific death. We could, however, not exclude that this association was confounded by treatment or by the tumour.In paper IV, we investigated if circulating levels of folate and vitamin B12 are associated with prostate cancer risk within the EPIC study. We observed no associations between levels of folate, vitamin B12 and overall prostate cancer risk, but elevated levels of vitamin B12 were associated with increased risk of advanced stage disease.In paper V, we investigated if circulating levels of ten B-vitamins and related metabolites within the one-carbon metabolism pathway are associated with prostate cancer risk within the NSHDC study. Overall positive associations with prostate cancer risk were observed for levels of choline, vitamin B2 and vitamin B12, and inverse associations were observed for levels of homocysteine and MMA. We also observed a biologically plausible risk modification by smoking status on the association between vitamin B12 and risk; in non-smokers vitamin B12 was positively associated with risk, whereas the association between vitamin B12 and risk was inverse or null in ever/current-smokers.In summary, our results suggest that genetic variation of the IGF1 gene affects prostate cancer risk by affecting circulating levels of IGF1. The association between circulating concentrations of intact IGFBP3 and prostate cancer-specific survival is intriguing, but further studies are needed to conclude if this association is caused by confounding. We also observed associations between several factors of one-carbon metabolism and risk, but these associations were statistically week and require confirmation in other prospective studies.
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| 3. |
- Lindmark, Fredrik, 1973-
(författare)
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Prostate cancer and inflammatory genes
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Prostate cancer remains a significant health concern for men throughout the world. Accumulating epidemiologic and molecular evidence suggests that inflammation is an important component in the aetiology of prostate cancer. Supporting this hypothesis, population studies have found an increased risk of prostate cancer in men with a prior history of certain sexually transmitted infections or prostatitis. More general evidence of a relationship between inflammation and prostate cancer has been provided by reports indicating that daily use of non steroidal anti-inflammatory drugs (NSAIDs) may be associated with a lower incidence of prostate cancer. The exact mechanism whereby inflammation might act in tumour development and progression remains to be elucidated, but is likely to be complex. The genetic contribution to inflammatory responses involved in the development of prostate cancer has not yet been extensively or systematically studied. However, this thesis evaluates the role of various inflammation-related genes in the pathogenesis of prostate cancer. The macrophage scavenger receptor 1 (MSR1) is a transmembrane protein that is mainly expressed by macrophages. This receptor mediates the binding, internalization and processing of a wide range of macromolecules, and is suggested to play a major role in the recognition and clearance of pathogenic and damaged cells. Recent reports have suggested MSR1 to be a candidate gene for hereditary prostate cancer. Therefore, we screened the MSR1 gene among men with hereditary prostate cancer and identified 18 sequence variants. One previously reported truncation mutation was found more frequently in men with prostate cancer than in unaffected men, in accordance with previously published results. However, the difference in frequencies we found between these groups was not statistically significant. In addition, we genotyped five common polymorphisms in MSR1 in 215 men with unselected prostate cancer and 425 controls. No association between any of the five common variants and prostate cancer were found. We then performed a comprehensive genetic study using extensive populationbased case-control material to evaluate possible associations between sequence variants in inflammation-related genes and prostate cancer. The first gene to be examined was interleukin-1 receptor antagonist (IL-1-RN), encoding a cytokine that plays an important role in regulation of the inflammatory response by binding to the IL-1 receptor and thus inhibiting the binding of the pro-inflammatory cytokines IL-1α and IL-1β. Collectively, these three cytokines exert a central role in the protection against diverse lesions, ranging from microbial colonisation to infection and malignant transformation. The genetic analysis of IL-1RN revealed that the most common haplotype was significantly associated with prostate cancer risk for patients with prostate cancer, and further this association appears to be stronger in cases with advanced disease. The macrophage inhibitory cytokine-1 (MIC-1), a member of the transforming growth-factor-β superfamily has been shown to exert diverse biological functions, including regulation of macrophage activity in the inflammatory response and both growth inhibition and induction of apoptosis in epithelial and other tumour cell lines. The genetic analysis of MIC-1 revealed that a seuqence variant (H6D) appears to be associated with a decreased prostate cancer risk. We also performed measurements of MIC-1 serum levels among patients with prostate cancer and healthy controls. These data indicate that serum MIC-1 levels are associated with an increased risk for prostate cancer. Further, the clear relation between clinical stage and MIC-1 level also suggest that MIC-1 may be useful as a prognostic factor, where high serum concentration is associated with a poor prognosis. In summary, our results provide further support for the assumption that polymorphisms in inflammatory genes play critical roles in prostate cancer susceptibility. Additional studies are needed to elucidate the mechanisms whereby the demonstrated variations contribute to prostate cancer development.
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| 4. |
- Lindström, Sara, 1979-
(författare)
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Genetic variation and prostate cancer : population-based association studies in Sweden
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Prostate cancer constitutes the most common malignancy and the most common cause of cancer‐related death in Swedish men. A large body of evidence suggests that inherited genetic variants contribute to both development and progression of prostate cancer. The aim of this thesis is to identify genetic variants that alter prostate cancer risk and progression. All papers included in this thesis are based on a Swedish population‐based case‐control study (CAPS) comprising 2,965 incident prostate cancer cases and 1,823 controls.In paper I, we investigated if genetic variants in the E‐cadherin gene altered prostate cancer risk. Seven haplotype tagging SNPs(tagSNPs) were selected and genotyped in CAPS and families with hereditary prostate cancer. We confirmed association of a promoter SNP rs16260 previously reported to increase risk of hereditary prostate cancer (OR: 2.6; 95% CI: 1.6‐4.3) for homozygous ‘A’ carriers.In paper II, we assessed 46 polymorphisms earlier reported to be associated with prostate cancer risk. Six polymorphisms in five different genes were replicated. Interestingly, three of these genes were involved in the androgen biosynthesis.In paper III, we followed up on the results from paper II by genotyping 23 tagSNPs located in the hormone regulating genes AR, CYP17 and SRD5A2. Multiple SNPs and haplotypes were associated withprostate cancer risk, especially in the AR gene. Combining risk alleles from all genes revealed a substantial risk increase for each additional allele carried (OR: 1.12; 95% CI: 1.1‐1.2, P=0.00009).In paper IV, we collected information about cause of death for all case patients in CAPS. At time of follow‐up 300 study subjects were deceased from prostate cancer. We assessed AR, CYP17 and SRD5A2 variants for association with lethal prostate cancer and found overall no association. However, one AR promoter SNP was associated with an increased risk of dying from prostate cancer amongst men who received palliative hormonal therapy as primary treatment.In paper V, we assessed common genetic variation at the ERG locus for association between prostate cancer risk and survival. ERG is recognized as a protooncogene frequently overexpressed in prostate cancer. A total of 21 tagSNPs in the 5’ region of ERG were genotyped. There was no correlation between ERG SNPs and prostate cancer risk but common genetic variation located approximately 100,000 basepairs upstream of ERG was significantly associated with prostate cancer specific survival.In summary, our results suggest that common genetic variation in Ecadherin alters prostate cancer risk in Swedish men with a positive family history of prostate cancer. Moreover, common genetic variation in the androgen‐related genes AR, CYP17 and SRD5A2 affects the risk of developing prostate cancer but is unlikely to alter prostate cancer progression. However, genetic variants in AR may affect hormonal therapy response. Finally, ERG polymorphisms are associated with prostate cancer‐specific death but are not likely to play a role in prostate cancer development.
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| 5. |
- Thellenberg Karlsson, Camilla, 1972-
(författare)
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Prostate cancer : epidemiological studies of risk factors
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In spite of the fact that prostate cancer is the most common male cancer in both Sweden and many other countries in the developed world, little is known of risk factors and predisposing conditions. The only well recognized risk factors are age, race and familial aggregation. More knowledge about risk factors could lead to better preventive measures together with better treatments. One way to evaluate this is to study second primary cancers; the connection between two different cancers can give valuable insight in etiology or clues to shared risk factors. This thesis aims at evaluating risk factors for prostate cancer. We constructed a cohort of 135,713 men diagnosed with prostate cancer and reported to the Swedish Cancer Registry 1958-1996. The cohort was followed for second primary cancers and a doubled risk of male breast cancer was found. We also noted increased risks for small intestine cancers and melanoma. As a follow-up on the increased risk of male breast cancer, we performed a nested case – control study. Included cases were men with first prostate and then breast cancer (n = 41) matched to men with only prostate cancer (n =81). For these men, we collected medical records and extracted data regarding treatment. Furthermore, all men diagnosed with both prostate and breast cancer irrespective which came first (n = 83) were used as probands. To both these sets of cases with breast and prostate cancer, we identified first degree relatives and grandchildren from parish offices throughout Sweden. Linking to the Cancer Registry retrieved all cancer diagnoses amongst relatives. Results from this study show a relation between estrogen treatment of prostate cancer and the risk of developing breast cancer. We also found that a small part of the cases with both cancers appeared in families with inheritance patterns possibly attributed to BRCA2. As estrogen treatment seemed involved in increased risk of breast cancer after prostate cancer, we wanted to investigate the newly discovered Estrogen receptor β and the relation to prostate cancer risk. Previous reports have shown that ERβ acts as a negative regulator of proliferation. ERβ expression occurs mainly in prostatic epithelial cells and the expression gradually diminishes when cancer develops and aggravates. We used a single nucleotide polymorphism (SNP) association study approach to evaluate genetic variation in ERβ as a risk factor for prostate cancer. One SNP, located in the promoter region associated with a small increased risk of prostate cancer whereas variation in the rest of the gene did not. In the last paper, we investigated trans-urethral resection (TURP) of the prostate due to benign prostate hyperplasia (BPH) as a risk factor for later development of prostate cancer. Evidence has gathered that both BPH and prostate cancer are associated to inflammation. By comparing incidence and mortality in a cohort of 7,901 men with the general population there appeared to be an increased risk of prostate cancer but decreased mortality. Analyzing this increased risk further, we conducted a nested case - control study with men extracted from the cohort. Cases had a TURP and later developed prostate cancer and controls just had a TURP. We then evaluated the specimens from TURP regarding extent of inflammation, degree of androgen receptor down regulation and expression of p53, all factors previous associated with prostate cancer. None of these parameters differed between cases and controls and they can therefore not explain the increased risk. Decreased mortality but increased risk might be explained by surveillance bias, which means more medical attention to these patients, resulting in diagnosing clinically non-significant cancers. In summary, our results show a doubled risk of male breast cancer following prostate cancer. A risk that can be attributed to the use of estrogen to treat prostate cancer or to some extent a possible mutation in BRCA2. We also propose that a SNP change in the ERβ promoter confer a small increased risk of prostate cancer. A small risk elevation of prostate cancer following TURP most probable could depend on surveillance bias.
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