| 1. |
- Halvarsson, Britta, et al.
(författare)
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Loss of mismatch repair protein immunostaining in colorectal adenomas from patients with hereditary nonpolyposis colorectal cancer.
- 2005
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Ingår i: Modern Pathology. - : Elsevier BV. - 1530-0285 .- 0893-3952. ; 18:8, s. 1095-1101
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal adenomas occur at younger age, at increased frequency and have a greater tendency for malignant transformation in patients with hereditary nonpolyposis colorectal cancer (HNPCC). We performed immunostaining for the mismatch repair proteins MLH1, PMS2, MSH2 and MSH6 in 35 colorectal adenomas from 26 patients with HNPCC and identified loss of immunostaining in 23/35 (0.66) adenomas. Loss of mismatch repair protein immunostaining was particularly frequent in large (>5 mm) (14/16) and proximally located (13/15) adenomas, whereas the gene mutated - MLH1 or MSH2 - and the type of mutation did not seem to affect the results. We conclude that loss of mismatch repair protein immunostaining is detected at a lower rate in adenomas than in carcinomas associated with HNPCC. Adenomatous tissue can thus be used for immunostaining of mismatch repair proteins in clinical investigations of HNPCC, but whereas loss of immunostaining may pinpoint the gene affected and thereby guide mutation analysis, retained staining cannot exclude that the adenoma developed as part of the syndrome due to reduced sensitivity. However, the analysis has a greater chance of being informative if large and proximally located adenomas are selected.
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| 2. |
- Halvarsson, Britta, et al.
(författare)
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The added value of PMS2 immunostaining in the diagnosis of hereditary nonpolyposis colorectal cancer.
- 2006
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Ingår i: Familial Cancer. - : Springer Science and Business Media LLC. - 1389-9600 .- 1573-7292. ; 5:4, s. 353-358
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Tidskriftsartikel (refereegranskat)abstract
- dentification and characterization of the genetic background in patients with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome is important since control programmes can in a cost-effective manner prevent cancer development in high-risk individuals. HNPCC is caused by germline mismatch repair (MMR) gene mutations and the genetic analysis of HNPCC therefore includes assessment of microsatellite instability (MSI) and immunohistochemical MMR protein expression in the tumor tissue. MSI is found in >95% of the HNPCC-associated tumors and immunostaining using antibodies against the MMR proteins MLH1, MSH2, and MSH6 has been found to correctly pinpoint the affected gene in about 90% of the cases. The PMS2 antibody was the most recently developed and we have in a clinical material assessed the added value of PMS2 immunostaining in 213 patients with suspected hereditary colorectal cancer. All 119 MSS tumors showed retained expression for all four antibodies and PMS2 did thus not identify any underlying MMR defect in these cases. However, PMS2 immunostaining contributed to the characterization of the MMR defect in a subset of the MSI tumors. Concomitant loss of MLH1 and PMS2, which functionally interact in the MutL alpha complex, was found in 98% of the tumors from patients with germline MLH1 mutations. Among the 12 MSI-high tumors with retained expression of MLH1, MSH2 and MSH6, 8 tumors showed loss of PMS2 staining, and mutations in MLH1 were identified in 2 and mutations in PMS2 in 3 of these individuals. In summary, isolated loss of PMS2 was found in 8% of the MSI-high tumors in our series, including 8/12 previously unexplained MSI-high tumors, in which mutations either in MLH1 or in PMS2 were identified in five cases.
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| 3. |
- Hammar, Björn, et al.
(författare)
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A new corneal disease with recurrent erosive episodes and autosomal-dominant inheritance
- 2008
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Ingår i: Acta Ophthalmologica. - : Wiley. - 1755-375X .- 1755-3768. ; 86:7, s. 758-763
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The aim of this study was to characterize the phenotype in a large family with autosomal-dominant recurrent corneal erosions, and also to exclude genetic linkage to known autosomal-dominant inherited corneal dystrophies with clinical resemblance. Methods: We describe the medical history and clinical findings in patients from a six-generation family with recurrent corneal erosions. A total of 28 individuals were evaluated by ophthalmological examination. Genomic DNA was prepared from peripheral blood and analysed with polymorphic microsatellite markers close to known genes causing autosomal-dominant corneal dystrophies. Results: The patients had erosive symptoms that usually lasted from 1 to 7 days. The symptoms were described as early as at 8 months of age, and by the age of 5 the majority of the affected individuals suffered from recurrent corneal erosions. The attacks generally declined in frequency and intensity with age, and 52% of the patients developed central keloid-like corneal opacities. Nine patients received corneal grafts, and recurrences were seen in all grafts. The affected patients did not share haplotypes for genetic microsatellite markers surrounding known genes causing autosomal-dominant corneal dystrophies. Conclusion: We describe a new hereditary disease with recurrent corneal erosions. Attacks of symptoms similar to recurrent erosions dominate the phenotype, but half of those affected also developed corneal, keloid-like, central opacities. This disorder was not genetically linked to any clinically resembling corneal dystrophies with autosomal-dominant inheritance.
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| 4. |
- Hammar, Björn, et al.
(författare)
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Dystrophia Helsinglandica : a new type of hereditary corneal recurrent erosions with late subepithelial fibrosis
- 2009
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Ingår i: Acta ophthalmologica. - : Wiley. - 1755-3768 .- 1755-375X. ; 87:6, s. 659-667
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To describe the phenotype of an autosomal-dominant corneal dystrophy with an early onset of recurrent corneal erosions and development of subepithelial fibrosis in the cornea, and also to exclude genetic linkage to known corneal dystrophies with autosomal-dominant inheritance and clinical resemblance. Methods: We describe the medical history and clinical findings in individuals from a seven-generation family with recurrent corneal erosions. A total of 43 individuals were evaluated by ophthalmological examination. Genomic DNA was prepared from peripheral blood and polymorphic microsatellite markers were analysed to study haplotypes surrounding genes causing corneal dystrophies with similar phenotypes. Results: Erosive symptoms usually lasted for between 1 and 10 days. By the age of 7 almost all of the affected individuals suffered from recurrent corneal erosions. The attacks generally declined in frequency and intensity from the late 20s, but all examined individuals had developed subepithelial fibrosis by the age of 37. The fibrosis generally started in the mid periphery and was followed in some family members by central fibrosis and the development of gelatinous superficial elevations. Only a marginal reduction of visual acuity was seen in a few individuals. The affected individuals did not share haplotypes for genetic microsatellite markers surrounding genes that are known to cause autosomal-dominant corneal dystrophies. Conclusion: We describe a new type of autosomal-dominant corneal disorder with recurrent corneal erosions and subepithelial fibrosis not significantly affecting visual acuity.
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| 5. |
- Lagerstedt, Kristina, 1976
(författare)
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Genetic Analyses of Tumor Progression in Colorectal Cancer
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Colorectal tumors are responsible for more than 600 000 deaths per year worldwide and thereby constitute the second most common cause of cancer related mortality. Early detection is related to improved prognosis and identification of genetic biomarkers would meliorate available diagnostic tools. Existing tumor classification systems lack precise monitoring within individual tumor stages in relation to progression. Therefore, we performed genetic characterization of tumor progression by analyses of colorectal tumors and normal colon mucosa. We used combined microarray analysis to obtain a set of candidate biomarkers, starting with genome-wide array-based DNA analyses to screen for tumor-specific aberrant DNA patterns followed by correlations to the associated changes in mRNA and microRNA expression. We also investigated the relation between functional p53 and tumor progression as well as survival in patients with colorectal cancer (CRC). Furthermore, we used high resolution oligonucleotide array based CGH to identify nonpolymorphic structural variation in DNA from normal colon biopsies from patients with confirmed CRC to reveal candidate regions with association to putative familial CRC genetic variants. Colorectal tumor progression is proposed to follow a step-wise transformation from normal cells into malignant tumors, and therefore we used different stages within this model to summarize our results, in terms of genetic events of potential importance. First, gain in parts of chromosome 20 encompassing AURKA, as well as alterations in p53 (17p13.1), may be involved in the development from adenoma to carcinoma. Second, loss of 18q and gain of 8q harboring SMAD7 and PTP4A3 appear to rise during progression defined as early (Dukes A and B) to late (Dukes C and D) tumor stage. Third, distant metastatic potential may be associated to loss of 8p and increased expression of miR-373. Fourth, putative structural variants observed in normal colon mucosa may predispose for the onset of malignant transformation in familial sporadic CRC. Finally, there is a clear relationship between increased properties of aberrant DNA content as well as the number of combined genetic events and tumor progression. We conclude that correlated changes in DNA and RNA abundance may represent a robust rationale for selection of genetic biomarkers. Moreover, our results also suggest that Dukes D tumors possibly develop in a way that does not fit into the stepwise progression model, illustrated by earlier onset and less genetic aberrations. These results represent a set of genetic events that can hopefully contribute to improved procedures considering diagnosis and prognosis in CRC patients by providing genetic biomarkers.
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| 6. |
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| 7. |
- Lagerstedt, Kristina, 1976, et al.
(författare)
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The role of combined allelic imbalance and mutations of p53 in tumor progression and survival following surgery for colorectal carcinoma
- 2005
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Ingår i: International journal of oncology. - 1019-6439. ; 27:6, s. 1707-15
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Tidskriftsartikel (refereegranskat)abstract
- The role of p53 mutations in disease progression and survival of colorectal cancer is unclear, since numerous studies have reported different conclusions. However, few reports, if any, have evaluated disease progression and survival in relationship to 'functional' and 'non-functional' p53 status defined by genetic and molecular indications. Malignant colorectal tumors, from 72 unselected patients who underwent primary and potentially curative elective tumor resections, were either classified as p53 functional (p53+/+, p53+/-) or non-functional (p53-/-) based on DNA sequence analysis of all p53 exons, including determination of allelic imbalance of p53 (LOH), according to four DNA markers; 2 within the coding gene and two markers in the immediate flanking regions of p53. Tumor frequency of microsatellite instability was also analyzed according to Dukes' A-D stages. Dukes' staging predicted survival as expected, while the conceptual p53 status, functional p53 vs non-functional p53, did not clear-cut predict disease specific survival. p53 mutations alone or allelic imbalance inside the reading frame of the gene were unpredictive of survival, while allelic imbalance downstream of p53 predicted reduced survival (p < 0.05). The present study demonstrates that base mutations in combination with allelic imbalance within the reading frame of p53 do not predict survival or progression of colorectal cancer, while allelic imbalance upstream coding parts of the gene predicted disease-specific survival in univariate analysis. Thus, structural alterations within the gene seem less important than alterations in regions with potential control elements.
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| 8. |
- Lagerstedt, Kristina, 1976, et al.
(författare)
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Tumor Genome Wide DNA Alterations Assessed by Array CGH in Patients with Poor and Excellent Survival Following Operation for Colorectal Cancer.
- 2007
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Ingår i: Cancer informatics. - 1176-9351. ; 3, s. 341-55
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Tidskriftsartikel (refereegranskat)abstract
- Genome wide DNA alterations were evaluated by array CGH in addition to RNA expression profiling in colorectal cancer from patients with excellent and poor survival following primary operations.DNA was used for CGH in BAC and cDNA arrays. Global RNA expression was determined by 44K arrays. DNA and RNA from tumor and normal colon were used from cancer patients grouped according to death, survival or Dukes A, B, C and D tumor stage. Confirmed DNA alterations in all Dukes A - D were judged relevant for carcinogenesis, while changes in Dukes C and D only were regarded relevant for tumor progression.Copy number gain was more common than loss in tumor tissue (p < 0.01). Major tumor DNA alterations occurred in chromosome 8, 13, 18 and 20, where short survival included gain in 8q and loss in 8p. Copy number gains related to tumor progression were most common on chromosome 7, 8, 19, 20, while corresponding major losses appeared in chromosome 8. Losses at chromosome 18 occurred in all Dukes stages. Normal colon tissue from cancer patients displayed gains in chromosome 19 and 20. Mathematical Vector analysis implied a number of BAC-clones in tumor DNA with genes of potential importance for death or survival.The genomic variation in colorectal cancer cells is tremendous and emphasizes that BAC array CGH is presently more powerful than available statistical models to discriminate DNA sequence information related to outcome. Present results suggest that a majority of DNA alterations observed in colorectal cancer are secondary to tumor progression. Therefore, it would require an immense work to distinguish primary from secondary DNA alterations behind colorectal cancer.
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| 9. |
- Lönnroth, Christina, 1946, et al.
(författare)
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Preoperative treatment with a non-steroidal anti-inflammatory drug (NSAID) increases tumor tissue infiltration of seemingly activated immune cells in colorectal cancer.
- 2008
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Ingår i: Cancer immunity : a journal of the Academy of Cancer Immunology. - 1424-9634. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- This study evaluates HLA gene expression and tumor infiltration by B-cells, macrophages, dendritic cells, T-helper and cytotoxic T-lymphocytes in response to short-term preoperative treatment with cyclooxygenase inhibitors. Patients with colorectal carcinoma were randomized to receive oral NSAID (indomethacin or celebrex) for three days preoperatively; controls received esomeprazol. Peroperative tumor biopsies and normal colon tissue were analyzed by microarray, quantitative PCR and immunohistochemistry. Efficacy of short-term systemic NSAID treatment was confirmed by measurement of PGE2 production in blood monocytes from healthy volunteers. NSAID treatment upregulated genes at the MHC locus on chromosome 6p21 in tumor tissue, but not in normal colon tissue, from the same patient. 23 of the 100 most upregulated genes belonged to MHC class II. HLA-DM, -DO (peptide loading), HLA-DP, -DQ, -DR (antigen presentation), granzyme B, H, perforin and FCGR3A (CD16) (cytotoxicity) displayed increased expression, as did CD8, a marker of cytotoxic T-lymphocytes, while HLA-A and -C expression were not increased by NSAID treatment. MHC II protein (HLA-DP, -DQ, -DR) levels and infiltration by CD4+ T-helper cells of tumor stroma increased upon NSAID treatment, while CD8+ cytotoxic T-lymphocytes increased in both tumor stroma and epithelium. Molecules associated with immunosuppressive T regulatory cells (FOXP3, IL-10) were significantly decreased in indomethacin-exposed tumors. Standard oral administration of NSAID three days preoperatively was enough to increase tumor infiltration by seemingly activated immune cells. These findings agree with previous information that high prostanoid activities in colorectal cancer increase the risk for reduced disease-specific survival following tumor resection.
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| 10. |
- Robinson, Kristina Lagerstedt, et al.
(författare)
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Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics
- 2007
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 99:4, s. 291-299
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Tidskriftsartikel (refereegranskat)abstract
- Background Preventive programs for individuals who have high lifetime risks of colorectal cancer may reduce disease morbidity and mortality. Thus, it is important to identify the factors that are associated with hereditary colorectal cancer and to monitor the effects of tailored surveillance. In particular, patients with Lynch syndrome, hereditary nonpolyposis colorectal cancer (HNPCC), have an increased risk to develop colorectal cancer at an early age. The syndrome is explained by germline mutations in DNA mismatch repair (MMR) genes, and there is a need for diagnostic tools to preselect patients for genetic testing to diagnose those with HNPCC. Methods Patients (n = 112) from 285 families who were counseled between 1990 and 2005 at a clinic for patients at high risk for HNPCC were selected for screening to detect mutations in MMR genes MLH1, MSH2, MSH6, and PMS2 based on family history, microsatellite instability (MSI), and immunohistochemical analysis of MMR protein expression. Tumors were also screened for BRAF V600E mutations; patients with the mutation were considered as non-HNPCC. Results Among the 112 patients who were selected for screening, 69 had germline MMR mutations (58 pathogenic and 11 of unknown biologic relevance). Sixteen of the 69 mutations (23%) were missense mutations. Among patients with MSI-positive tumors, pathogenic MMR mutations were found in 38 of 43 (88%) of patients in families who met Amsterdam criteria and in 13 of 22 (59%) of patients in families who did not. Among patients with MSI-negative tumors, pathogenic MMR mutations were found in 5 of 17 (29%) of families meeting Amsterdam criteria and in 1 of 30 (3%) of non-Amsterdam families with one patient younger than age 50 years. In three patients with MSI-negative tumors who had pathogenic mutations in MLH1 or MSH6, immunohistochemistry showed loss of the mutated protein. Conclusion Our findings suggest that missense MMR gene mutations are common in HNPCC and that germline MMR mutations are also found in patients with IVISI-negative tumors.
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| 11. |
- Vandrovcova, Jana, et al.
(författare)
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Somatic BRAF-V600E Mutations in Familial Colorectal Cancer
- 2006
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 15:11, s. 2270-2273
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Tidskriftsartikel (refereegranskat)abstract
- The BRAF gene is mutated in 4% to 12% of unselected colorectal cancers, particularly those with high microsatellite instability and in premalignant lesions, such as serrated adenomas and hyperplastic polyps. However, it has been shown that activating BRAF mutations are almost never found in tumors from hereditary nonpolyposis colorectal cancer patients. To evaluate the role of oncogenic BRAF mutations in non-hereditary nonpolyposis colorectal cancer/ non-familial adenomatous polyposis familial colorectal cancer, we did a mutation screening of the most common BRAT mutation, the V600E mutation, in 194 colorectal tumors from patients with a positive family history of the disease. The BRAF-V600E mutation was identified in 100% (8 of 8) of microsatellite-unstable tumors and in 9.7% (18 of 186) of microsatellite-stable tumors. Interestingly, families with extracolonic tumors showed a much higher mutation frequency (17.5%) compared with families with colonic cancer only (3.5%; P = 0.009). In addition, we studied colonoscopic results from 448 family members who had been under colonoscopic surveillance for several years. Subjects from families where the V600E mutation was identified had less adenomas compared with those from families where no BRAT mutation had been found (odds ratio, 8.5; 95% confidence interval, 1.1-64.6). These findings indicate that adenomas might be less important in the cancer development in the group of families with BRAF-V600E mutations and indirectly support a previous hypothesis that tumors might develop through the yperplastic polyp-serrated adenoma pathway. In conclusion, our results suggest that BRAF-V600E mutations are mainly involved in colorectal. cancer families characterized by an increased risk of other common malignancies.
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