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- Djureinovic, Tatjana, et al.
(author)
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The CHEK2 1100delC variant in Swedish colorectal cancer
- 2006
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In: Anticancer Research. - 0250-7005 .- 1791-7530. ; 26:6C, s. 4885-4888
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Journal article (peer-reviewed)abstract
- BACKGROUND: The cell cycle checkpoint kinase 2 (CHEK2) 1100delC variant has recently been identified at high frequency in families with both breast and colorectal cancer, suggesting the possible role of this variant in colorectal cancer predisposition. PATIENTS AND METHODS: To evaluate the role of CHEK2 ll00delC among Swedish colorectal cancer patients, the variant frequency was determined in 174 selected familial cases, 644 unselected cases and 760 controls, as well as in l8 families used in the genome-wide linkage analysis, where weak linkage was seen for the region harboring the CHEK2 gene. RESULTS: CHEK2 l100delC was found in 1.15% of familial and in 0.93% of unselected cases, compared to 0.66% of controls, showing no significant difference between groups. One out of 45 familial cases with a family history of breast cancer was shown to be a carrier. The variant was not identified in the 18 families included in the linkage analysis. CONCLUSION: The CHEK2 1100delC was not significantly increased in Swedish colorectal cancer patients, however, in order to determine the role of the variant in colorectal cancer families with the history of breast cancer a larger sample size is needed.
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| 2. |
- Lenander, Claes
(author)
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Molecular markers and new techniques in the evaluation of colorectal cancer
- 2002
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Doctoral thesis (other academic/artistic)abstract
- Colorectal cancer (CRC) is ranked in the Western world as the third leading cause of death from malignant tumors. Despite improvements in early detection of the disease, new surgical techniques and adjuvant and neoadjuvant chemoradiation, more than 50% of these patients die within 5 years. Patients suffering from colorectal polyps or ulcerative colitis run a considerable risk of developing CRC and may be used as models to study early cancer development. Furthermore, the origin of poorly differentiated pelvic adenocarcinomas often presents diagnostic difficulties and markers used for discrimination have to be interpreted with caution. Therefore, it is important to identify and evaluate new molecular markers and techniques used in diagnostics and for prognostic decision-making. The overall aim of this study was to elucidate and investigate how specific factors in colorectal premalignant and malignant tissue act as early markers for risk assessment, diagnosis, and prognosis. Other goals included the characterization of the protein expression profile of colorectal tumors in order to improve diagnostic decisionmaking as well as the development of a new method for evaluating the three-dimensional structure of tumor vessels. In ulcerative colitis, two surveillance groups with long-standing colitis and with similar risk factors were investigated. One group comprised patients with ulcerative colitis-associated colorectal carcinomas (UCC) who were compared to a control group. There was no difference in inflammatory activity and dysplasia between the two groups. One important finding was that aneuploid cell populations were scattered all over the colon and rectum early on during the observation period and almost exclusively in the group of patients finally developing UCC. Laminin-5 gamma2 chain (ln- 5)-positive cell populations were more frequently observed in the UCC group than in the controls. The ln-5 positive cells were distributed over the whole colon and rectum and did not correlate with dysplasia or inflammatory activity, but strongly with aneuploidy. According to the proliferation marker cyclin A, there was an increased expression in the UCC group during the surveillance period. Furthermore, the majority of the ln-5 and cyclin A-positive cells were aneuploid over a constructed cutoff point for high-risk level. Although this investigation is too small to yield reliable results, our data indicate that DNA assessment, In5 and cyclin A expression may help to identify patients at increased risk for cancer development in UC surveillance programs. Ln-5 expression was evaluated as a marker for early invasion and was found to increase progressively from hyperplastic polyps (0%) to tubular adenomas (12.5%) and, finally, adenomas with a villous component (25%). Furthermore, ln-5 was upregulated during progression toward a more malignant stage of colon cancer. In total, 15% of the investigated polyps stained positive for ln-5 as compared to 96% of the colon adenocarcinomas. Ln-5 expression was also correlated with increasing size in both polyps and carcinomas. Univariate analysis identified ln-5, tumor differentiation, and Dukes grade as significant variables in predicting prognosis. Our interpretation is that ln-5 expression can be used as a sensitive marker to trace early malignant transition and may also serve as an indicator of aggressiveness in colon carcinomas. We employed protein profiling to improve diagnostic decision-making in tumor samples where pathologic investigations did not give reliable results. A poorly differentiated adenocarcinoma of unclear origin in the pelvis served as a model for the evaluation of the method. Firstly, we characterized the protein expression profile in eight colon and seven ovarian carcinomas by using two-dimensional gel electrophoresis (2-DE). This was followed by a multivariate data analysis to match the protein profiles. Eighty-nine percent of the unclear tumor sample spots were matched with the colon standard gel, whereas only 63% of the spots could be matched with the ovarian standard. The degree of similarity was also assessed by correlation coefficient analysis (r-value calculation) in which the tested tumor sample showed an average r value of 0.70 (0.58-0.73) matched with the colon cancer, compared to 0.36 (0.3-0.41) matched with the ovarian cancer. Principal component analysis displayed the clustering of the unclear case within the colon cancer samples, whereas this case did not cluster at all within the group of ovarian adenocarcinomas. We conclude that these results show that 2-DE protein expression profiling combined with principal component analysis appears to be a sensitive method for diagnosing undifferentiated adenocarcinomas of unclear origin. Current standard methods do not provide information about the three-dimensional structure of the vessel biopsy specimens and further, hampered by the experience of the investigator's ability to identify and quantify angiogenic "hot spots". We developed a new fast and easy method to visualize vessels in human biopsy specimens. By using a computerized deconvolution technique, it was possible to facilitate the identification of three-dimensional vascular structures in normal and tumor specimens. Furthermore, this technique does not destroy the tissue surrounding the vessels (i.e. the tumor) and therefore it could be used in experimental studies to analyze for instance, tumor vessel morphology in response to angiogenic therapy.
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| 4. |
- Picelli, Simone, et al.
(author)
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Common variants in human CRC genes as low-risk alleles
- 2010
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In: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 46:6, s. 1041-1048
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Journal article (peer-reviewed)abstract
- The genetic susceptibility to colorectal cancer (CRC) has been estimated to be around 35% and yet high-penetrance germline mutations found so far explain less than 5% of all cases. Much of the remaining variations could be due to the co-inheritance of multiple low penetrant variants. The identification of all the susceptibility alleles could have public health relevance in the near future. To test the hypothesis that what are considered polymorphisms in human CRC genes could constitute low-risk alleles, we selected eight common SNPs for a pilot association study in 1785 cases and 1722 controls. One SNP, rs3219489:G>C (MUTYH Q324H) seemed to confer an increased risk of rectal cancer in homozygous status (OR = 1.52; CI = 1.06-2.17). When the analysis was restricted to our 'super-controls', healthy individuals with no family history for cancer, also rs1799977:A>G (MLH1 I219V) was associated with an increased risk in both colon and rectum patients with an odds ratio of 1.28 (CI = 1.02-1.60) and 1.34 (CI = 1.05-1.72), respectively (under the dominant model); while 2 SNPs, rs1800932:A>G (MSH6 P92P) and rs459552:T>A (APC D1822V) seemed to confer a protective effect. The latter, in particular showed an odds ratio of 0.76 (CI = 0.60-0.97) among colon patients and 0.73 (CI = 0.56-0.95) among rectal patients. In conclusion, our study suggests that common variants in human CRC genes could constitute low-risk alleles. (C) 2010 Elsevier Ltd. All rights reserved.
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| 5. |
- Rubio, Carlos A., et al.
(author)
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Reliability of the reported size of removed colorectal polyps
- 2006
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In: Anticancer Research. - 0250-7005 .- 1791-7530. ; 26:6C, s. 4895-4899
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Journal article (peer-reviewed)abstract
- Background: The size of colorectal polyps is important in the clinical management of these lesions. Aim: To audit the accuracy in calculating the size of polyps by various specialists. Materials and Methods: Eighteen pathologists and four surgeons measured, with a conventional millimetre ruler, the largest diameter of 12 polyp phantoms. The results of two independent measurements (two weeks apart) were compared with the gold standard-size assessed at The Royal Institute of Technology, Sweden. Results: Thirty-one percent (83/264-trial 1) and 33% (88/264-trial 2) of the measurements underestimated or overestimated the gold standard size by > 1 mm. Of the 22 experienced participants, 95% (21/22-trial 1) and 91% (20/22-trial 2) misjudged by > 1 mm the size of one or more polyps. Values given by 13 participants (4.9%) in trial I and by 15 participants (5.7%) in trial 2, differed by ! 4 mm from the gold standard size. In addition, a big difference between the highest and the lowest values was recorded in some polyps (up to 11.4 mm). Those disparate values were regarded as a human error in reading the scale on the ruler. Conclusion: Using a conventional ruler (the tool of pathologists worldwide) unacceptably high intra-observer and inter-observer variations in assessing the size of polyp-phantoms was found. The volume and the shape of devices, as well as human error in reading the scale of the ruler were confounding factors in size assessment. In praxis, the size is crucial in the management of colorectal polyps. Considering the clinical implications of the results obtained, the possibility of developing a method that will allow assessment of the true size of removed clinical polyps is being explored.
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