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Common variants in human CRC genes as low-risk alleles.

https://arctichealth.org/en/permalink/ahliterature98081
Source
Eur J Cancer. 2010 Apr;46(6):1041-8
Publication Type
Article
Date
Apr-2010
Author
Simone Picelli
Pawel Zajac
Xiao-Lei Zhou
David Edler
Claes Lenander
Johan Dalén
Fredrik Hjern
Nils Lundqvist
Ulrik Lindforss
Lars Påhlman
Kennet Smedh
Anders Törnqvist
Jörn Holm
Martin Janson
Magnus Andersson
Susanne Ekelund
Louise Olsson
Joakim Lundeberg
Annika Lindblom
Author Affiliation
Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
Source
Eur J Cancer. 2010 Apr;46(6):1041-8
Date
Apr-2010
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
Aged
Alleles
Case-Control Studies
Colorectal Neoplasms - epidemiology - genetics
Female
Genetic Predisposition to Disease - epidemiology - genetics
Genome-Wide Association Study
Genotype
Germ-Line Mutation - genetics
Humans
Male
Middle Aged
Penetrance
Polymorphism, Genetic
Risk factors
Sweden - epidemiology
Young Adult
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.
PubMed ID
20149637 View in PubMed
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Detection of thymidylate synthase expression in lymph node metastases of colorectal cancer can improve the prognostic information.

https://arctichealth.org/en/permalink/ahliterature16895
Source
J Clin Oncol. 2005 Aug 20;23(24):5628-34
Publication Type
Article
Date
Aug-20-2005
Author
Katarina Ohrling
David Edler
Marja Hallström
Peter Ragnhammar
Henric Blomgren
Author Affiliation
Department of Oncology at Radiumhemmet, Karolinska University Hospital, S-171 76 Stockholm, Sweden. katarina.ohrling@karolinska.se
Source
J Clin Oncol. 2005 Aug 20;23(24):5628-34
Date
Aug-20-2005
Language
English
Publication Type
Article
Keywords
Aged
Chemotherapy, Adjuvant
Chi-Square Distribution
Colorectal Neoplasms - enzymology - pathology - therapy
Female
Humans
Lymph Nodes - metabolism - pathology
Lymphatic Metastasis
Male
Middle Aged
Predictive value of tests
Prognosis
Proportional Hazards Models
Randomized Controlled Trials
Research Support, Non-U.S. Gov't
Retrospective Studies
Survival Analysis
Thymidylate Synthase - metabolism
Abstract
PURPOSE: The level of thymidylate synthase (TS) in primary colorectal cancer (CRC) has been reported as a prognostic marker. The purpose of this study was to determine whether TS expression in lymph node metastases of Dukes' C CRC is a prognostic marker. PATIENTS AND METHODS: TS expression in the primary tumor and lymph node metastases from 348 patients with Dukes' C CRC was retrospectively assessed using immunohistochemistry and the monoclonal antibody TS 106. The patients had all been enrolled onto our previous study of 862 CRC patients who were included in Nordic trials that randomly assigned the patients to either surgery alone or surgery plus adjuvant chemotherapy. RESULTS: TS expression in lymph node metastases was a distinct prognostic marker in the entire study group for overall survival (OS; P = .02) and disease-free survival (DFS; P = .04). A low TS expression in the lymph node metastases correlated with a better clinical outcome. In the subgroup of patients treated with surgery alone, the expression of TS in lymph node metastases also had a prognostic value for OS (P = .04) and DFS (P = .03), but this was not the case for the other subgroup who received adjuvant fluorouracil-based chemotherapy (OS, P = .5; DFS, P = .2). The expression of TS in the primary tumor only had a significant prognostic value among patients who were treated with surgery alone (OS, P = .03; DFS, P = .03) and not among the entire patient population. CONCLUSION: These data show that TS expression in lymph node metastases is a prognostic marker for patients with Dukes' C CRC.
Notes
Comment In: J Clin Oncol. 2005 Aug 20;23(24):5452-416009953
PubMed ID
16009948 View in PubMed
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Mismatch repair protein expression is an independent prognostic factor in sporadic colorectal cancer.

https://arctichealth.org/en/permalink/ahliterature97622
Source
Acta Oncol. 2010 Aug;49(6):797-804
Publication Type
Article
Date
Aug-2010
Author
Katarina Ohrling
David Edler
Marja Hallström
Peter Ragnhammar
Author Affiliation
Karolinska Institutet, Department of Oncology-Pathology, CCK, R8:03, Karolinska University Hospital Solna, S-171 76 Stockholm, Sweden. katarina.ohrling@karolinska.se
Source
Acta Oncol. 2010 Aug;49(6):797-804
Date
Aug-2010
Language
English
Publication Type
Article
Abstract
Abstract Background. Mismatch repair (MMR) status has been reported as a prognostic and predictive factor in sporadic colorectal cancer (CRC). The purpose of this study was to determine the prognostic and predictive value of MMR protein expression in the adjuvant setting. Patients and methods. The MMR status in the primary tumor was retrospectively assessed on paraffin-embedded formalin-fixed samples from 1 006 patients with sporadic CRC (488 stage II and 518 stage III) using immunohistochemical analysis (IHC) of MLH1 and MSH2 expression. The patients were included in adjuvant Nordic trials between 1991 and 1996 randomly assigned to surgery alone or surgery plus adjuvant 5-fluorouracil (5-FU)-based chemotherapy. Data was censored at 120 months after surgery. Results. One hundred fifty-seven patients (15.6%) showed a loss of MMR protein expression (139 MLH1 negative, 15 MSH2 negative and 3 MLH1 and MSH2 negative) and were classified as MMR protein negative. A normal MMR protein expression was found in 849 patients who were defined as MMR protein positive. MMR protein expression was a significant prognostic marker in the entire study group with a better overall survival (OS) among patients with MMR protein negative tumors compared to patients with MMR protein positive tumors (p=0.01). In a multivariate analysis the MMR protein expression was significantly associated with OS, (HR 0.70 [95% CI, 0.40 to 0.99]; p=0.01). The MMR status did not predict survival benefit from adjuvant 5-FU-based chemotherapy. Conclusion. This study reveals that IHC of MLH1 and MSH2 expression can yield important prognostic information but is not a predictive factor for adjuvant 5-FU-based chemotherapy in sporadic CRC.
PubMed ID
20307245 View in PubMed
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Thymidylate synthase and p53 expression in primary tumor do not predict chemotherapy outcome in metastatic colorectal carcinoma.

https://arctichealth.org/en/permalink/ahliterature18656
Source
Anticancer Res. 2002 Nov-Dec;22(6B):3653-9
Publication Type
Article
Author
Ake Berglund
David Edler
Daniel Molin
Hans Nordlinder
Wilhelm Graf
Bengt Glimelius
Author Affiliation
Departments of Oncology, Radiology and Clinical Immunology, University of Uppsala, Akademiska Sjukhuset, Uppsala, Sweden. ake.berglund@onkologi.uu.se
Source
Anticancer Res. 2002 Nov-Dec;22(6B):3653-9
Language
English
Publication Type
Article
Keywords
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Clinical Trials, Phase III
Colorectal Neoplasms - drug therapy - enzymology - metabolism - pathology
Disease-Free Survival
Female
Fluorouracil - administration & dosage
Humans
Leucovorin - administration & dosage
Male
Methotrexate - administration & dosage
Neoplasm Metastasis
Neoplasm Staging
Palliative Care
Randomized Controlled Trials
Research Support, Non-U.S. Gov't
Thymidylate Synthase - biosynthesis
Treatment Outcome
Tumor Suppressor Protein p53 - biosynthesis
Abstract
INTRODUCTION: Thymidylate synthase (TS) and p53 expression have been reported to predict the results of palliative chemotherapy in advanced colorectal carcinoma (ACRC), but the knowledge is still limited and partly conflicting. PATIENTS AND METHODS: One hundred and twenty-two patients with ACRC were treated with 5-fluorouracil (5-FU)-based therapy at the University Hospital in Uppsala, Sweden, in four different randomised phase III studies between 1989 and 1997. Fifty-nine (48%) of the patients were initially diagnosed with advanced disease. There were 32 (26%) complete or partial radiological responders. The paraffin-embedded tumours at primary diagnosis were retrospectively analysed with immunohistochemical techniques (IHC) for TS using the specific monoclonal antibody, TS 106, and for p53 with the mouse monoclonal antibody DO-7. RESULTS: All analyses were independently reviewed. High TS values were seen in 78% and p53 positivity in 60% of the tumours. None of the markers predicted the outcome of the later palliative treatment, either in terms of an objective response or survival. However, for the subgroup who initially had curative resection (Dukes' A-C), TS expression had prognostic information and significantly predicted time to recurrence (median for low TS tumours 30 months and for high TS tumours 11 months, p = 0.001). CONCLUSION: Immunohistochemical investigation of TS and p53 of the primary tumour is not useful to predict the outcome of palliative chemotherapy in ACRC. Instead, TS can be regarded as a marker for prediction of time to recurrence.
PubMed ID
12552972 View in PubMed
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