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Biomarker mRNAs for staging and prognosis of colorectal cancer
Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mesenteric lymph node (ln) metastasis is the single most important prognostic characteristic in colorectal cancer (CRC). The ln status is used for staging and is a decisive selection criterion for postoperative adjuvant therapy. However, it is difficult to accurately determine ln status by routine histopathology (H&E). Thus, ~25% of CRC patients, who by H&E are considered to lack tumor cells in their lns, i.e. stage I+II, die from CRC.

To explore the utility of biomarker mRNA analysis for staging and prognosis of CRC, lns were collected at surgery and mRNA levels for fourteen biomarkers, including carcinoembryonic antigen (CEA), kallikrein 6 (KLK6), cytokeratin 20 (CK20), guanylyl cyclase C (GCC), CEACAM1-S, CEACAM6 and mucin 2 (MUC2), were determined by quantitative RT-PCR with RNA copy standards. Results were compared to routine H&E analysis.

The biomarkers were analyzed for capacity to detect disseminated tumor cells in lns. mRNA levels were determined in CRC- and control lns, primary tumor, normal colon, immune cells and fibroblasts. Lack of expression in immune cells and fibroblasts and high and homogenous expression in primary tumors showed to be the determining factors. CEA fulfilled these criteria best, followed by KLK6, CK20, GCC, and MUC2.

Utility of the biomarker mRNAs for staging and prognosis was examined in 174 CRC patients. CEA was the best predictor of disease-free survival time after surgery with a 71 months difference between CEA(+) and CEA(-) patients and a hazard ratio of 5.1 for risk of recurrence for CEA(+) patients. CEA, CK20 and MUC2 were more sensitive than H&E in that these biomarkers identified patients who succumbed from recurrent CRC although H&E analysis had failed to detect the disseminated tumor cells. Combined analysis of CEA and MUC2 mRNAs improved prediction of outcome. Patients with high risk for recurrence had low MUC2/CEA ratios.

KLK6 mRNA was identified as a potential progression marker by genome-wide microarray analysis of gene expression. It was found to be ectopically expressed in CRC tumor cells. KLK6(+) lns was an indicator of poor prognosis (hazard ratio 3.7). Notably, the actual level was of importance for outcome. The higher the KLK6 mRNA levels the greater the risk of recurrence. At the 90

thpercentile the hazard risk ratio for KLK6(+) patients was 5.6. KLK6 positivity in lns with low numbers of tumor cells, as indicated by low CEA mRNA levels, indicated poor prognosis (hazard ratio 2.8). Thus, KLK6 adds prognostic information to CEA analysis.

Increased levels of mRNA for the proinflammatory cytokine interferon- and the down-regulatory cytokine interleukin-10 in lns of CRC patients suggested ongoing immune reactions against the infiltrating tumor cells. Elevated TGF-1 levels correlated weakly with survival, suggesting protection by the antiproliferative effect of TGF-1 in sporadic cases.

CEA mRNA was the best single biomarker for staging and prediction of disease-free survival time and risk of recurrence after surgery. In addition to CEA, KLK6 positivity and low MUC2/CEA ratio correlate with poor prognosis. Thus, CEA, MUC2 and KLK6 mRNAs form a strong "trio" for staging and prediction of outcome for CRC patients.

Place, publisher, year, edition, pages
Umeå: Umeå university , 2011. , 74 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1458
Keyword [en]
colorectal cancer
National Category
Microbiology in the medical area
Research subject
Immunology
Identifiers
URN: urn:nbn:se:umu:diva-49742ISBN: 978-91-7459-318-1 (print)OAI: oai:DiVA.org:umu-49742DiVA: diva2:457001
Public defence
2011-12-09, Astrid Fagraeussalen, byggnad 6A, Umeå Universitet, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2011-11-18 Created: 2011-11-16 Last updated: 2013-03-25Bibliographically approved
List of papers
1. Biomarker selection for detection of occult tumour cells in lymph nodes of colorectal cancer patients using real-time quantitative RT-PCR
Open this publication in new window or tab >>Biomarker selection for detection of occult tumour cells in lymph nodes of colorectal cancer patients using real-time quantitative RT-PCR
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2006 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 95, no 2, 218-225 p.Article in journal (Refereed) Published
Abstract [en]

Accurate identification of lymph node involvement is critical for successful treatment of patients with colorectal carcinoma (CRC). Real-time quantitative RT–PCR with a specific probe and RNA copy standard for biomarker mRNA has proven very powerful for detection of disseminated tumour cells. Which properties of biomarker mRNAs are important for identification of disseminated CRC cells? Seven biomarker candidates, CEA, CEACAM1-S/L, CEACAM6, CEACAM7-1/2, MUC2, MMP7 and CK20, were compared in a test-set of lymph nodes from 51 CRC patients (Dukes' A–D) and 10 controls. Normal colon epithelial cells, primary tumours, and different immune cells were also analysed. The biomarkers were ranked according to: (1) detection of haematoxylin/eosin positive nodes, (2) detection of Dukes' A and B patients, who developed metastases during a 54 months follow-up period and (3) identification of patients with Dukes' C and D tumours using the highest value of control nodes as cutoff. The following properties appear to be of importance; (a) no expression in immune cells, (b) relatively high and constant expression in tumour tissue irrespective of Dukes' stage and (c) no or weak downregulation in tumours compared to normal tissue. CEA fulfilled these criteria best, followed by CK20 and MUC2.

Place, publisher, year, edition, pages
London: Harcourt Publishers, 2006
Keyword
carcinoembryonic antigen (CEA), CEA cell adhesion molecule (CEACAM), mucin 2 (MUC2), cytokeratin 20 (CK20), matrix metalloproteinase 7 (MMP7)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-21205 (URN)10.1038/sj.bjc.6603206 (DOI)16755296 (PubMedID)
Available from: 2009-04-07 Created: 2009-04-07 Last updated: 2013-04-17Bibliographically approved
2. Lymph node CEA and MUC2 mRNA as useful predictors of outcome in colorectal cancer
Open this publication in new window or tab >>Lymph node CEA and MUC2 mRNA as useful predictors of outcome in colorectal cancer
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2012 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 130, no 8, 1833-1843 p.Article in journal (Refereed) Published
Abstract [en]

The aim was to explore the utility for staging and prognostic impact of carcinoembryonic antigen (CEA), cytokeratin 20 (CK20), guanylyl cyclase C (GCC), CUB domain protein 1 (CDCP1) and mucin 2 (MUC2) mRNA levels in mesenteric lymph nodes of colorectal cancer (CRC) patients. Lymph nodes were collected at surgery and bisected; one half was subjected to biomarker mRNA analysis using real-time quantitative RT-PCR and the other half to routine histopathology. Lymph nodes from 174 CRC patients and 24 controls were analyzed. The median follow-up time was 59 (range 17-131) months. Cut-off levels were defined by analyzing quintiles by Cox regression model. CEA mRNA showed the best discriminating power between patients with recurrence in CRC after surgery and patients who were apparently disease-free (P=0.015). The risk of recurrence for the CEA(+) patients was 4.6 times greater than for the CEA(-) patients (P<0.0001). The other biomarkers gave lower hazard ratios. Cumulative survival analysis demonstrated that the average survival time was 99 months for CEA(-) patients compared to 39 months for CEA(+) patients, a difference of 60 months (P<0.0001). Six to nine percent of the stage I and II patients [H&E(-)] had CEA(+), CK20(+), GCC(+) and/or MUC2(+) lymph nodes. Two of these patients died from recurrent CRC. Low lymph node MUC2/CEA mRNA ratio identified patients with high risk for recurrence (P=0.011). Thus, qRT-PCR of CEA mRNA is a sensitive method to identify tumor cells in lymph nodes of CRC patients and, in combination with MUC2 mRNA, allows improved prediction of clinical outcome. © 2011 Wiley-Liss, Inc.

Keyword
colorectal cancer
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-49812 (URN)10.1002/ijc.26182 (DOI)21618511 (PubMedID)
Available from: 2011-11-18 Created: 2011-11-18 Last updated: 2017-12-08Bibliographically approved
3. Lymph node kallicrein 6 mRNA: a new progression marker for colorectal cancer
Open this publication in new window or tab >>Lymph node kallicrein 6 mRNA: a new progression marker for colorectal cancer
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(English)Article in journal (Other academic) Submitted
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-49814 (URN)
Available from: 2011-11-18 Created: 2011-11-18 Last updated: 2015-03-24Bibliographically approved
4. Pro-inflammatory and down-regulatory cytokine expression in tumor infiltrated mesenteric lymph nodes of patients with colorectal cancer
Open this publication in new window or tab >>Pro-inflammatory and down-regulatory cytokine expression in tumor infiltrated mesenteric lymph nodes of patients with colorectal cancer
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(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-49815 (URN)
Available from: 2011-11-18 Created: 2011-11-18 Last updated: 2011-11-18Bibliographically approved

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