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The role of the CpG island methylator phenotype in colorectal cancer prognosis depends on microsatellite instability screening status
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.ORCID iD: 0000-0002-9933-2843
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
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2010 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 16, no 6, 1845-1855 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE: The aim of this study was to relate the CpG island methylator phenotype (CIMP; characterized by extensive promoter hypermethylation) to cancer-specific survival in colorectal cancer, taking into consideration relevant clinicopathologic factors, such as microsatellite instability (MSI) screening status and the BRAF V600E mutation.

EXPERIMENTAL DESIGN: Archival tumor samples from 190 patients from the Northern Sweden Health and Disease Study (NSHDS) and 414 patients from the Colorectal Cancer in Umeå Study (CRUMS), including 574 with cancer-specific survival data, were analyzed for an eight-gene CIMP panel using quantitative real-time PCR (MethyLight). MSI screening status was assessed by immunohistochemistry.

RESULTS: CIMP-low patients had a shorter cancer-specific survival compared with CIMP-negative patients (multivariate hazard ratio in NSHDS, 2.01; 95% confidence interval, 1.20-3.37; multivariate hazard ratio in CRUMS, 1.48; 95% confidence interval, 1.00-2.22). This result was similar in subgroups based on MSI screening status and was statistically significant in microsatellite stable (MSS) tumors in NSHDS. For CIMP-high patients, a shorter cancer-specific survival compared with CIMP-negative patients was observed in the MSS subgroup. Statistical significance was lost after adjusting for the BRAF mutation, but the main findings were generally unaffected.

CONCLUSIONS: In this study, we found a poor prognosis in CIMP-low patients regardless of MSI screening status, and in CIMP-high patients with MSS. Although not consistently statistically significant, these results were consistent in two separate patient groups and emphasize the potential importance of CIMP and MSI status in colorectal cancer research.

Place, publisher, year, edition, pages
2010. Vol. 16, no 6, 1845-1855 p.
National Category
Pathobiology
Research subject
Pathology
Identifiers
URN: urn:nbn:se:umu:diva-34142DOI: 10.1158/1078-0432.CCR-09-2594ISI: 000278595600018PubMedID: 20197478OAI: oai:DiVA.org:umu-34142DiVA: diva2:319156
Available from: 2010-05-14 Created: 2010-05-14 Last updated: 2017-12-12Bibliographically approved
In thesis
1. The CpG island methylator phenotype in colorectal cancer: studies on risk and prognosis
Open this publication in new window or tab >>The CpG island methylator phenotype in colorectal cancer: studies on risk and prognosis
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background Colorectal cancer (CRC) is the second most common malignancy in developed countries. The mortality is high, with nearly half of patients dying from the disease. The primary treatment of CRC is surgery, and decisions about additional treatment with chemotherapy are based mainly on tumor stage. Novel prognostic markers that identify patients at high risk of recurrence and cancer-related death are needed.

The development of CRC has been described in terms of two different pathways; the microsatellite instability (MSI) and chromosomal instability (microsatellite stable, MSS) pathway. More recently, the CpG island methylator phenotype (CIMP), characterized by frequent DNA hypermethylation, has been described as an alternative pathway of tumorigenesis. The event of DNA methylation is dependent on one-carbon metabolism, in which folate and vitamin B12 have essential functions.

The purpose of this thesis was to study CIMP in CRC. The specific aims were to investigate the potential role of components of one-carbon metabolism as risk factors for this subgroup of tumors, and the prognostic importance of CIMP status, taking into consideration important confounding factors, such as MSI and tumor-infiltrating T cells.

Methods CRC cases and referents included in the Northern Sweden Health and Disease Study (NSHDS, 226 cases and 437 referents) and CRC cases in the Colorectal Cancer in Umeå Study (CRUMS, n=490) were studied. Prediagnostic plasma concentrations of folate and vitamin B12 were analyzed in NSHDS. In both study groups, CIMP status was determined in archival tumor tissue by real-time quantitative PCR using an eight-gene panel (CDKN2A, MLH1, CACNA1G, NEUROG1, RUNX3, SOCS1, IGF2 and CRABP1). MSI screening status and the density of tumor-infiltrating T cells were determined by immunohistochemistry. 

Results An inverse association was found between plasma concentrations of vitamin B12 and rectal, but not colon, cancer risk. We also found a reduced risk of CIMP-high and CIMP-low CRC in study subjects with the lowest levels of plasma folate.

We found that patients with CIMP-low tumors in both NSHDS and CRUMS had a poorer prognosis compared with CIMP-negative, regardless of MSI screening status. We also found that MSS CIMP-high patients had a poorer prognosis compared with MSS CIMP-negative. The density of tumor-infiltrating T cells and CIMP status were both found to be independent predictors of CRC patient prognosis. A particularly poor prognosis was found in patients with CIMP-low tumors poorly infiltrated by T cells. In addition, the density of T cells appeared to be more important than MSI screening status for predicting CRC patient prognosis.

Conclusion Rather than being one disease, CRC is a heterogeneous set of diseases with respect to clinico-pathological and molecular characteristics. We found that the association between risk and plasma concentration of vitamin B12 and folate depends on tumor site and CIMP status, respectively. Patient prognosis was found to be different depending on CIMP and MSI screening status, and the density of tumor-infiltrating T cells.

Place, publisher, year, edition, pages
Umeå: Umeå university, 2011. 57 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1412
Keyword
Colorectal cancer, DNA methylation, folate, microsatellite instability (MSI), prognosis, risk factors, t-lymphocytes, the CpG island methylator phenotype (CIMP), Vitamin B12
National Category
Cell and Molecular Biology Cell and Molecular Biology
Research subject
Pathology
Identifiers
urn:nbn:se:umu:diva-41270 (URN)978-91-7459-177-4 (ISBN)
Public defence
2011-04-15, Betula, Norrlands universitetssjukhus, byggnad 6M, bottenvåningen, Umeå, 09:00 (English)
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Available from: 2011-03-24 Created: 2011-03-22 Last updated: 2015-03-24Bibliographically approved

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Dahlin, Anna MPalmqvist, RichardHenriksson, Maria LEklöf, VincyRutegård, JörgenVan Guelpen, Bethany

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