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One-carbon metabolism and CpG island methylator phenotype status in incident colorectal cancer: a nested case-referent study
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
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2010 (Engelska)Ingår i: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 21, nr 4, s. 557-566Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

OBJECTIVE: We related prediagnostic plasma folate, vitamin B12, and total homocysteine concentrations, and the MTHFR 677C>T and 1298A>C polymorphisms, to the risk of colorectal cancer with and without the CpG island methylator phenotype (CIMP).

METHODS: This was a nested case-referent study of 190 cases and double, matched referents from the large, population-based Northern Sweden Health and Disease Study. Using archival tumor tissue, promoter methylation in an eight-gene panel was analyzed by MethyLight.

RESULTS: A reduced risk of CIMP-low/CIMP-high CRC (>/=1 gene methylated) was observed in subjects with very low plasma folate concentrations [multivariate odds ratio 2.96 (95% CI 1.24-7.08) for quintiles two to five versus one (lowest)]. With the exception of a reduced risk in MTHFR 677 TT-homozygotes, none of the other one-carbon variables were associated with the risk of CIMP-low/CIMP-high CRC. For CIMP-negative CRC, only the MTHFR polymorphisms were statistically significantly related to risk, inversely for 677C>T and positively for 1298A>C, but a tendency toward a reduced risk was observed in subjects with an adequate methyl availability, combining the plasma variables [multivariate odds ratio 0.61 (95% CI 0.32-1.15)].

CONCLUSION: Though limited by low power, these findings suggest the possibility of different roles for one-carbon metabolism in different pathways of colorectal tumorigenesis.

Ort, förlag, år, upplaga, sidor
2010. Vol. 21, nr 4, s. 557-566
Identifikatorer
URN: urn:nbn:se:umu:diva-31577DOI: 10.1007/s10552-009-9484-yISI: 000275631900006PubMedID: 20012180OAI: oai:DiVA.org:umu-31577DiVA, id: diva2:293373
Tillgänglig från: 2010-02-11 Skapad: 2010-02-11 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
Ingår i avhandling
1. The CpG island methylator phenotype in colorectal cancer: studies on risk and prognosis
Öppna denna publikation i ny flik eller fönster >>The CpG island methylator phenotype in colorectal cancer: studies on risk and prognosis
2011 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå university, 2011. s. 57
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1412
Nyckelord
Colorectal cancer, DNA methylation, folate, microsatellite instability (MSI), prognosis, risk factors, t-lymphocytes, the CpG island methylator phenotype (CIMP), Vitamin B12
Nationell ämneskategori
Cell- och molekylärbiologi Cell- och molekylärbiologi
Forskningsämne
patologi
Identifikatorer
urn:nbn:se:umu:diva-41270 (URN)978-91-7459-177-4 (ISBN)
Disputation
2011-04-15, Betula, Norrlands universitetssjukhus, byggnad 6M, bottenvåningen, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2011-03-24 Skapad: 2011-03-22 Senast uppdaterad: 2018-06-08Bibliografiskt granskad

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Van Guelpen, BethanyDahlin, Anna MHultdin, JohanEklöf, VincyJohansson, IngegerdHenriksson, Maria LCullman, IngerHallmans, GöranPalmqvist, Richard

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Van Guelpen, BethanyDahlin, Anna MHultdin, JohanEklöf, VincyJohansson, IngegerdHenriksson, Maria LCullman, IngerHallmans, GöranPalmqvist, Richard
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