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The CpG island methylator phenotype in colorectal cancer: studies on risk and prognosis
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. (Richard Palmqvist)
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 [en]
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: urn:nbn:se:umu:diva-41270ISBN: 978-91-7459-177-4OAI: oai:DiVA.org:umu-41270DiVA: diva2:405650
Public defence
2011-04-15, Betula, Norrlands universitetssjukhus, byggnad 6M, bottenvåningen, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2011-03-24 Created: 2011-03-22 Last updated: 2015-03-24Bibliographically approved
List of papers
1. Plasma vitamin B12 concentrations and the risk of colorectal cancer: a nested case-referent study
Open this publication in new window or tab >>Plasma vitamin B12 concentrations and the risk of colorectal cancer: a nested case-referent study
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2008 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 32, no 2, 304-314 p.Article in journal (Refereed) Published
Abstract [en]

In this nested case-referent study, we related plasma concentrations of vitamin B12 to the risk of colorectal cancer, taking into consideration prediagnostic plasma folate and total homocysteine concentrations. Subjects were 226 cases and double matched referents from the population-based Northern Sweden Health and Disease Study. Follow-up times from recruitment to diagnosis ranged from 0.1 to 12.7 years, with a median of 4.2 years. Plasma vitamin B12 concentrations were inversely associated with the risk of rectal cancer: univariate odds ratio for the highest versus lowest quintile 0.34 (95% confidence interval (95% CI) 0.13-0.83), p(trend) = 0.004. Risk estimates were attenuated slightly but remained statistically significant after adjustment for body mass index, current smoking, recreational and occupational physical activity, alcohol intake and prediagnostic plasma folate and total homocysteine concentrations: OR 0.30 (95% CI 0.08-0.99), p(trend) = 0.025. The corresponding univariate and fully adjusted odds ratios for colon cancer were 1.25 (CI 0.66-2.36), p(trend) = 0.185 and 1.42 (CI 0.67-3.05), p(trend) = 0.113, respectively. The observed over-risk was attributable to left-sided colon cancer. Interaction analyses including vitamin B12, folate and homocysteine were in line with the results for vitamin B12 alone. In conclusion, these results suggest that increasing levels of plasma vitamin B12, alone or together with other factors involved in one-carbon metabolism, may reduce the risk of rectal cancer, whereas for colon cancer, the association appears to be less clear.

Identifiers
urn:nbn:se:umu:diva-8775 (URN)10.1002/ijc.23299 (DOI)18092327 (PubMedID)
Available from: 2008-11-18 Created: 2008-11-18 Last updated: 2015-04-22Bibliographically approved
2. One-carbon metabolism and CpG island methylator phenotype status in incident colorectal cancer: a nested case-referent study
Open this publication in new window or tab >>One-carbon metabolism and CpG island methylator phenotype status in incident colorectal cancer: a nested case-referent study
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2010 (English)In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 21, no 4, 557-566 p.Article in journal (Refereed) 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.

Identifiers
urn:nbn:se:umu:diva-31577 (URN)10.1007/s10552-009-9484-y (DOI)000275631900006 ()20012180 (PubMedID)
Available from: 2010-02-11 Created: 2010-02-11 Last updated: 2015-04-22Bibliographically approved
3. The role of the CpG island methylator phenotype in colorectal cancer prognosis depends on microsatellite instability screening status
Open this publication in new window or tab >>The role of the CpG island methylator phenotype in colorectal cancer prognosis depends on microsatellite instability screening status
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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.

National Category
Pathobiology
Research subject
Pathology
Identifiers
urn:nbn:se:umu:diva-34142 (URN)10.1158/1078-0432.CCR-09-2594 (DOI)000278595600018 ()20197478 (PubMedID)
Available from: 2010-05-14 Created: 2010-05-14 Last updated: 2015-03-24Bibliographically approved
4. Colorectal cancer prognosis depends on T-cell infiltration and molecular characteristics of the tumor
Open this publication in new window or tab >>Colorectal cancer prognosis depends on T-cell infiltration and molecular characteristics of the tumor
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2011 (English)In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 24, 671-682 p.Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to relate the density of tumor infiltrating T cells to cancer-specific survival in colorectal cancer, taking into consideration the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) screening status. The T-cell marker CD3 was stained by immunohistochemistry in 484 archival tumor tissue samples. T-cell density was semiquantitatively estimated and scored 1-4 in the tumor front and center (T cells in stroma), and intraepithelially (T cells infiltrating tumor cell nests). Total CD3 score was calculated as the sum of the three CD3 scores (range 3-12). MSI screening status was assessed by immunohistochemistry. CIMP status was determined by quantitative real-time PCR (MethyLight) using an eight-gene panel. We found that patients whose tumors were highly infiltrated by T cells (total CD3 score ≥7) had longer survival compared with patients with poorly infiltrated tumors (total CD3 score ≤4). This finding was statistically significant in multivariate analyses (multivariate hazard ratio, 0.57; 95% confidence interval, 0.31-1.00). Importantly, the finding was consistent in rectal cancer patients treated with preoperative radiotherapy. Although microsatellite unstable tumor patients are generally considered to have better prognosis, we found no difference in survival between microsatellite unstable and microsatellite stable (MSS) colorectal cancer patients with similar total CD3 scores. Patients with MSS tumors highly infiltrated by T cells had better prognosis compared with intermediately or poorly infiltrated microsatellite unstable tumors (log rank P=0.013). Regarding CIMP status, CIMP-low was associated with particularly poor prognosis in patients with poorly infiltrated tumors (multivariate hazard ratio for CIMP-low versus CIMP-negative, 3.07; 95% confidence interval, 1.53-6.15). However, some subset analyses suffered from low power and are in need of confirmation by independent studies. In conclusion, patients whose tumors are highly infiltrated by T cells have a beneficial prognosis, regardless of MSI, whereas the role of CIMP status in this context is less clear.

Keyword
colorectal neoplasms; host immune response; immunotherapy; microsatellite instability (MSI); prognosis; T-lymphocytes; the CpG island methylator phenotype (CIMP)
National Category
Other Basic Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:umu:diva-41268 (URN)10.1038/modpathol.2010.234 (DOI)21240258 (PubMedID)
Available from: 2011-03-22 Created: 2011-03-22 Last updated: 2015-03-24Bibliographically approved

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