DNA demethylation in normal colon tissue predicts predisposition to multiple cancers View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2012-02-06

AUTHORS

H Kamiyama, K Suzuki, T Maeda, K Koizumi, Y Miyaki, S Okada, Y J Kawamura, J K Samuelsson, S Alonso, F Konishi, M Perucho

ABSTRACT

Some colon cancer (CC) patients present synchronous cancers at diagnosis and others develop metachronous neoplasms, but the risk factors are unclear for non-hereditary CC. We showed previously that global DNA demethylation increased with aging and correlated with genomic damage in CC, and we show now that preferentially associates to CCs with wild-type p53. This study aimed to elucidate the extent of DNA hypomethylation in patients with single and multiple CC, its relationship with aging, and its potential as predictive tool. We compared by real-time methylation-specific PCR the relative demethylation level (RDL) of long interspersed nucleotide element-1 (LINE-1) sequences in matched cancer tissues and non-cancerous colonic mucosa (NCM) from patients with single and multiple right-sided CCs. Although no RDL difference was found in NCM from single CC patients and healthy volunteers (P=0.5), there was more demethylation (higher RDL) in NCM from synchronous cancer patients (P=1.1 × 10−5) multiple CCs also were more demethylated than single CCs (P=0.0014). High NCM demethylation was predictive for metachronous neoplasms (P=0.003). In multivariate logistic regression analyses RDL was the only independent predictor for metachronous (P=0.02) and multiple (P=4.9 × 10−5) tumors. The higher LINE-1 demethylation in NCM from patients with multiple (synchronous and metachronous) tumors (P=9.6 × 10−7) was also very significant in patients with tumors without (P=3.8 × 10−6), but not with (P=0.16) microsatellite instability. NCM demethylation increased with aging in patients with single tumors, but decreased in those with multiple tumors. Moreover, the demethylation difference between patients with single vs multiple tumors appeared higher in younger (P=3.6 × 10−4) than in older (P=0.0016) patients. These results predict that LINE-1 hypomethylation in NCM can be used as an epigenetic predictive biomarker for multiple CC risk. The stronger association of demethylation in NCM with multiple CC risk from younger patients also suggests an inherited predisposition for the apparent field cancerization effect of somatic demethylation. More... »

PAGES

5029-5037

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/onc.2011.652

DOI

http://dx.doi.org/10.1038/onc.2011.652

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1042947884

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/22310288


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28 schema:description Some colon cancer (CC) patients present synchronous cancers at diagnosis and others develop metachronous neoplasms, but the risk factors are unclear for non-hereditary CC. We showed previously that global DNA demethylation increased with aging and correlated with genomic damage in CC, and we show now that preferentially associates to CCs with wild-type p53. This study aimed to elucidate the extent of DNA hypomethylation in patients with single and multiple CC, its relationship with aging, and its potential as predictive tool. We compared by real-time methylation-specific PCR the relative demethylation level (RDL) of long interspersed nucleotide element-1 (LINE-1) sequences in matched cancer tissues and non-cancerous colonic mucosa (NCM) from patients with single and multiple right-sided CCs. Although no RDL difference was found in NCM from single CC patients and healthy volunteers (P=0.5), there was more demethylation (higher RDL) in NCM from synchronous cancer patients (P=1.1 × 10−5) multiple CCs also were more demethylated than single CCs (P=0.0014). High NCM demethylation was predictive for metachronous neoplasms (P=0.003). In multivariate logistic regression analyses RDL was the only independent predictor for metachronous (P=0.02) and multiple (P=4.9 × 10−5) tumors. The higher LINE-1 demethylation in NCM from patients with multiple (synchronous and metachronous) tumors (P=9.6 × 10−7) was also very significant in patients with tumors without (P=3.8 × 10−6), but not with (P=0.16) microsatellite instability. NCM demethylation increased with aging in patients with single tumors, but decreased in those with multiple tumors. Moreover, the demethylation difference between patients with single vs multiple tumors appeared higher in younger (P=3.6 × 10−4) than in older (P=0.0016) patients. These results predict that LINE-1 hypomethylation in NCM can be used as an epigenetic predictive biomarker for multiple CC risk. The stronger association of demethylation in NCM with multiple CC risk from younger patients also suggests an inherited predisposition for the apparent field cancerization effect of somatic demethylation.
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36 CC patients
37 CC risk
38 DNA demethylation
39 DNA hypomethylation
40 High NCM demethylation
41 LINE-1 demethylation
42 LINE-1 hypomethylation
43 NCM demethylation
44 PCR
45 RDL
46 RDL difference
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48 apparent field cancerization effect
49 association
50 biomarkers
51 cancer
52 cancer patients
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54 cancer tissues
55 cancerization effect
56 colon cancer patients
57 colon tissues
58 colonic mucosa
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61 demethylation difference
62 demethylation levels
63 diagnosis
64 differences
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66 element-1 (LINE-1) sequences
67 epigenetic predictive biomarker
68 extent
69 factors
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71 genomic damage
72 global DNA demethylation
73 healthy volunteers
74 higher LINE-1 demethylation
75 hypomethylation
76 independent predictors
77 inherited predisposition
78 instability
79 levels
80 logistic regression analyses RDL
81 metachronous neoplasms
82 methylation-specific PCR
83 microsatellite instability
84 more demethylation
85 mucosa
86 multiple CC
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88 multiple cancers
89 multiple right-sided CCs
90 multiple tumors
91 multivariate logistic regression analyses RDL
92 neoplasms
93 non-cancerous colonic mucosa
94 non-hereditary CC
95 normal colon tissues
96 only independent predictor
97 p53
98 patients
99 patients (P=1.1 × 10−5) multiple CCs
100 potential
101 predictive biomarkers
102 predictive tool
103 predictors
104 predisposition
105 real-time methylation-specific PCR
106 regression analyses RDL
107 relationship
108 results
109 right-sided CCs
110 risk
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112 sequence
113 single CC
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115 single tumor
116 single vs multiple tumors
117 somatic demethylation
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