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Faecal methylation, gene expression and disease outcome in people 5 consuming fish. (FishMet)
Project Code: N12014
Institute of Food Research
Three major risk factors in relation to colorectal cancer, apart from known genetic mutations 66 that account for only a few percent of cases, include age, diet and inflammation. The 67 mechanisms by which these factors impact on cancer initiation and progression are still poorly 68 understood but one important potential mechanism is gene silencing of tumour suppressor 69 genes through hypermethylation of CpG islands (cytosine,guanine rich sequences in the 70 promoter region of genes) in their promoter regions. For example ESR1 becomes increasingly 71 methylated with ageing, a process which is accelerated in patients with ulcerative colitis. It is 72 hypothesised that changes in the methylation status of genes may be a causative factor in 73 cancer development as a result of reduced apoptosis (e.g. p14 ARF) and DNA repair (e.g. 74 hMLH1) and poorer control of cell proliferation rates (e.g. APC).
Faecal samples were collected from patients from three main groups: a) those with 89 apparently healthy mucosa, b) those with polyps and c) those with ulcerative colitis in 90 remission. Each patient group was randomly allocated to one of three dietary groups: 1) dietary 91 advice, 2) 300g cod/week and 3) 300g salmon/week. Fish was provided by the study team. Of 92 the 242 people who completed the study 94 gave sufficient stool sample for analysis at the start 93 and end of the study. Thus this study only looks at small groups of participants, especially 94 when the sample size is sub-divided into different patient and dietary groups and so can only 95 be considered as a pilot study. Of the six genes that were assessed: 1) HPP1/TMEFF2 , 2), 96 ESR1 (Estrogen receptor α), 3) APC, 4) MLH1 (MutL homologue),5) P14ARF and 6) CDH1 (E-97
cadherin), most showed no significant change in methylation in any of the dietary groups 98 However, salmon consumption increased the levels of APC methylation detected in faecal 99 samples from patients with ulcerative colitis and decreased levels of P14 ARF in patients with 100 apparently healthy mucosa. Possible explanations for these observations are discussed in the 101 report. 102
We also analysed serum selenium as elevated levels of selenium have been shown to 103 reduce colorectal cancer risk, potentially via modification of DNA methylation. The levels of 104 selenium in our study population were very low (90.4 ng/ml) compared to those reported in the 105 USA but quite typical of a UK population, and although cod consumption increased levels by 106 5% this would not have elevated median levels out of the lowest quartile reported in the study 107 from the USA that showed a protective effect of selenium. Thus the effects were minimal. 108 There was no correlation between any of the dietary factors assessed at baseline and faecal 109 methylation but this initial pilot study was not necessarily powered sufficiently to detect such 110 correlations. However, the data can provide information on variance to be used in future 111 studies. 112
In conclusion, consumption of salmon led to measurable changes in CpG island 113 methylation, but the interpretation of these changes requires further investigation. Despite 114 causing a small increase in serum selenium levels cod had no impact on methylation.
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