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  • 1
    Online Resource
    Online Resource
    Dietary, lifestyle and clinicopathological factors associated with BRAF and K-ras mutations arising in distinct subsets of colorectal cancers in the EPIC Norfolk study
    Springer Science and Business Media LLC ; 2010
    In:  BMC Cancer Vol. 10, No. 1 ( 2010-12)
    Details
    In: BMC Cancer, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2010-12)
    Abstract: BRAF and K-ras proto-oncogenes encode components of the ERK signalling pathway and are frequently mutated in colorectal cancer. This study investigates the associations between BRAF and K-ras mutations and clinicopathological, lifestyle and dietary factors in colorectal cancers. Methods 186 adenocarcinomas and 16 adenomas from the EPIC Norfolk study were tested for BRAF and K-ras mutations. Diet and lifestyle data were collected prospectively using seven day food diaries. Results BRAF V600E mutation was found in 15.6% of colorectal cancers but at higher frequencies in cancers with proximal location, poor differentiation and microsatellite instability (MSI) (all p 〈 0.001). K-ras mutation (mostly in codons 12 and 13) was found in 22.0% of colorectal cancers but at higher frequencies in cancers of more advanced Dukes' stage (p = 0.001), microsatellite stable (MSS) status (p = 0.002) and in individuals with lower blood high-density lipoprotein concentrations (p = 0.04). Analysis of dietary factors demonstrated no link between BRAF mutation and any specific dietary constituent, however, K-ras mutation was found at higher frequencies in individuals with higher white meat consumption (p 〈 0.001). Further analysis of specific mutation type demonstrated that G to A transitions in K-ras were observed at higher frequencies in individuals consuming lower amounts of fruit (p = 0.02). Conclusion These data support the model of BRAF and K-ras mutations arising in distinct colorectal cancer subsets associated with different clinicopathological and dietary factors, acting as mutually exclusive mechanisms of activation of the same signalling pathway.
    Type of Medium: Online Resource
    ISSN: 1471-2407
    URL: Article
    DOI: 10.1186/1471-2407-10-99
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2010
    detail.hit.zdb_id: 2041352-X
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  • 2
    Online Resource
    Online Resource
    Alterations in PTEN and PIK3CA in colorectal cancers in the EPIC Norfolk study: associations with clinicopathological and dietary factors
    Springer Science and Business Media LLC ; 2011
    In:  BMC Cancer Vol. 11, No. 1 ( 2011-12)
    Details
    In: BMC Cancer, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2011-12)
    Abstract: The PTEN tumour suppressor gene and PIK3CA proto-oncogene encode proteins which contribute to regulation and propagation of signal transduction through the PI3K/AKT signalling pathway. This study investigates the prevalence of loss of PTEN expression and mutations in both PTEN and PIK3CA in colorectal cancers (CRC) and their associations with tumour clinicopathological features, lifestyle factors and dietary consumptions. Methods 186 adenocarcinomas and 16 adenomas from the EPIC Norfolk study were tested for PTEN and PIK3CA mutations by DNA sequencing and PTEN expression changes by immunohistochemistry. Dietary and lifestyle data were collected prospectively using seven day food diaries and lifestyle questionnaires. Results Mutations in exons 7 and 8 of PTEN were observed in 2.2% of CRC and PTEN loss of expression was identified in 34.9% CRC. Negative PTEN expression was associated with lower blood low-density lipoprotein concentrations (p = 0.05). PIK3CA mutations were observed in 7% of cancers and were more frequent in CRCs in females (p = 0.04). Analysis of dietary intakes demonstrated no link between PTEN expression status and any specific dietary factor. PTEN expression negative, proximal CRC were of more advanced Dukes' stage (p = 0.02) and poor differentiation (p 〈 0.01). Testing of the prevalence of PIK3CA mutations and loss of PTEN expression demonstrated that these two events were independent (p = 0.55). Conclusion These data demonstrated the frequent occurrence (34.9%) of PTEN loss of expression in colorectal cancers, for which gene mutations do not appear to be the main cause. Furthermore, dietary factors are not associated with loss of PTEN expression. PTEN expression negative CRC were not homogenous, as proximal cancers were associated with a more advanced Dukes' stage and poor differentiation, whereas distal cancers were associated with earlier Dukes' stage.
    Type of Medium: Online Resource
    ISSN: 1471-2407
    URL: Article
    DOI: 10.1186/1471-2407-11-123
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2011
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  • 3
    Online Resource
    Online Resource
    Dietary, lifestyle and clinicopathological factors associated with APC mutations and promoter methylation in colorectal cancers from the EPIC‐Norfolk study
    Wiley ; 2012
    In:  The Journal of Pathology Vol. 228, No. 3 ( 2012-11), p. 405-415
    Details
    In: The Journal of Pathology, Wiley, Vol. 228, No. 3 ( 2012-11), p. 405-415
    Abstract: The tumour suppressor APC is the most commonly altered gene in colorectal cancer (CRC). Genetic and epigenetic alterations of APC may therefore be associated with dietary and lifestyle risk factors for CRC. Analysis of APC mutations in the extended mutation cluster region (codons 1276‐1556) and APC promoter 1A methylation was performed on 185 archival CRC samples collected from participants of the European Prospective Investigation into Cancer (EPIC)‐Norfolk study, with the aim of relating these to high‐quality seven‐day dietary and lifestyle data collected prospectively. Truncating APC mutations (APC + ) and promoter 1A methylation (PM + ) were identified in 43% and 23% of CRCs analysed, respectively. Distal CRCs were more likely than proximal CRCs to be APC + or PM + ( p = 0.04). APC + CRCs were more likely to be moderately/well differentiated and microsatellite stable than APC − CRCs ( p = 0.05 and 0.03). APC + CRC cases consumed more alcohol than their counterparts ( p = 0.01) and PM + CRC cases consumed lower levels of folate and fibre ( p = 0.01 and 0.004). APC + or PM + CRC cases consumed higher levels of processed meat and iron from red meat and red meat products ( p = 0.007 and 0.006). Specifically, CRC cases harbouring GC‐to‐AT transition mutations consumed higher levels of processed meat (35 versus 24 g/day, p = 0.04) and iron from red meat and red meat products (0.8 versus 0.6 mg/day, p = 0.05). In a logistic regression model adjusted for age, sex and cigarette‐smoking status, each 19 g/day (1SD) increment increase in processed meat consumption was associated with cases with GC‐to‐AT mutations (OR 1.68, 95% CI 1.03–2.75). In conclusion, APC + and PM + CRCs may be influenced by diet and GC‐to‐AT mutations in APC are associated with processed meat consumption, suggesting a mechanistic link with dietary alkylating agents, such as N ‐nitroso compounds. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
    Type of Medium: Online Resource
    ISSN: 0022-3417 , 1096-9896
    URL: Issue
    URL: Article
    DOI: 10.1002/path.2012.228.issue-3
    DOI: 10.1002/path.4085
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2012
    detail.hit.zdb_id: 1475280-3
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