Skip Navigation


Carcinogenesis Advance Access originally published online on March 28, 2008
Carcinogenesis 2008 29(9):1774-1780; doi:10.1093/carcin/bgn082
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Supplementary Data
Right arrow All Versions of this Article:
29/9/1774    most recent
bgn082v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (1)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Theodoratou, E.
Right arrow Articles by Farrington, S. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Theodoratou, E.
Right arrow Articles by Farrington, S. M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Modification of the associations between lifestyle, dietary factors and colorectal cancer risk by APC variants

Evropi Theodoratou1,*, Harry Campbell1,2, Albert Tenesa2, Geraldine McNeill3, Roseanne Cetnarskyj4, Rebecca A. Barnetson2, Mary E. Porteous5, Malcolm G. Dunlop2 and Susan M. Farrington2

1 Public Health Sciences, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK
2 Colon Cancer Genetics Group, Western General Hospital, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK
3 Environmental & Occupational Medicine Department, University of Aberdeen, Liberty Safe Work Research Centre, Aberdeen AB25 2DP, UK
4 School of Nursing, Midwifery & Social Care, Faculty of Health, Life and Social Sciences, Napier University, Edinburgh EH9 2TB, UK
5 Clinical Genetics Department, University of Edinburgh, Edinburgh EH4 2XU, UK

* To whom correspondence should be addressed. Tel: +44 131 650 3036; Fax: +44 131 650 6909; Email: e.theodoratou{at}sms.ed.ac.uk

Correspondence may also be addressed to Susan M.Farrington. Tel: +44 131 467 8422; Fax: +44 131 467 8450; Email: susan.farrington{at}hgu.mrc.ac.uk


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Supplementary material
 Funding
 References
 
In a large Scottish case–control study, we investigated the effects of adenomatous polyposis coli (APC) Asp1822Val (rs459552) and APC Glu1317Gln substitutions on colorectal cancer (CRC) risk and whether these associations were influenced by lifestyle and dietary factors. We did not observe any associations between the variants and CRC risk in the whole population. Post-menopausal women taking hormone replacement therapy (HRT) and participants who consumed a diet low in total fat, saturated fatty acids, monounsaturated fatty acids (MUFAs) and trans fatty acids had a lower risk of CRC [odds ratio (95% confidence interval): 0.53 (0.41, 0.68); 0.84 (0.72, 0.98); 0.72 (0.62, 0.85); 0.85 (0.73, 1.00) and 0.78 (0.67, 0.92), respectively]. This risk reduction was stronger in those homozygous for the variant APC 1822 allele with significant interaction relationships for HRT, red meat and MUFA intakes (P for interaction case-only design: 0.02, 0.002 and 0.02, respectively). Low n3 polyunsaturated fatty acids intake was associated with an increased CRC risk for the wild-type and heterozygous APC 1822 individuals but with a decreased CRC risk in those homozygous for the variant allele (P for interaction case-only design: 0.09). The interaction relationships with the APC 1317 variant were of the same direction though not significant, possibly due to the low frequency of the variant allele. Our results confirm the findings of three recent case–control studies suggesting a number of possible biological mechanisms. However, further large-scale studies are necessary in order to replicate these findings and confirm the role of these APC gene variants and their interaction with dietary and lifestyle exposures in colorectal carcinogenesis.

Abbreviations: APC, adenomatous polyposis coli; CI, confidence interval; CRC, colorectal cancer; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; FA, fatty acid; HRT, hormone replacement therapy; MUFA, monounsaturated fatty acid; OR, odds ratio; PUFA, polyunsaturated fatty acid; SFA, saturated fatty acid; tFA, trans fatty acid; tMUFA, trans monounsaturated fatty acid


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Supplementary material
 Funding
 References
 
Adenomatous polyposis coli (APC) is a tumour suppressor gene and mutations resulting in loss of the APC protein function are associated with carcinogenesis (1). APC germ line mutations lead to familial APC, whereas APC somatic mutations are found in ~72% of sporadic cancers (2,3). More than 60% of sporadic mutations occur mainly in exon 15 between codons 1286 and 1513 (mutation cluster region) (1,4,5). At least 12 single-nucleotide polymorphsisms have been identified, with 8 of them being in exon 15 (5). Three of them are responsible for amino acid substitutions (5), with the most common of them (allele frequency 10–22%) being an aspartic acid to valine change at codon 1822 (rs459552) (2,4), which is located close to the fifth β-catenin-binding region (5). This polymorphism was found not to be associated with the development of colorectal cancer (CRC) in three previous studies (2,6,7) but it has been suggested as a low-penetrance allele that increases risk of CRC in two others (5,8). The possible influence of the association between APC 1822 variant and CRC by dietary factors (intake of total fat and specific fat subgroups) has been investigated in four epidemiological studies (4,6,9,10) and by lifestyle factors [taking hormone replacement therapy (HRT)] in one case–control study (6).

We have investigated previously the effect of fatty acids (FAs) on CRC risk and have identified a significant association with specific FA components (11). Therefore, in this study, our main research question was to further investigate whether the associations between fat, FA subgroups (primary hypothesis) and individual FA compounds (secondary hypothesis) and CRC are modified by two APC variants at codons 1822 and 1317 (gene–environment interaction analysis). Furthermore, interactions of meat intake, red meat intake and HRT with the APC variants were investigated to follow up the findings of previous studies (4,6).

The dietary variables addressing our main research question and included in the interaction analysis were intake of total fat, cholesterol, meat, red meat and seven FA subgroups [total FAs, saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), polyunsaturated fatty acids (PUFAs), n6PUFAs, n3PUFAs, trans fatty acids (tFAs)]. In the secondary hypothesis interaction analysis, trans monounsaturated fatty acids (tMUFAs) and nine individual FA compounds were examined [palmitic and stearic acids (SFAs); oleic acid (MUFA); linoleic, {gamma}-linolenic and arachidonic acids (n6PUFAs), {alpha}-linolenic, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (n3PUFAs)].


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Supplementary material
 Funding
 References
 
Study population
The samples are from a Scottish case–control study of CRC (Study Of Colorectal Cancer in Scotland). Ethical approval was obtained from the Multicentre Research Ethics committee for Scotland and relevant local research ethics committees, and all participants provided written informed consent. We aimed to recruit prospectively all incident cases of adenocarcinoma of colorectum in patients aged 16–79 years presenting to surgical units in Scotland. Exclusions were patient death before ascertainment, patient too ill to participate, recurrent cases or patient unable to give informed consent due to learning difficulties or other medical conditions. We recruited ~40% of all incident cases in Scotland over the study period. During the same period, controls were drawn at random from a population-based register (community health index) and invited to participate. Participation rates among those approached were ~58% for cases and an estimated 57% for controls. Questionnaire completion was sufficient for valid analysis in 82% of cases and 97% of controls recruited. More than 99% of the study participants were white Caucasians [see (12) for further recruitment details]. Genetic analysis was performed on 2789 cases and 2749 controls and gene–environment interaction analysis was performed on 1656 cases and 2292 controls. (Missing individuals had not completed the environmental and dietary data questionnaires and therefore could not been included in the gene–environment interaction analysis.)

Lifestyle and dietary data
Subjects completed one questionnaire with lifestyle and cancer information and women were asked to report HRT intake, reporting their status 1 year prior to diagnosis or recruitment (12). Participants also completed a semi-quantitative food frequency questionnaire for the same reference period (Scottish Collaborative Group food frequency questionnaire, Version 6.41; http://www.foodfrequency.org). Its validity for ranking macro- and micronutrients in younger adults (13) and its main characteristics (12) have been described previously.

Genotype data
Blood DNA samples were obtained from patients and controls after counselling and receipt of informed consent. The approach used to efficiently identify subjects carrying heterozygous or homozygous APC Asp1822Val and APC Glu1317Gln variants was allelic discrimination, employing allele-specific TaqMan MGB probes (Applied Biosystems), resolved on an ABI 7900 Analyzer with the use of SDS v2.1 software. Assays were designed using Primer Express v2.0 software (Applied Biosystems) probe and primer details are available on request. A proportion (13%) of Asp1822Val variants identified by the TaqMan approach were confirmed by repeated DNA sequence analysis.

Fat and FA data
Fat and FA data were obtained from the UK food composition tables (McCance and Widdowson's The Composition of Foods, sixth summary edition) and the FOODBASE database (version 1.04, Institute of Brain Chemistry, London), a nutrient database for FAs. The data that were calculated included the intake of total FAs, SFAs, MUFAs, PUFAs, n6PUFAs, n3PUFAs, tFAs, tMUFAs and cholesterol. Data were also obtained for the FAs palmitic and stearic (SFAs), oleic ({omega}-9 PUFA), linoleic, {gamma}-linolenic and arachidonic (n6PUFAs), {alpha}-linolenic, EPA and DHA (n3PUFAs). The list of FAs included in the analysis was determined prior to the analysis after investigating their distributions in this study population and their correlation coefficients and was also based on the quality of the compositional information for that compound.

Statistical analysis
The statistical package used was Intercooled STATA version 10.0 (Stata Corp., College Station, TX). The statistical methods (Spearman rank correlation coefficient, Pearson {chi}2 test, t-test and Wilcoxon rank-sum test) used for the initial tests were described previously (11). Logistic regression models were used to estimate the strength of the effect of the APC Asp1822Val and Glu1317Gln variants, HRT, fat and FA tertiles (based on the combined distributions of cases and controls) on CRC risk. FA intake was adjusted for total energy intake by using the residual method (14). Interaction associations were examined by investigating the combined effects of the single-nucleotide polymorphsisms and dietary exposures. Interaction associations were estimated by using two interaction analysis designs that are compatible (case control and case only). In the case–control design, both the genetic (i.e. one of the APC variant) and the environmental (i.e. fat intake) factors were assessed for all the cases and controls and interaction was tested by fitting an interactive model and its nested multiplicative one. In the case-only design, the genetic and environmental factors are assessed only in the cases (independence between genotypes and environment exposure is assumed). Odds ratios (ORs) in a case-only study are interpreted as a synergy index on a multiplicative scale (15). For both designs, the reference category used was homozygotes of the wild-type allele being at greatest risk (high dietary intake for all the fat and FA categories; no intake of HRT). The statistical models were corrected for sex, age (years, continuously), body mass index (kg/m2, continuously), regular non-steroidal anti-inflammatory drugs intake (intake versus no intake) and Carstairs Deprivation Index (based on the 2001 Census data; seven categories ranging from very low to very high deprivation). Models were additionally corrected for smoking habits (non-smokers, former smokers and current smokers) and family history of cancer (data not shown). In addition to the whole sample analysis, ORs and 95% confidence intervals (CIs) were calculated in stratified subgroups according to sex, age and menopausal status (for the female-related variables; pre/peri-menopausal and post-menopausal women).


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Supplementary material
 Funding
 References
 
There were no significant differences between cases and controls in terms of age, sex, body mass index and area deprivation index (Table I). Control individuals reported a significantly lower total daily energy intake (P = 0.0007) and reported taking non-steroidal anti-inflammatory drugs regularly (P < 0.0005) and having taken HRT (P < 0.0005) more often than cases (Table I). The allele frequency in the control population was 22.4% for APC 1822Val and 1.12% for APC 1317Gln. Both genotypes were under Hardy–Weinberg equilibrium (P-values: 0.79 and 0.51, respectively). Those heterozygous and homozygous for the variant allele for the APC 1317 polymorphism were analysed together, since there was no control individual with the APC 1317 CC genotype.


View this table:
[in this window]
[in a new window]

  		Table I. Demographic characteristics and lifestyle factors for the study population of the gene-environment interaction (cases: 1656; controls: 2292)

 
There was no association between the APC variants and CRC risk in the whole population (Table II). The APC 1822Val allele was inversely associated with CRC risk in individuals younger than 55 years old (P-value from chi-square test 0.05) (Table II). Additionally, APC 1317 GC/CC females were associated with an increased CRC risk (P = 0.03) (Table II).


View this table:
[in this window]
[in a new window]

  		Table II. Chi-square test and logistic regression analysis of the effect of the two APC single-nucleotide polymorphisms on CRC in the whole sample and after sex and age stratification (cases: 2704; controls: 2696)

 
HRT intake was strongly inversely associated with CRC (intake versus no intake: OR, 95% CI: 0.67 (0.54, 0.83), P-value <0.0005) and the effect was even stronger among post-menopausal women [intake versus no intake: OR (95% CI): 0.53 (0.41, 0.68), P-value <0.0005] (data not shown). Associations with CRC when assessing separately subgroups of FAs and individual FAs were presented in a previous study (11). Briefly, a dose-dependent decrease in risk of CRC for subjects that consumed low amounts of total fat, SFAs, MUFAs, tFAs, tMUFAs and cholesterol was observed, whereas there was an increase in risk for subjects that consumed low amounts of n3PUFAs and CRC. Meat, red meat, PUFAs and n6PUFAs intakes were not significantly associated with CRC. Furthermore subjects who consumed low amounts of palmitic, stearic and oleic acids and high amounts of EPA and DHA had a decreased risk for developing CRC. In contrast, there was no effect for linoleic, {gamma}-linolenic, arachidonic and {alpha}-linolenic acids. When stratified by sex, the effects of the above dietary factors were not significantly different among males and females (data not shown).

APC and HRT intake
When stratified according to the APC genotype at codon 1822, post-menopausal women in HRT had a low risk of CRC (supplementary Table I is available at Carcinogenesis Online). The risk was lower for the APC TT individuals and there was statistical evidence to suggest that there is an interaction effect greater than the one expected from a multiplicative model (case–control design, P interaction: 0.04) (supplementary Table I is available at Carcinogenesis Online). In addition, according to the case-only analysis, APC 1822 interacted significantly with HRT (P for interaction: all women 0.05 and post-menopausal women 0.02) (Table III). Results from the interaction analyses (case–control and case-only designs) for the APC 1317 were not significant (supplementary Table II is available at Carcinogenesis Online, Table IV).


View this table:
[in this window]
[in a new window]

  		Table III. Interaction effects between APC 1822 genotypes and HRT and dietary intake on the risk of CRC (case-only design)

 


View this table:
[in this window]
[in a new window]

  		Table IV. Interaction effects between APC 1317 genotypes and HRT and dietary intake on the risk of CRC (case-only design)

 
APC and fat intake
When stratified according to the APC genotype at codon 1822, participants who consumed a diet low in total fat, red meat, SFAs, MUFAs and tFAs had a low risk of CRC (supplementary Table I is available at Carcinogenesis Online). The risk was lower for the APC TT individuals; however, no statistical evidence was found to suggest that there is an interaction effect greater than the one expected from a multiplicative model (case–control design, P interaction: 0.33, 0.13, 0.16, 0.38, 0.09, 0.20, 0.22 and 0.14, respectively) (supplementary Table I is available at Carcinogenesis Online). Low intake of n3PUFAs was associated with an increase CRC risk among the wild-type homozygotes and heterozygotes [OR (95% CI): 1.36 (1.11, 1.68) and 1.38 (1.06, 1.80), respectively]. However, for APC TT individuals, low intake of n3PUFAs was associated with a lower CRC risk [P-value for interaction not significant; OR (95% CI): 0.85 (0.42, 1.72)] (supplementary Table I is available at Carcinogenesis Online). According to the case-only analysis, APC 1822 interacted significantly with red meat (0.002) and MUFA (0.02), results that are in accordance with the case–control analysis (Table III). Results from the interaction analyses (case–control and case-only designs) for the APC 1317 were not significant (supplementary Tables II and IV are available at Carcinogenesis Online). However, lower intakes of MUFAs, PUFAs and n6PUFAs were associated with a stronger decrease risk of CRC for the heterozygous and homozygous for the variant individuals when compared with the homozygous for the wild-type allele (supplementary Table II is available at Carcinogenesis Online). Furthermore, after sex stratification, there was no difference between males and females.

Results of the interaction analysis between the APC variants and the specific FAs (secondary hypothesis) on CRC risk were similar to the results of the FA subgroups analysis (supplementary Tables III and VI are available at Carcinogenesis Online), with the specific FAs behaving as their subgroups, that they belong to. In particular, individuals homozygous for the APC 1822 variant who consumed a diet low in palmitic and stearic (SFAs), oleic (MUFA), EPA and DHA (n3PUFAs) had a non-statistically significant lower risk of CRC when compared with the wild-type or heterozygous individuals (case–control design, supplementary Table III is available at Carcinogenesis Online) and the P-values for interaction from the case-only design were significant for oleic acid (0.05), EPA (0.02) and DHA intakes (0.01) (supplementary Table IV is available at Carcinogenesis Online). In addition, none of the specific FAs interacted significantly with the APC 1317 variant (case–control and case-only designs; supplementary Tables V and VI are available at Carcinogenesis Online).


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Supplementary material
 Funding
 References
 
APC and HRT intake
We did not observe an association between the APC 1822 and 1317 variants and risk of CRC in the whole sample. HRT intake was inversely associated with CRC with the risk being lower among those homozygous for the APC 1822 variant. The HRT–CRC association is supported by several previous studies that showed a reduction in risk of CRC among post-menopausal women (16–18). In particular, a meta-analysis of 18 observational studies showed a 20% reduction in CRC risk among those who ever used HRT and a 34% reduction among the current users versus those who never used HRT (17). In addition, this APC variant/HRT intake interaction effect on CRC risk was also observed in the study by Tranah et al. (6) (study size: 471 cases, 946 controls). Possible biological mechanisms for an HRT effect on CRC risk include through the properties of exogenous oestrogens when there is decreased production of secondary bile acid in the colonic epithelium, reduced estrogen receptor gene methylation, inhibition of cell proliferation and increased vitamin D receptor activity (19–21). All these mechanisms have been found to inhibit colonic carcinogenesis. However, at present, there is no strong experimental evidence to support the role of any specific biological pathway in modulating this effect of HRT intake on CRC risk, so the mechanism of the interaction with APC variants is not known.

APC and fat intake
Participants who consumed a diet low in fat (including cholesterol, SFAs, MUFAs, tFAs and tMUFAs) and high in n3PUFAs had a lower risk of CRC. When stratified according to the APC Asp1822Val variant, however, individuals homozygous for the variant who consumed a diet low in total fat, red meat, SFAs, MUFAs n3PUFAs and tFAs had a non-statistically significant lower risk of CRC when compared with the wild-type or heterozygous individuals. In the case-only analysis, there was a statistically significant interaction between APC 1822 variant and red meat, MUFA and PUFA intake. Interaction relationships between the APC 1317, fat variables were generally of the same direction as for the APC 1822 variant but did not reach statistical significance, possibly because of the very low frequency of the variant allele.

Four previous studies have investigated the possible influence of the APC Asp1822Val variant on the association between dietary and lifestyle factors and CRC (4,6,9,10). Similar to our findings, Slattery et al. (4) showed that a diet low in total saturated and unsaturated fats resulted in a low CRC risk among those homozygous for the APC 1822 variant but with a larger CRC risk reduction among those homozygous for the APC 1822 variant than we report here (study size: 1585 cases, 1945 controls). In addition, the interaction relationship between APC 1822 variant and red meat intake was similar with the one we report, though not significant (4). Guerreiro et al. (10) reported a significant interaction between the Asp1822Val polymorphism and the dietary intakes of cholesterol, calcium, and fibre for CRC risk (study size: 196 cases, 200 controls). However, this strong interaction was not found by Tranah et al. (6) (study size: 471 cases, 946 controls) and Menendez et al. (9) (study size: 346 cases, 297 controls).

One function of the tumour suppressor APC gene (13,14) is its participation in the Wg/Wnt signalling pathway by interacting with β-catenin and regulating cytoskeletal networks (4). β-catenin binds to at least two APC domains, a first series of three 15 amino acid repeats and a second of seven 20 amino acid repeats (22), and codon 1822 is located within one of these domains. Therefore, the aspartic acid to valine change may affect the binding and down-regulation of β-catenin (4). However, down-regulation of β-catenin could occur equally efficiently with just three of the 20 amino acid bindings of the second series and therefore, the APC Asp1822Val polymorphism might not have an effect on β-catenin degradation (23). We have described mechanisms by which fats and FAs influence CRC risk (11). It has been suggested that the observed fat–APC interaction might be due to gene–gene interactions with a modifier gene that encodes a phospholipase involved in the prostaglandin pathway (4) but genetic association studies with very large sample size are required to address this hypothesis, and to also explain the meat/red meat–APC interactions.

Study limitations
Possible limitations of the study design in terms of degree of representativeness to the general population and validity of nutrient estimates has been described previously (13,24). In addition, the observed associations might be confounded since the type and amount of consumed fat depends on the cooking type (frying, baking, etc.). We tried to limit this type of confounding by taking into consideration the way of preparation of certain foods (e.g. meat and fish). We attempted to limit recall bias, misclassification bias due to imprecise measures of dietary intake and residual confounding by adoption of identical study procedures in cases and controls, use of a food frequency questionnaire that had been validated (13), use of images of portion sizes and careful instructions to improve accuracy of reporting diet and adoption of a recall period of 1 year before diagnosis or recruitment date to reduce recall bias. Any measurement error would tend to attenuate observed relationships.

Conclusions
In conclusion, this study with 1656 cases and 2292 controls is the largest study (in terms of number cases) investigating the modification by two APC variants of the associations between lifestyle (HRT) and dietary (fat and red meat intake) factors and CRC risk. We observed a reduction in CRC risk among individuals with a diet low in FAs and specific FA subgroups. Most of these reductions were stronger among those homozygous for the APC 1822 variant (compared with those heterozygous and those homozygous for the wild-type allele) with interaction relationships reaching significance in the case-only analysis. In addition, the association with lower CRC risk and HRT intake in post-menopausal women was greater among those with the variant genotype. These results confirm the findings of three previous case–control studies; however, further large-scale epidemiological and experimental studies are necessary in order to clarify further the role of APC variants in colorectal carcinogenesis.


   Supplementary material
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Supplementary material
Funding
 References
 
Supplementary Tables I–VI can be found at http://carcin.oxfordjournals.org/


   Funding
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Supplementary material
 Funding
References
 
Medical Research Council (G0000657-53203), Chief Scientist Office (K/OPR/2/2/D333), Melville Trust and Cancer Research UK (C348/A3758) to M.G.D, H.C., S.M.F., M.E.P. and A.T.


   Acknowledgments
 
Ms E.T. was supported by a studentship from the Greek State Scholarship Foundation.

Conflict of Interest Statement: None declared.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Supplementary material
 Funding
 References
 

  1. Diergaarde B, et al. Dietary factors and the occurrence of truncating APC mutations in sporadic colon carcinomas: a Dutch population-based study. Carcinogenesis (2003) 24:283–290.[Abstract/Free Full Text]
  2. Powell SM, et al. APC mutations occur early during colorectal tumorigenesis. Nature (1992) 359:235–237.[CrossRef][Web of Science][Medline]
  3. Takayama T, et al. Colorectal cancer: genetics of development and metastasis. J. Gastroenterol. (2006) 41:185–192.[CrossRef][Web of Science][Medline]
  4. Slattery ML, et al. A molecular variant of the APC gene at codon 1822: its association with diet, lifestyle, and risk of colon cancer. Cancer Res. (2001) 61:1000–1004.[Abstract/Free Full Text]
  5. Chen SP, et al. Single nucleotide polymorphisms of the APC gene and colorectal cancer risk: a case-control study in Taiwan. BMC Cancer (2006) 6:83.[CrossRef][Medline]
  6. Tranah GJ, et al. APC Asp1822Val and Gly2502Ser polymorphisms and risk of colorectal cancer and adenoma. Cancer Epidemiol. Biomarkers Prev. (2005) 14:863–870.[Abstract/Free Full Text]
  7. Ruiz-Ponte C, et al. The Asp1822Val variant of the APC gene is a common polymorphism without clinical implications. J. Med. Genet. (2001) 38:E33.[CrossRef][Medline]
  8. Wallis YL, et al. Molecular analysis of the APC gene in 205 families: extended genotype-phenotype correlations in FAP and evidence for the role of APC amino acid changes in colorectal cancer predisposition. J. Med. Genet. (1999) 36:14–20.[Abstract/Free Full Text]
  9. Menendez M, et al. Colorectal cancer risk and the APC D1822V variant. Int. J. Cancer (2004) 112:161–163.[CrossRef][Web of Science][Medline]
  10. Guerreiro CS, et al. The D1822V APC polymorphism interacts with fat, calcium, and fiber intakes in modulating the risk of colorectal cancer in Portuguese persons. Am. J. Clin. Nutr. (2007) 85:1592–1597.[Abstract/Free Full Text]
  11. Theodoratou E, et al. Dietary fatty acids and colorectal cancer: a case-control study. Am. J. Epidemiol. (2007) 166:181–195.[Abstract/Free Full Text]
  12. Theodoratou E, et al. Dietary flavonoids and the risk of colorectal cancer. Cancer Epidemiol. Biomarkers Prev. (2007) 16:684–693.[Abstract/Free Full Text]
  13. Masson LF, et al. Statistical approaches for assessing the relative validity of a food-frequency questionnaire: use of correlation coefficients and the kappa statistic. Public Health Nutr. (2003) 6:313–321.[CrossRef][Web of Science][Medline]
  14. Willett W, et al. Total energy intake: implications for epidemiologic analyses. Am. J. Epidemiol. (1986) 124:17–27.[Free Full Text]
  15. Khoury MJ, et al. Nontraditional epidemiologic approaches in the analysis of gene-environment interaction: case-control studies with no controls! Am. J. Epidemiol. (1996) 144:207–213.[Abstract/Free Full Text]
  16. Chan JA, et al. Hormone replacement therapy and survival after colorectal cancer diagnosis. J. Clin. Oncol. (2006) 24:5680–5686.[Abstract/Free Full Text]
  17. Grodstein F, et al. Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis. Am. J. Med. (1999) 106:574–582.[CrossRef][Web of Science][Medline]
  18. Nanda K, et al. Hormone replacement therapy and the risk of colorectal cancer: a meta-analysis. Obstet. Gynecol. (1999) 93:880–888.[CrossRef][Web of Science][Medline]
  19. Smirnoff P, et al. The protective effect of estrogen against chemically induced murine colon carcinogenesis is associated with decreased CpG island methylation and increased mRNA and protein expression of the colonic vitamin D receptor. Oncol. Res. (1999) 11:255–264.[Web of Science][Medline]
  20. Schwartz B, et al. Estrogen controls expression and bioresponse of 1,25-dihydroxyvitamin D receptors in the rat colon. Mol. Cell. Biochem. (2000) 203:87–93.[CrossRef][Web of Science][Medline]
  21. Issa JP, et al. Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat. Genet. (1994) 7:536–540.[CrossRef][Web of Science][Medline]
  22. Akiyama T, et al. Wnt signalling and the actin cytoskeleton. Oncogene (2006) 25:7538–7544.[CrossRef][Web of Science][Medline]
  23. Bright-Thomas RM, et al. APC, beta-Catenin and hTCF-4; an unholy trinity in the genesis of colorectal cancer. Eur. J. Surg. Oncol. (2003) 29:107–117.[CrossRef][Web of Science][Medline]
  24. Kyle J, et al. Estimating dietary flavonoid intake: comparison of a semi-quantitative food frequency questionnaire with 4-day weighed diet records in a Scottish population [abstract]. Proc. Nutr. Soc. (2002) 61:69A.
Received October 31, 2007; revised March 18, 2008; accepted March 19, 2008.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 JCOHome page
G. Rennert, H. S. Rennert, M. Pinchev, O. Lavie, and S. B. Gruber
Use of Hormone Replacement Therapy and the Risk of Colorectal Cancer
J. Clin. Oncol., September 20, 2009; 27(27): 4542 - 4547.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Supplementary Data
Right arrow All Versions of this Article:
29/9/1774    most recent
bgn082v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (1)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Theodoratou, E.
Right arrow Articles by Farrington, S. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Theodoratou, E.
Right arrow Articles by Farrington, S. M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?