Affiliations of authors: Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School (ATC); Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School (ATC, JM, ELG, DJH, CSF); Cancer Epidemiology Program, DanaFarber/Harvard Cancer Center (ELG, DJH, CSF); Departments of Epidemiology (GJT, ELG, DJH) and Nutrition (ELG, DJH), Harvard School of Public Health; Department of Laboratory Medicine, Children's Hospital (NR); Department of Medical Oncology, DanaFarber Cancer Institute (CSF), Boston, MA
Correspondence to: Andrew Chan, MD, MPH, Gastrointestinal Unit, Massachusetts General Hospital GRJ-722, Boston, MA 02114 (e-mail: achan{at}partners.org).
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ABSTRACT |
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INTRODUCTION |
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Nevertheless, a genetic predisposition to colorectal cancer mediated through iron homeostasis has been hypothesized. In particular, mutations associated with hereditary hemochromatosis, an autosomal recessive disorder associated with total body iron overload, are the most likely candidates to mediate an association between iron homeostasis and colorectal cancer. Hereditary hemochromatosis is most commonly associated with polymorphisms of the HFE gene on chromosome 6. In Caucasian populations, the two most common mutations in HFE are C282Y, a guanine-to-adenine transition resulting in a cysteine-to-tyrosine change with an allele frequency of 0.06, and H63D, a cysteine-to-guanine transversion resulting in a histidine-toaspartic acid change with an allele frequency of 0.15 (20,21). Although HFE gene mutations in the heterozygous state have been found to be associated with iron overload (20,22,23), studies evaluating the association between HFE gene mutation carrier status and colorectal cancer or adenoma have been conflicting (2429). Moreover, to our knowledge, no study has examined the association of HFE gene mutations with colorectal neoplasia in conjunction with other biochemical measures of iron status, such as the concentration of plasma iron, transferrin (i.e., total iron binding capacity), and ferritin.
Given these equivocal data on iron status and colorectal neoplasia, we performed an evaluation of the risk of colorectal adenoma in relation to HFE gene mutations, dietary iron intake, and biochemical markers of total body iron in a prospective, nested casecontrol study of women in the Nurses' Health Study. Because traditional biochemical markers such as plasma iron, transferrin, and ferritin may be perturbed by acute-phase responses and generalized inflammation, we also used soluble transferrin receptors, a novel marker of iron stores. In addition, we measured the ratio of the concentrations of transferrin receptors to ferritin; this ratio is widely considered the most reliable noninvasive measure of body iron stores (30). Because we collected dietary information, plasma, and DNA for genetic analysis prior to the diagnosis of adenoma, we had the unique opportunity to prospectively evaluate each of these measures of iron status in relation to the risk of subsequent adenoma.
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SUBJECTS AND METHODS |
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Case subjects and control subjects were drawn from the Nurses' Health Study, which began in 1976 when 121 701 U.S. female registered nurses, aged 30 to 55 years, completed a questionnaire about their health history. Questionnaires have been mailed to the participants every 2 years to update information on lifestyle factors, medication usage, examination by colonoscopy or sigmoidoscopy, and indications for these procedures. The participants also report newly diagnosed cases of colorectal polyps, cancer, and other diseases. In 1989 through 1990, we collected a blood specimen from 32 826 participants (31). As previously detailed (32), women who provided a blood specimen were generally similar to women who did not; however, the proportion of women who were current smokers was lower among women who gave a blood specimen (14.4%) than among women who did not (25.0%). Subsequent follow-up of this subcohort of women has been greater than 96%. The Human Research Committee at the Brigham and Women's Hospital and the Harvard School of Public Health approved this study.
Selection of Colorectal Adenoma Case Subjects and Control Subjects
When a participant reported a polyp on a biennial questionnaire, we asked for her informed consent to obtain medical records and pathology reports. With each biennial questionnaire, we obtained records on over 90% of reported polyps. Study investigators, blinded to risk factors and other medical history, reviewed all records and extracted data on histologic type, anatomic location, and size of polyps. Women were eligible for selection as either an adenoma case subject or a control subject if they were among the 14 019 women who had provided a blood specimen in 19891990 and reported having at least one sigmoidoscopy or colonoscopy from 1990 through 1998 after providing a blood sample. Women who had a history of inflammatory bowel disease, a familial polyposis syndrome, or diagnosed adenoma or cancer (except non-melanoma skin cancer) prior to blood draw were excluded. Case subjects among the eligible women were women who reported an incident polyp that was confirmed to be adenomatous after blinded review of medical and pathology records. We confirmed only 149 incident colorectal cancers during the study period and were therefore unable to include women with colorectal cancer in this analysis.
Consistent with other studies (33), we defined advanced lesions as adenomas of at least 1 cm in diameter or any size with tubulovillous, villous, or severely dysplastic features. Early lesions were defined as adenomas with tubular histologic characteristics and of less than 1 cm in diameter. We matched one control subject (i.e., women who did not report a polyp, including hyperplastic, on endoscopy) to each case subject on date of endoscopy (i.e., had to be performed during the same 2-year period), birth year, indication for endoscopy, time period of any prior endoscopy, month and year of blood draw, and fasting status. We initially identified a total of 557 matched pairs that were eligible for analysis. We subsequently excluded five matched pairs for whom one member of the pair did not provide dietary data and 25 matched pairs for whom one member of the pair had insufficient DNA sample for genotyping. Thus, 1054 women (527 case subjects and 527 control subjects) were included in this analysis.
Laboratory Procedures
We sent a phlebotomy kit to all women willing to provide a blood specimen in 19891990. After receipt by overnight courier, the chilled heparinized blood was immediately centrifuged; aliquoted into plasma, erythrocytes, and buffy coat fractions; and stored in continuously monitored liquid nitrogen freezers. Over 97% of the blood samples arrived in our laboratory within 26 hours of phlebotomy. Quality control samples were routinely frozen along with study samples to monitor for changes associated with storage and to assess any assay variability.
Laboratory personnel blinded to quality control and casecontrol status conducted all assays. For genotyping, we extracted genomic DNA from 50 µL of buffy coat diluted with 150 µL of phosphate-buffered saline (PBS) using the QIAmp (Qiagen Inc., Chatsworth, CA) 96-spin blood protocol. Genomic DNA concentrations were calculated using PicoGreen technology (Molecular Probes, Eugene, OR). Using the 5' nuclease assay (TaqMan) (Applied Biosystems, Foster City, CA), we performed genotyping of the HFE gene mutations C282Y (rs1800562) and H63D (rs1799945) using TaqMan primers and probes. The polymerase chain reaction amplifications were carried out on 520 ng of DNA using 1x TaqMan Universal PCR Mix (No AmpErase UNG). Amplification conditions on an AB9700 dual plate thermal cycle (Applied Biosystems, Foster City, CA) were as follows: 1 cycle of 95 °C for 10 minutes followed by 50 cycles of 92 °C for 15 seconds and 58 °C for 60 seconds. Following PCR amplification, end-point fluorescence of the reporter dyes was read with the Applied Biosystems 7900HT instrument, and genotypes were assigned using Allelic Discrimination Software (Applied Biosystems SDS Software v1.7a). We inserted quality-control samples equal to 10% of the total number of samples to validate genotype identification procedures; concordance for blinded samples was 100%.
Because of the substantial expense of the plasma-based assays, we were funded to conduct measurements of concentrations of iron, transferrin, ferritin, and soluble transferrin receptors among only the 759 subjects with either distal adenoma (n = 380) or a control subject matched to a woman with distal adenoma (n = 379). Moreover, we obtained similar results for genotype, dietary iron, and distal adenoma risk among these subjects. We used a Hitachi 917 analyzer (Roche Diagnostics, Indianapolis, IN) to measure iron by a colorimetric assay (Roche Diagnostics, Indianapolis, IN), transferrin by an immunoturbidimetric assay (Roche Diagnostics, Indianapolis, IN), ferritin by a particle-enhanced immunoturbidimetric assay (Kamiya Biomedical, Seattle, WA), and soluble transferrin receptors by a particle-enhanced immunoturbidimetric assay (Roche Diagnostics, Indianapolis, IN). The intra-assay coefficients of variations from the blinded quality control samples for each analyte were as follows: iron, 5.2%; transferrin, 6.4%; ferritin, 4.6%; and transferrin receptors, 7.6%. We calculated transferrin saturation as plasma iron/transferrin x 100.
Assessment of Dietary and Nutrient Intake
Every 4 years, we assessed diet in the Nurses' Health Study by using a validated semiquantitative food frequency questionnaire (34,35). In the present analysis, we used data from the baseline dietary questionnaire (from 1990), which included 131 food items. For each food, a commonly used unit or portion size was specified, and the women were asked how often, on average, they had consumed that food over the past year. We computed nutrient intakes by multiplying the frequency of consumption of each food by the nutrient content of the specified portions using composition values from US Department of Agriculture sources, supplemented with other data, including the components of specific multivitamins and breakfast cereals (34,35).
Statistical Analysis
We first calculated means (± standard deviation [SD]) and proportions of baseline characteristics for the case subjects and control subjects at the time of blood draw. The chi-square (2) test was used to assess whether the HFE genotypes in the control subjects were in HardyWeinberg equilibrium. Because of the low prevalence of homozygous mutant genotypes, we combined women with one (heterozygous) and two (homozygous) mutant alleles for analysis and used women with no (homozygous wild-type) mutant alleles as the reference group for all analyses. We evaluated mean levels of iron markers in women with no mutation in the HFE gene compared with women with any HFE gene mutation. We categorized women into quartiles according to the distribution of biochemical markers and nutrient intakes in the control participants.
Wilcoxon signed-rank and 2 tests were used for comparisons of the means and proportions of the baseline characteristics. We calculated Pearson coefficients to estimate the correlation between mean levels of dietary or biochemical iron. We estimated relative risks (RR) and corresponding 95% confidence intervals (CI) for associations among genotype, quartile-specific markers, and quartile-specific nutrient intakes and colorectal adenoma using logistic regression models. We obtained similar results using conditional logistic regression models or unconditional logistic regression models adjusting for matching factors. To increase statistical power in our stratified analyses of nutrient intake, biomarkers, and genotype, we used unconditional regression models adjusting for matching factors and adenoma risk factors. Tests for trend were conducted using the median values for each quartile of iron markers or nutrient intake as a continuous variable in the regression models. To reflect participant characteristics when measures of total body iron were assessed, we used baseline data for all nutrient intake and covariate data at the time of blood draw. Details of the assessment of covariates have been previously described (3641).
Although we did not ask the participants to specify whether they had had a colonoscopy or sigmoidoscopy, based on secular trends (42) we assumed that a substantial portion of the procedures performed early in the study period may have been sigmoidoscopies, which encompass examination of the distal colon and rectum only. Hence, we also performed a secondary analysis in which we restricted our analyses to case subjects and their matched control subjects who received endoscopies later in the study period (19961998). We also assessed for the potential effect modification or statistical interaction by using a log-likelihood ratio test to compare the goodness of fit of the model with interaction terms (genotype * dietary iron intake), with the reduced model containing indicator variables of the main effects of genotype and iron intake (without interaction terms). We used the SAS version 8.2 statistical package (SAS Institute, Cary, NC) for all analyses. All P values are two-sided.
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RESULTS |
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We considered the possibility that an association of HFE mutations with adenoma risk may be restricted to women whohad exposure to sufficient levels of dietary iron. However, our assessment of the joint effect of dietary iron and genotype (Table 6) revealed that there were no statistically significant interactions between genotype and either total iron intake (Pinteraction = .70) or heme iron intake (Pinteraction = .69). Compared with women with no HFE gene mutation in the lowest quartile of intake, women with any HFE gene mutation did not have a statistically significantly elevated risk of adenoma, even those women in the highest quartiles of total iron intake (multivariable RR = 1.14; 95% CI = 0.64 to 2.03; P = .65) or of heme iron intake (multivariable RR = 1.11; 95% CI = 0.64 to 1.93; P = .71).
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We adjusted all of the multivariable models not only for several established or purported adenoma risk factors but also for a number of potential confounding factors, including age, fasting status, indication for endoscopy, time period of endoscopy, family history of colorectal cancer, alcohol intake, age at menarche, and age at menopause or most recent menses for premenopausal women. However, to minimize the potential for residual confounding, we also conducted additional analyses restricted to those women who provided a blood specimen at least 8 hours after a meal, to women who underwent endoscopy without any occult or visible bleeding, to women with no family history of colorectal cancer, and to postmenopausal women. We found no association between HFE genotype, dietary iron, and all iron biomarkers and risk of adenoma in any subgroup (data not shown). In addition, because age, alcohol use, and menses may influence iron stores (5,51) and because secular patterns in use of endoscopy may have influenced adenoma risk, we stratified the study population according to categories of these characteristics. Again, there were no associations between HFE genotype, dietary iron, and iron biomarkers and risk of adenoma within strata of age, alcohol intake, years of menstruation, or time period of endoscopy (data not shown).
Because we did not ask the study participants to specify whether they had had a colonoscopy or sigmoidoscopy, a substantial portion of procedures might have been sigmoidoscopies, which encompass examination of the distal colon and rectum only. To investigate the possibility that the observed null relationships for genotype and dietary iron and risk of adenoma may have been attenuated by undiagnosed proximal adenoma among control subjects, we repeated our analyses among the subgroup of 127 case subjects and 127 control subjects who underwent endoscopy during the last few years of the study (19961998), when a greater proportion of the control subjects were likely to have had colonoscopies than in earlier years (42). Among women who underwent endoscopy after 1996, the multivariable odds ratio (OR) for adenoma in women with any HFE gene mutation compared with women with no HFE gene mutation was 1.16 (95% CI = 0.67 to 2.01). Moreover, there was no statistically significant association between either total iron intake or heme iron intake and risk of adenoma (Ptrend = .48 and .19, respectively).
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DISCUSSION |
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Although iron has been hypothesized to enhance oxidative stress (1), our findings are consistent with considerable evidence (8,17,19,25,26,28,5255) that iron loading does not appear to be related to colorectal carcinogenesis. Individuals with hereditary hemochromatosis at the most extreme levels of chronic total body iron overload do not appear to have a higher risk of colorectal cancer. Early cohort studies (52,53) of hemochromatosis subjects found that they were at greater risk of other chronic disease but not of colorectal cancer. The largest population-based study to date (54) found a nearly 20-fold-higher risk of liver cancer in 1847 hemochromatosis subjects and a 1.5-fold higher risk of hepatobiliary cancer in their 5973 first-degree relatives. However, the risk of colorectal cancer was not increased in either group. Finally, a study of 230 hemochromatosis subjects found an elevated risk of non-hepatic cancers but no statistically significant elevation in risk of colorectal cancer (55).
This study is also consistent with several previous casecontrol studies (25,26,28) that demonstrated no statistically significant association between heterozygosity for mutations in the HFE gene and colorectal cancer. A prior study of heterozygote carriers of hereditary hemochromatosis mutations (24) demonstrated a modestly increased risk of colorectal cancer (in both men and women) and adenoma (in women only). However, that study was performed before wide-scale genotyping became available; consequently, risk of adenoma was based on data obtained from hemochromatosis subjects and on the medical histories of their parents, who were presumed to be heterozygote carriers of the HFE gene. In another casecontrol study (27), HFE gene mutations were a potential risk factor only when an additional mutation in the transferrin receptor was present and only for the combined endpoint of breast and colorectal cancer.
In the North Carolina Colon Cancer Study (29), individuals with an HFE gene mutation had an odds ratio for colon cancer of 1.4, after multivariable adjustment, compared with control subjects without HFE gene mutations. However, assessment of covariates in that study may have been prone to recall or selection bias because lifestyle and dietary factors were measured after cancer diagnosis and because the cooperation rate among control subjects was statistically significantly lower than that among case subjects. Indeed, there was no statistically significant difference in the prevalence of HFE gene mutations between case subjects and control subjects. Moreover, the collection of blood from case subjects after cancer diagnosis precluded measurements of biochemical iron markers because these values would likely be influenced by cancer symptoms (e.g., bleeding or inflammation). Retrospective analyses would also be biased if HFE gene mutations are differentially associated with survival (56).
Our study is also consistent with prior findings that traditional markers of total body iron, including transferrin saturation, plasma iron, and ferritin, are not related to risk of either colorectal cancer (8,17) or adenoma (19). Although our results are not consistent with an initial report (14) that found an elevated risk of colon cancer related to transferrin saturation after early follow-up in men participating in the National Health and Nutritional Evaluation Survey (NHANES), the finding in that study was based on only 12 cases of colon cancer and was not observed in women (14); moreover, the association in men was attenuated after additional follow-up (16). Analysis of a subcohort of NHANES participants that was followed through the National Health Evaluation Follow-Up Study (4) yielded inconsistent results according to cancer site and sex. In addition, a study of a Finnish cohort (15) found an elevated risk of colorectal cancer at extremely high transferrin saturations; however, the study included only 11 case subjects. Finally, two studies (9,18) demonstrated an association between ferritin and risk of adenoma. However, both studies measured ferritin either after or immediately before sigmoidoscopy or colonoscopy. Both also included mainly participants who were bleeding (18) or found a relationship only after adjustment for adenoma risk factors in a limited subgroup of participants (9).
Our results are in agreement with several prior studies (6,7,1013) that also found no association between dietary iron and risk of adenoma. Although a casecontrol study (9) observed a nonstatistically significant increase in the risk of adenoma with high dietary iron intake, the association disappeared when subjects who obtained most of their iron intake from supplements was excluded. In contrast, studies of dietary iron intake and invasive colorectal cancer risk have been less consistent. Two casecontrol studies (3,29) observed no association between dietary iron intake and risk of colorectal cancer, whereas other studies (2,4,5,8) have reported an elevated risk of colorectal using varying measures of iron intake. However, only one of the studies (4) also controlled for the influence of iron-rich red meat, which may independently increase the risk for colorectal cancer through carcinogenic heterocyclic amines generated in the cooking process (29,48,5759).
The strengths of our study include its prospective design, high follow-up rate, well-validated and repeated measures of exposures (34,35), detailed data on potential confounders of both colorectal neoplasia and iron status, and analysis of incident adenomas. In particular, measures of plasma total body iron taken before diagnosis of adenoma minimize potential bias by symptoms associated with neoplasia. In addition, we also assessed levels of transferrin receptors that, compared with traditional biomarkers of iron stores measured in prior studies (6062), vary less within individuals (60), are less affected by chronic disease (61), are not statistically significantly different between healthy adult men and women, and are not associated with age (62). Levels of transferrin receptors have already been shown to correlate with risk of other chronic diseases related to iron overload (63,64). Finally, our study uniquely examines three measures of iron statusgenetic mutations, biochemical markers of iron stores, and dietary iron intakeand their combined influence on risk of neoplasia. Unlike previous studies, we have shown that, despite an association with a variety of biochemical markers of total body iron, HFE gene mutations were not associated with risk of neoplasia.
We acknowledge several limitations to our study. First, we evaluated the risk of adenoma rather than the risk of invasive cancer. Although we also found no association between several measures of iron and high-risk advanced adenomas, we cannot exclude the possibility that iron may be associated with later-stage cancer progression. However, because adenomas rarely cause symptoms, the assessment of nutritional factors and biochemical parameters prior to adenoma diagnosis rather than invasive cancer is less likely to be biased by factors associated with symptomatic disease (e.g., inflammation or bleeding). Nonetheless, future prospective analyses of individuals with colorectal cancers are needed in which a range of biochemical and genetic markers of iron status are measured.
Second, our analysis was focused only on women, who generally experience greater lifetime iron loss through menstruation than do men. Thus, it is possible that men may experience a differential risk of iron-related complications. However, additional analyses restricted to postmenopausal women and stratified by years of menstruation did not show any statistically significant influence of menstrual history on risk of adenoma.
Third, our study was limited largely to Caucasians. This did not substantially affect our analysis, however, because the HFE gene mutations that we studied are observed mainly in Caucasians. Nevertheless, further studies on iron and adenoma risk should examine other racial and ethnic groups, especially because the risk of colon cancer associated with HFE gene mutations in a prior study (29) appeared to be largely limited to African-Americans.
Fourth, our results may also have been influenced by the iron loss through bleeding that provoked the initial endoscopic examination. However, our results were unchanged when restricted to participants who underwent endoscopy for non-bleeding indications. Moreover, we observed similar results for large adenomas, which may be more likely to cause bleeding than small adenomas.
Fifth, our study included only a few participants who were homozygous for HFE gene mutations. Thus, we were unable to separately examine the influence of two gene mutations on adenoma risk. We also did not consider other polymorphisms in the HFE gene (e.g., S65C) or additional genes related to iron metabolism (e.g., transferrin receptor 2, hepcidin, and hemojuvelin); however, these mutations are considerably less common than the C282Y and H63D mutations of the HFE gene (65) and are of uncertain clinical significance (66).
Finally, during the time period under study, many of our participants may have had only a sigmoidoscopy. Thus, case subjects may have differed from control subjects in the extent of colon examination. Although misclassification of control subjects with proximal adenoma would have biased our findings toward the null, previous data (67) suggest that only a small number of participants would have proximal adenoma without distal findings. Most important, our results did not change when restricting the analyses to participants who underwent endoscopy in later time periods, when the prevalence of colonoscopy was higher (42). In addition, we obtained similar results for genotype, dietary iron, and distal adenoma risk for the subcohort of subjects with distal adenoma and their matched control subjects.
In conclusion, using a variety of parameters to assess iron status, we did not find a statistically significant relationship between iron and risk of colorectal adenoma in women. Our findings do not support a substantial role for iron or the HFE genotype on the pathogenesis of colorectal adenoma. Furthermore, although several studies (29,48,57,68,69) have suggested an association between red meat intake and the risk of colorectal neoplasia, our data suggest that the influence of red-meat consumption is mediated through mechanisms other than iron.
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NOTES |
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We are thankful to the participants of the Nurses' Health Study for their continued dedication to the study. We are also thankful to Hardeep Ranu and the DanaFarber/Harvard Cancer Center High Throughput Genotyping Core for technical assistance. This work was presented in abstract form at the GI Oncology Plenary Session at Digestive Disease Week, May 1419, 2005, in Chicago.
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REFERENCES |
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(1) Weinberg ED. The role of iron in cancer. Eur J Cancer Prev 1996;5:1936.
(2) Freudenheim JL, Graham S, Marshall JR, Haughey BP, Wilkinson G. A casecontrol study of diet and rectal cancer in western New York. Am J Epidemiol 1990;131:61224.[Abstract]
(3) Benito E, Stiggelbout A, Bosch FX, Obrador A, Kaldor J, Mulet M, et al. Nutritional factors in colorectal cancer risk: a casecontrol study in Majorca. Int J Cancer 1991;49:1617.[ISI][Medline]
(4) Wurzelmann JI, Silver A, Schreinemachers DM, Sandler RS, Everson RB. Iron intake and the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev 1996;5:5037.[Abstract]
(5) Lee DH, Anderson KE, Harnack LJ, Folsom AR, Jacobs DR Jr. Heme iron, zinc, alcohol consumption, and colon cancer: Iowa Women's Health Study. J Natl Cancer Inst 2004;96:4037.
(6) Hoff G, Moen IE, Trygg K, Frolich W, Sauar J, Vatn M, et al. Epidemiology of polyps in the rectum and sigmoid colon. Evaluation of nutritional factors. Scand J Gastroenterol 1986;21:199204.[Medline]
(7) Macquart-Moulin G, Riboli E, Cornee J, Kaaks R, Berthezene P. Colorectal polyps and diet: a casecontrol study in Marseilles. Int J Cancer 1987;40:17988.[ISI][Medline]
(8) Kato I, Dnistrian AM, Schwartz M, Toniolo P, Koenig K, Shore RE, et al. Iron intake, body iron stores and colorectal cancer risk in women: a nested casecontrol study. Int J Cancer 1999;80:6938.[CrossRef][ISI][Medline]
(9) Bird CL, Witte JS, Swendseid ME, Shikany JM, Hunt IF, Frankl HD, et al. Plasma ferritin, iron intake, and the risk of colorectal polyps. Am J Epidemiol 1996;144:3441.[Abstract]
(10) Benito E, Cabeza E, Moreno V, Obrador A, Bosch FX. Diet and colorectal adenomas: a casecontrol study in Majorca. Int J Cancer 1993;55:2139.[ISI][Medline]
(11) Little J, Logan RF, Hawtin PG, Hardcastle JD, Turner ID. Colorectal adenomas and diet: a casecontrol study of subjects participating in the Nottingham faecal occult blood screening programme. Br J Cancer 1993;67:17784.[ISI][Medline]
(12) Tseng M, Murray SC, Kupper LL, Sandler RS. Micronutrients and the risk of colorectal adenomas. Am J Epidemiol 1996;144:100514.[Abstract]
(13) Tseng M, Sandler RS, Greenberg ER, Mandel JS, Haile RW, Baron JA. Dietary iron and recurrence of colorectal adenomas. Cancer Epidemiol Biomarkers Prev 1997;6:102932.[Abstract]
(14) Stevens RG, Jones DY, Micozzi MS, Taylor PR. Body iron stores and the risk of cancer. N Engl J Med 1988;319:104752.[Abstract]
(15) Knekt P, Reunanen A, Takkunen H, Aromaa A, Heliovaara M, Hakulinen T. Body iron stores and risk of cancer. Int J Cancer 1994;56:37982.[ISI][Medline]
(16) Stevens RG, Graubard BI, Micozzi MS, Neriishi K, Blumberg BS. Moderate elevation of body iron level and increased risk of cancer occurrence and death. Int J Cancer 1994;56:3649.[ISI][Medline]
(17) Herrinton LJ, Friedman GD, Baer D, Selby JV. Transferrin saturation and risk of cancer. Am J Epidemiol 1995;142:6928.[Abstract]
(18) Nelson RL, Davis FG, Sutter E, Sobin LH, Kikendall JW, Bowen P. Body iron stores and risk of colonic neoplasia. J Natl Cancer Inst 1994;86:45560.[Abstract]
(19) Tseng M, Greenberg ER, Sandler RS, Baron JA, Haile RW, Blumberg BS, et al. Serum ferritin concentration and recurrence of colorectal adenoma. Cancer Epidemiol Biomarkers Prev 2000;9:62530.
(20) Beutler E, Felitti V, Gelbart T, Ho N. The effect of HFE genotypes on measurements of iron overload in patients attending a health appraisal clinic. Ann Intern Med 2000;133:32937.
(21) Steinberg KK, Cogswell ME, Chang JC, Caudill SP, McQuillan GM, Bowman BA, et al. Prevalence of C282Y and H63D mutations in the hemochromatosis (HFE) gene in the United States. JAMA 2001;285:221622.
(22) Jackson HA, Carter K, Darke C, Guttridge MG, Ravine D, Hutton RD, et al. HFE mutations, iron deficiency and overload in 10 500 blood donors. Br J Haematol 2001;114:47484.[CrossRef][ISI][Medline]
(23) Beutler E, Felitti V, Gelbart T, Waalen J. Haematological effects of the C282Y HFE mutation in homozygous and heterozygous states among subjects of northern and southern European ancestry. Br J Haematol 2003;120:88793.[CrossRef][ISI][Medline]
(24) Nelson RL, Davis FG, Persky V, Becker E. Risk of neoplastic and other diseases among people with heterozygosity for hereditary hemochromatosis. Cancer 1995;76:8759.[ISI][Medline]
(25) Macdonald GA, Tarish J, Whitehall VJ, McCann SJ, Mellick GD, Buttenshaw RL, et al. No evidence of increased risk of colorectal cancer in individuals heterozygous for the Cys282Tyr haemochromatosis mutation. J Gastroenterol Hepatol 1999;14:118891.[CrossRef][ISI][Medline]
(26) Altes A, Gimferrer E, Capella G, Barcelo MJ, Baiget M. Colorectal cancer and HFE gene mutations. Haematologica 1999;84:47980.[ISI][Medline]
(27) Beckman LE, Van Landeghem GF, Sikstrom C, Wahlin A, Markevarn B, Hallmans G, et al. Interaction between haemochromatosis and transferrin receptor genes in different neoplastic disorders. Carcinogenesis 1999;20:12313.
(28) van der A DL, van der Hel O, Roest M, van der Schouw YT, van Gils CH, Marx JJ, et al. Heterozygosity for the Cys282Tyr mutation in the HFE gene and the risk of colorectal cancer (Netherlands). Cancer Causes Control 2003;14:5415.[CrossRef][ISI][Medline]
(29) Shaheen NJ, Silverman LM, Keku T, Lawrence LB, Rohlfs EM, Martin CF, et al. Association between hemochromatosis (HFE) gene mutation carrier status and the risk of colon cancer. J Natl Cancer Inst 2003;95:1549.
(30) Cook JD, Flowers CH, Skikne BS. The quantitative assessment of body iron. Blood 2003;101:335964.
(31) Hankinson SE, Willett WC, Manson JE, Hunter DJ, Colditz GA, Stampfer MJ, et al. Alcohol, height, and adiposity in relation to estrogen and prolactin levels in postmenopausal women. J Natl Cancer Inst 1995;87:1297302.[Abstract]
(32) Hunter DJ, Hankinson SE, Hough H, Gertig DM, Garcia-Closas M, Spiegelman D, et al. A prospective study of NAT2 acetylation genotype, cigarette smoking, and risk of breast cancer. Carcinogenesis 1997;18:212732.[Abstract]
(33) Baron JA, Cole BF, Sandler RS, Haile RW, Ahnen D, Bresalier R, et al. A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med 2003;348:8919.
(34) Willett WC, Sampson L, Stampfer MJ, Rosner B, Bain C, Witschi J, et al. Reproducibility and validity of a semiquantitative food frequency questionnaire. Am J Epidemiol 1985;122:5165.[Abstract]
(35) Willett WC, Sampson L, Browne ML, Stampfer MJ, Rosner B, Hennekens CH, et al. The use of a self-administered questionnaire to assess diet four years in the past. Am J Epidemiol 1988;127:18899.[Abstract]
(36) Giovannucci E, Colditz GA, Stampfer MJ, Hunter D, Rosner BA, Willett WC, et al. A prospective study of cigarette smoking and risk of colorectal adenoma and colorectal cancer in U.S. women. J Natl Cancer Inst 1994;86:1929.[Abstract]
(37) Fuchs C, Giovannucci E, Colditz G, Hunter D, Speizer F, Willett W. A prospective study of family history and the risk of colorectal cancer. N Engl J Med 1994;331:166974.
(38) Giovannucci E, Colditz GA, Stampfer MJ, Willett WC. Physical activity, obesity, and risk of colorectal adenoma in women (United States). Cancer Causes Control 1996;7:25363.[CrossRef][ISI][Medline]
(39) Giovannucci E, Stampfer MJ, Colditz GA, Hunter DJ, Fuchs C, Rosner BA, et al. Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study. Ann Intern Med 1998;129:51724.
(40) Grodstein F, Martinez ME, Platz EA, Giovannucci E, Colditz GA, Kautzky M, et al. Postmenopausal hormone use and risk for colorectal cancer and adenoma. Ann Intern Med 1998;128:70512.
(41) Chan AT, Giovannucci EL, Schernhammer ES, Colditz GC, Hunter DJ, Willett WC, et al. A prospective study of aspirin use and the risk of colorectal adenoma. Ann Intern Med 2004;140:15766.
(42) Gatto NM, Frucht H, Sundararajan V, Jacobson JS, Grann VR, Neugut AI. Risk of perforation after colonoscopy and sigmoidoscopy: a population-based study. J Natl Cancer Inst 2003;95:2306.
(43) Olynyk JK, Cullen DJ, Aquilia S, Rossi E, Summerville L, Powell LW. A population-based study of the clinical expression of the hemochromatosis gene. N Engl J Med 1999;341:71824.
(44) Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T. Penetrance of 845G>A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 2002;359:2118.[CrossRef][ISI][Medline]
(45) Rossi E, Olynyk JK, Cullen DJ, Papadopoulos G, Bulsara M, Summerville L, et al. Compound heterozygous hemochromatosis genotype predicts increased iron and erythrocyte indices in women. Clin Chem 2000;46:1626.
(46) Rossi E, Bulsara MK, Olynyk JK, Cullen DJ, Summerville L, Powell LW. Effect of hemochromatosis genotype and lifestyle factors on iron and red cell indices in a community population. Clin Chem 2001;47:2028.
(47) Gochee PA, Powell LW, Cullen DJ, Du Sart D, Rossi E, Olynyk JK. A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation. Gastroenterology 2002;122:64651.[ISI][Medline]
(48) Willett WC, Stampfer MJ, Colditz GA, Rosner BA, Speizer FE. Relation of meat, fat, and fiber intake to the risk of colon cancer in a prospective study among women. N Engl J Med 1990;323:166472.[Abstract]
(49) Tavill AS. Diagnosis and management of hemochromatosis. Hepatology 2001;33:13218.[CrossRef][ISI][Medline]
(50) Adams P, Brissot P, Powell LW. EASL International Consensus Conference on Haemochromatosis. J Hepatol 2000;33:485504.[CrossRef][ISI][Medline]
(51) Ioannou GN, Dominitz JA, Weiss NS, Heagerty PJ, Kowdley KV. The effect of alcohol consumption on the prevalence of iron overload, iron deficiency, and iron deficiency anemia. Gastroenterology 2004;126:1293301.[CrossRef][ISI][Medline]
(52) Bradbear RA, Bain C, Siskind V, Schofield FD, Webb S, Axelsen EM, et al. Cohort study of internal malignancy in genetic hemochromatosis and other chronic nonalcoholic liver diseases. J Natl Cancer Inst 1985;75:814.[ISI][Medline]
(53) Niederau C, Fischer R, Sonnenberg A, Stremmel W, Trampisch HJ, Strohmeyer G. Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis. N Engl J Med 1985;313:125662.[Abstract]
(54) Elmberg M, Hultcrantz R, Ekbom A, Brandt L, Olsson S, Olsson R, et al. Cancer risk in patients with hereditary hemochromatosis and in their first-degree relatives. Gastroenterology 2003;125:173341.[ISI][Medline]
(55) Fracanzani AL, Conte D, Fraquelli M, Taioli E, Mattioli M, Losco A, et al. Increased cancer risk in a cohort of 230 patients with hereditary hemochromatosis in comparison to matched control patients with non-iron-related chronic liver disease. Hepatology 2001;33:64751.[CrossRef][ISI][Medline]
(56) Kelsey KT, Hankinson SE, Colditz GA, Springer K, Garcia-Closas M, Spiegelman D, et al. Glutathione S-transferase class mu deletion polymorphism and breast cancer: results from prevalent versus incident cases. Cancer Epidemiol Biomarkers Prev 1997;6:5115.[Abstract]
(57) Giovannucci E, Rimm EB, Stampfer MJ, Colditz GA, Ascherio A, Willett WC. Intake of fat, meat, and fiber in relation to risk of colon cancer in men. Cancer Res 1994;54:23907.[Abstract]
(58) Sinha R, Chow WH, Kulldorff M, Denobile J, Butler J, Garcia-Closas M, et al. Well-done, grilled red meat increases the risk of colorectal adenomas. Cancer Res 1999;59:43204.
(59) Chao A, Thun MJ, Connell CJ, McCullough ML, Jacobs EJ, Flanders WD, et al. Meat consumption and risk of colorectal cancer. JAMA 2005;293:17282.
(60) Cooper MJ, Zlotkin SH. Day-to-day variation of transferrin receptor and ferritin in healthy men and women. Am J Clin Nutr 1996;64:73842.[Abstract]
(61) Kohgo Y, Torimoto Y, Kato J. Transferrin receptor in tissue and serum: updated clinical significance of soluble receptor. Int J Hematol 2002;76:2138.
(62) Allen J, Backstrom KR, Cooper JA, Cooper MC, Detwiler TC, Essex DW, et al. Measurement of soluble transferrin receptor in serum of healthy adults. Clin Chem 1998;44:359.
(63) Tuomainen TP, Punnonen K, Nyyssonen K, Salonen JT. Association between body iron stores and the risk of acute myocardial infarction in men. Circulation 1998;97:14616.
(64) Jiang R, Manson JE, Meigs JB, Ma J, Rifai N, Hu FB. Body iron stores in relation to risk of type 2 diabetes in apparently healthy women. JAMA 2004;291:7117.
(65) Pointon JJ, Wallace D, Merryweather-Clarke AT, Robson KJ. Uncommon mutations and polymorphisms in the hemochromatosis gene. Genet Test 2000;4:15161.[CrossRef][ISI][Medline]
(66) Pietrangelo A. Hereditary hemochromatosisa new look at an old disease. N Engl J Med 2004;350:238397.
(67) Lewis JD, Ng K, Hung KE, Bilker WB, Berlin JA, Brensinger C, et al. Detection of proximal adenomatous polyps with screening sigmoidoscopy: a systematic review and meta-analysis of screening colonoscopy. Arch Intern Med 2003;163:41320.
(68) Neugut AI, Garbowski GC, Lee WC, Murray T, Nieves JW, Forde KA, et al. Dietary risk factors for the incidence and recurrence of colorectal adenomatous polyps. A casecontrol study. Ann Intern Med 1993;118:915.
(69) Giovannucci E, Stampfer MJ, Colditz G, Rimm EB, Willett WC. Relationship of diet to risk of colorectal adenoma in men. J Natl Cancer Inst 1992;84:918.[Abstract]
Manuscript received November 15, 2004; revised April 12, 2005; accepted April 25, 2005.
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