excess iron yields hydroxyl radicals , which may cause conformational changes in the nuclear and cytoplasm membranes and results in activation of oncogenes [ 1 , 2 ] . moreover , iron can sustain the growth of neoplastic cells by suppressing host defences or inflammation . in addition , iron functions as a vital nutrient for unlimited cell multiplication and is required for the unlimited and unrestricted proliferation of cells . several studies have reported that there is no correlation between dietary iron intake and risk of different types of cancer including pancreatic , breast , endometrial , and colorectal [ 3 , 4 ] . additionally , fewer studies assessed serum levels of markers of the iron metabolism . one study , a nested case  control study in the prostate , lung , colorectal , and ovarian cancer screening trial , prospectively evaluated dietary intake and serum measures of iron , ferritin , transferrin , and total iron - binding capacity ( tibc ) in relation to colorectal cancer ( n  =  356 ) . they found a positive association with red meat intake , an inverse association with serum tibc , but no association with the other serum markers . in contrast , a study of over 6,000 us adults by wu et al .   determined that people with higher levels of serum iron had an increased risk of dying from cancer . other studies have found no correlation between serum iron and cancer , but none of these studies took the inflammatory state of the patient into consideration . inflammation is thought to be one of the underlying mechanisms linking iron metabolism and carcinogenesis as iron is involved in both processes . for instance , kooistra et al .   showed that the absorption of iron from the gut was impaired in patients with elevated levels of c - reactive protein ( crp ) , which in turn has been positively linked with risk of cancer . moreover , it is important to note that the relationship between serum iron and tibc can vary depending on the status of the individual . for example , in iron deficient anaemia , tibc is high and serum iron is low . however , under conditions of inflammation  leading to anaemia of chronic disease ( acd)the influence of hepcidin results in low serum iron due to iron being bound intracellularly with ferritin , and this is concomitant with low tibc due to decreased synthesis of transferrin . this results in a positive correlation between si and tibc . to improve our understanding of iron metabolism in the context of carcinogenesis and inflammation , we examined possible associations between serum iron ( si ) , tibc , crp , and cancer risk in a prospective cohort study of 220,642 persons of whom 9,269 were diagnosed with cancer . the central automation laboratory ( calab ) database ( 19851996 ) includes laboratory measurements obtained from 351,487 men and 338,101 women , mainly from the greater stockholm area ( sweden ) . all individuals were either healthy individuals referred for clinical laboratory testing as part of a general health check - up or outpatients referred for laboratory testing . no individuals were inpatients at the time their blood samples were taken , and none were excluded due to disease symptoms or because of treatment . apart from the information on blood testing , no personal data were included in the calab database . this database was linked to several swedish national registries such as the national cancer register , the hospital discharge register , the cause of death register , the consecutive swedish censuses during 19701990 , and the national register of emigration by using the swedish 10-digit personal identity number to provide information on socio - economic status ( ses ) , vital status , cancer diagnosis , and emigration . this linkage of national registers to the calab database is called amoris and has been described in detail elsewhere [ 1117 ] . this study complied with the declaration of helsinki , and the ethics review board of the karolinska institute approved the study . we selected all participants aged 20 or older with baseline measurements of si , tibc , and crp ( n  =  220,642 ) who were free from cancer at baseline and were not diagnosed with cancer or died within 3  years after baseline . follow - up time was defined as time from iron measurement until date of cancer diagnosis , emigration , death , or study closing date ( 31st of december 2002 ) , whichever occurred first . the calab database also contained information on age and fasting status at time of blood sampling . ses is based on occupational status and categorizes gainfully employed subjects into manual and non - manual employees , as well as blue and white - collar workers . history of hospitalization for lung disease was obtained from the national patient register and was used as a proxy for smoking . serum iron was measured via acidification with citric acid in order to dissociate the fe3 transferring complex ( coefficient of variation < 5  % ) , whereas tibc ( which indicates the maximum amount of iron required to saturate si transport protein ) was assessed by adding fe to the serum . both markers were assessed with a dax 96 , technicon instruments corporation , tarrytown , ny , usa , 19931996 . the quantitative determination of crp was done with an established turbidimetric assay ( reagents from orion diagnostics , finland ) using fully automated multichannel analyzers ( an autochemist - prisma , new clinicon , stockholm , sweden , 19851992 ) and dax 96 , technicon instruments corporation , tarrytown , ny , usa , 19931996 ( coefficient of variation : 12  % at crp level 40  mg it was not possible to study high - sensitive ( hs ) crp because at time of blood sampling and analysis ( 19851996 ) , assay methods for plasma proteins had limited sensitivity , so that crp concentrations < 10  mg / l could not be measured precisely ( i.e. , non - hscrp ) . however , the cut - off of 10  mg / l is widely accepted as the upper limit of the health - associated reference range [ 1921 ] . all methods were fully automated with automatic calibration and accredited laboratory facilities . to assess the effect of small changes in si and tibc levels , we calculated standardized values of calcium ( i.e. , dividing by the standard deviation ) using its standard deviation ( sd ) as a unit when performing statistical models . moreover , levels of si and tibc calcium were categorized into quartiles , based on the entire study population . pearson s correlation coefficients were calculated to quantify the association between si , tibc , and crp . to evaluate the association between si , tibc , and risk of incident cancer , multivariate hazard ratios a test for trend was conducted by using assignment to quartiles as an ordinal scale . all cox proportional hazards models took into account potential confounding factors including age as a continuous variable , gender , ses , history of lung disease , and continuous crp . models for si were also adjusted for tibc and vice versa . additionally , we performed stratified analyses by levels of crp ( < 10 and 10 mg / l ) to identify how inflammation affects the association between iron and cancer risk . a test for interaction was performed by adding the product of standardized serum iron and levels of crp ( < 10 and 10 mg / l ) , and the product of standardized serum iron and serum tibc . the above - mentioned analyses were then repeated for specific types of cancer : pancreatic , colon , liver , respiratory , kidney , prostate , stomach , and breast . these cancers were chosen based on the current pre - clinical findings for an association between the iron metabolism and carcinogenesis . risk of breast cancer was analysed for pre- and post - menopausal women separately by using age as a proxy for menopausal status . this stratification was performed as pre - menopausal women are known to have lower iron levels . in the analysis of pre - menopausal women , individuals were followed to age 50 after which they were censored . in the assessment of post - menopausal risk , individuals with a baseline measurement taken before age 50 entered the study at age 50 by means of delayed entry . all analyses were performed with statistical analysis systems ( sas ) release 9.3 ( sas institute , cary , nc , usa ) . the central automation laboratory ( calab ) database ( 19851996 ) includes laboratory measurements obtained from 351,487 men and 338,101 women , mainly from the greater stockholm area ( sweden ) . all individuals were either healthy individuals referred for clinical laboratory testing as part of a general health check - up or outpatients referred for laboratory testing . no individuals were inpatients at the time their blood samples were taken , and none were excluded due to disease symptoms or because of treatment . apart from the information on blood testing , no personal data were included in the calab database . this database was linked to several swedish national registries such as the national cancer register , the hospital discharge register , the cause of death register , the consecutive swedish censuses during 19701990 , and the national register of emigration by using the swedish 10-digit personal identity number to provide information on socio - economic status ( ses ) , vital status , cancer diagnosis , and emigration . this linkage of national registers to the calab database is called amoris and has been described in detail elsewhere [ 1117 ] . this study complied with the declaration of helsinki , and the ethics review board of the karolinska institute approved the study . we selected all participants aged 20 or older with baseline measurements of si , tibc , and crp ( n  =  220,642 ) who were free from cancer at baseline and were not diagnosed with cancer or died within 3  years after baseline . follow - up time was defined as time from iron measurement until date of cancer diagnosis , emigration , death , or study closing date ( 31st of december 2002 ) , whichever occurred first . the calab database also contained information on age and fasting status at time of blood sampling . ses is based on occupational status and categorizes gainfully employed subjects into manual and non - manual employees , as well as blue and white - collar workers . history of hospitalization for lung disease was obtained from the national patient register and was used as a proxy for smoking . serum iron was measured via acidification with citric acid in order to dissociate the fe3 transferring complex ( coefficient of variation < 5  % ) , whereas tibc ( which indicates the maximum amount of iron required to saturate si transport protein ) was assessed by adding fe to the serum . both markers were assessed with a dax 96 , technicon instruments corporation , tarrytown , ny , usa , 19931996 . the quantitative determination of crp was done with an established turbidimetric assay ( reagents from orion diagnostics , finland ) using fully automated multichannel analyzers ( an autochemist - prisma , new clinicon , stockholm , sweden , 19851992 ) and dax 96 , technicon instruments corporation , tarrytown , ny , usa , 19931996 ( coefficient of variation : 12  % at crp level 40  mg it was not possible to study high - sensitive ( hs ) crp because at time of blood sampling and analysis ( 19851996 ) , assay methods for plasma proteins had limited sensitivity , so that crp concentrations < 10  mg / l could not be measured precisely ( i.e. , non - hscrp ) . however , the cut - off of 10  mg / l is widely accepted as the upper limit of the health - associated reference range [ 1921 ] . all methods were fully automated with automatic calibration and accredited laboratory facilities . to assess the effect of small changes in si and tibc levels , we calculated standardized values of calcium ( i.e. , dividing by the standard deviation ) using its standard deviation ( sd ) as a unit when performing statistical models . moreover , levels of si and tibc calcium were categorized into quartiles , based on the entire study population . pearson s correlation coefficients were calculated to quantify the association between si , tibc , and crp . to evaluate the association between si , tibc , and risk of incident cancer , multivariate hazard ratios a test for trend was conducted by using assignment to quartiles as an ordinal scale . all cox proportional hazards models took into account potential confounding factors including age as a continuous variable , gender , ses , history of lung disease , and continuous crp . models for si were also adjusted for tibc and vice versa . additionally , we performed stratified analyses by levels of crp ( < 10 and 10 mg / l ) to identify how inflammation affects the association between iron and cancer risk . a test for interaction was performed by adding the product of standardized serum iron and levels of crp ( < 10 and 10 mg / l ) , and the product of standardized serum iron and serum tibc . the above - mentioned analyses were then repeated for specific types of cancer : pancreatic , colon , liver , respiratory , kidney , prostate , stomach , and breast . these cancers were chosen based on the current pre - clinical findings for an association between the iron metabolism and carcinogenesis . risk of breast cancer was analysed for pre- and post - menopausal women separately by using age as a proxy for menopausal status . this stratification was performed as pre - menopausal women are known to have lower iron levels . in the analysis of pre - menopausal women , individuals were followed to age 50 after which they were censored . in the assessment of post - menopausal risk , individuals with a baseline measurement taken before age 50 entered the study at age 50 by means of delayed entry . all analyses were performed with statistical analysis systems ( sas ) release 9.3 ( sas institute , cary , nc , usa ) . a total of 9,269 persons developed cancer during mean follow - up of 10.57  years . the pearson s correlation between si and tibc was 0.04 ( p  <  0.001 ) . the pearson s correlation between si and crp was 0.06 ( p  <  0.001 ) and 0.03 between tibc and crp ( p  <  0.001 ) . table  1baseline characteristics of study populationno cancer ( n  =  211,373)cancer ( n  =  9,269)age ( years ) [ mean ( sd)]42.29 ( 13.78)54.63 ( 12.19)sex [ n ( % ) ]  male110,079 ( 52.08 ) ( 52.15)4,768 ( 51.44 ) ( 50.82 )  female101,294 ( 47.92)4,501 ( 48.56 ) ( 49.18)ses [ n ( % ) ]  white collar76,076 ( 35.99)3,711 ( 40.04 )  blue collar97,298 ( 46.03)4,132 ( 44.58 )  not gainfully employed or missing37,999 ( 17.98)1,426 ( 15.38)follow - up time ( years ) [ mean ( sd)]10.68 ( 2.97)8.05 ( 3.14)serum iron ( mol / l ) [ mean ( sd)]18.36 ( 5.91)17.96 ( 5.55 )  q1 : < 1440,647 ( 19.23)1,855 ( 20.01 )  q2 : 141859,419 ( 28.11)2,718 ( 29.32 )  q3 : 182256,505 ( 26.73)2,600 ( 28.05 )  q4 : 2254,803 ( 25.93)2,096 ( 22.61)total iron - binding capacity ( mol / l ) [ mean ( sd)]60.02 ( 8.09)59.38 ( 7.74 )  q1 : < 5445,368 ( 21.46)2,121 ( 22.88 )  q2 : 545950,900 ( 24.08)2,349 ( 25.34 )  q3 : 596558,540 ( 27.70)2,567 ( 27.69 )  q4 : 6556,565 ( 26.76)2,232 ( 24.08)crp ( mg / l ) [ mean ( sd)]5.75 ( 15.85)6.77 ( 22.49 )  < 10183,042 ( 86.1150)7,428 ( 80.14 )  1028,331 ( 13.40)1,841 ( 19.86)history of lung disease [ n ( % ) ] 15,439 ( 7.30)571 ( 6.16 ) baseline characteristics of study population multivariate cox proportional hazard ratios for incident cancer and si and tibc are shown in table  2 . a positive association was found between standardized values of tibc and cancer risk [ hr per sd of tibc 1.05 ( 95  % ci 1.031.07 ) ] , which was also seen when using quartiles ( i.e. , hr for 2nd , 3rd and 4th quartile versus 1st quartile : 1.01 ( 95  % ci 0.961.08 ) ; 1.05 ( 0.991.11 ) ; and 1.15 ( 1.081.22 ) , respectively , p value for trend < 0.0001 ) . no statistically significant association was found between si and cancer risk . similar findings were found after stratification by crp levels , although the link between tibc and cancer risk became weaker among those with crp 10  mg / l . we observed no statistically significant interaction between si and tibc and between si and crp levels ( pinteraction 0.08 and 0.42 , respectively ) ( table  2 ) . table  2hazard ratios and 95  % confidence intervals for the risk of overall cancer for quartiles and standardized values of si and tibchazard ratio ( 95  % ci)standardized si ( mol / l ) sd  =  5.911.00 ( 0.971.02)quartiles of si ( mol / l )  < 141.00 ( ref )  14180.91 ( 0.860.96 )  18220.95 ( 0.891.00 )  220.96 ( 0.901.02)p value for trend0.55standardized tibc ( mol / l ) sd  =  8.101.05 ( 1.031.07)quartiles of tibc ( mol / l )  < 541.00 ( ref )  54591.01 ( 0.961.08 )  59651.05 ( 0.991.11 )  651.15 ( 1.081.22)p value for trend<0.0001crp < 10  mg / l ( n  =  195,546)standardized si ( mol / l ) sd  =  5.911.00 ( 0.971.02)quartiles of si ( mol / l )  < 151.00 ( ref )  15180.90 ( 0.840.96 )  18220.93 ( 0.871.00 )  220.95 ( 0.891.03)p value for trend0.58standardized tibc ( mol / l ) sd  =  8.101.05 ( 1.021.07)quartiles of tibc ( mol / l )  < 541.00 ( ref )  54601.03 ( 0.961.10 )  60651.04 ( 0.971.10 )  651.15 ( 1.071.23)p value for trend0.0001crp 10  mg / l ( n  =  31,527)standardized si ( mol / l ) sd  =  5.911.00 ( 0.951.05)quartiles of si ( mol / l )  < 141.00 ( ref )  14180.93 ( 0.821.05 )  18221.01 ( 0.891.14 )  220.96 ( 0.841.10)p value for trend0.91standardized tibc ( mol / l ) sd  =  8.101.06 ( 1.001.11)quartiles of tibc ( mol / l )  < 541.00 ( ref )  54600.97 ( 0.851.10 )  59651.09 ( 0.961.24 )  651.16 ( 1.001.33)p value for trend0.01p for interaction for si and tibc0.08p for interaction for si and crp levels0.42all models were adjusted for age , sex , ses , crp , and history of lung diseasealso adjusted for tibc as a continuous variablealso adjusted for si as a continuous variable hazard ratios and 95  % confidence intervals for the risk of overall cancer for quartiles and standardized values of si and tibc all models were adjusted for age , sex , ses , crp , and history of lung disease also adjusted for tibc as a continuous variable also adjusted for si as a continuous variable finally , we performed the above analyses for specific types of cancer ( table  3 ) . the above pattern was also observed for colon cancer ( i.e. , hr per sd of tibc 1.17 ( 95  % ci 1.081.28 ) ) as well as pancreatic , respiratory , liver , kidney , prostate , stomach , and premenopausal breast cancer  although most findings were not statistically significant . interestingly , a positive relation between si and cancer risk was observed postmenopausal breast cancer ( hr per sd of tibc 1.09 ( 95  % ci 1.021.15 ) ) , and similar trend for si quartiles was also observed . an interaction effect between si and tibc was observed for respiratory cancer ( pinteraction 0.003 ) ( table  3 ) . meanwhile , no statistically significant interaction between si and levels of crp was observed , but a borderline interaction in stomach cancer ( pinteraction : 0.05 ) . table  3hazard ratios and 95  % confidence intervals for the risk of specific types of cancer for quartiles , and standardized values of si levels and tibcn ( % ) hazard ratio ( 95  % ci)hazard ratio ( 95  % ci)no cancercanceroverallcrp < 10  mg / lcrp 10  mg / lpancreatic cancer220,445197n cancer  =  157n cancer  =  40standardized si ( mol / l ) sd  =  5.911.03 ( 0.891.20)0.97 ( 0.821.16)1.34 ( 0.981.83)quartiles of si ( mol / l )  < 1442,463 ( 19.25)39 ( 19.80)1.00 ( ref)1.00 ( ref)1.00 ( ref )  141862,081 ( 28.16)56 ( 28.43)0.90 ( 0.601.36)0.91 ( 0.571.44)0.88 ( 0.342.28 )  182259,045 ( 26.78)60 ( 30.46)1.07 ( 0.711.60)0.93 ( 0.581.48)1.90 ( 0.824.37 )  2256,856 ( 25.79)42 ( 21.32)0.98 ( 0.631.52)0.92 ( 0.561.52)1.44 ( 0.553.82)p value for trend0.810.820.17standardized tibc ( mol / l ) sd  =  8.101.12 ( 0.971.30)1.19 ( 1.011.39)0.84 ( 0.581.23)quartiles of tibc ( mol / l )  < 4247,446 ( 21.52)43 ( 21.83)1.00 ( ref)1.00 ( ref)1.00 ( ref )  425453,204 ( 24.13)45 ( 22.84)0.98 ( 0.641.49)0.79 ( 0.481.32)1.48 ( 0.673.24 )  546761,049 ( 27.69)58 ( 29.44)1.21 ( 0.821.80)1.37 ( 0.892.13)0.62 ( 0.232.33 )  6758,746 ( 26.65)51 ( 25.89)1.36 ( 0.912.06)1.48 ( 0.942.33)0.84 ( 0.302.33)p value for trend0.080.020.32p for interaction for si and tibc0.91p for interaction for si and crp levels0.42colon cancer220,066576n cancer  =  459n cancer  =  117standardized si ( mol / l ) sd  =  5.730.94 ( 0.861.32)0.91 ( 0.811.01)1.05 ( 0.871.27)quartiles of si ( mol / l )  < 1442,379 ( 19.26)123 ( 21.35)1.00 ( ref)1.00 ( ref)1.00 ( ref )  141861,969 ( 28.16)168 ( 29.17)0.84 ( 0.661.06)0.77 ( 0.591.00)1.08 ( 0.641.82 )  182258,933 ( 26.78)172 ( 29.86)0.93 ( 0.741.18)0.86 ( 0.661.12)1.17 ( 0.691.98 )  2256,785 ( 25.80)113 ( 19.62)0.79 ( 0.611.02)0.69 ( 0.510.92)1.25 ( 0.722.16)p value for trend0.200.050.39standardized tibc ( mol / l ) sd  =  0.111.17 ( 1.081.28)1.16 ( 1.051.27)1.21 ( 0.981.49)quartiles of tibc ( mol / l )  < 4247,359 ( 21.52)130 ( 22.57)1.00 ( ref)1.00 ( ref)1.00 ( ref )  425453,119 ( 24.14)130 ( 22.57)0.95 ( 0.741.21)0.96 ( 0.731.26)0.88 ( 0.521.50 )  546760,946 ( 27.69)161 ( 27.95)1.14 ( 0.911.44)1.11 ( 0.851.44)1.22 ( 0.742.01 )  6758,642 ( 26.65)155 ( 26.91)1.45 ( 1.151.84)1.41 ( 1.091.84)1.52 ( 0.882.60)p value for trend0.00060.0050.08p for interaction for si and tibc0.36p for interaction for si and crp levels0.53liver cancer220,503139n cancer  =  139n cancer  =  24standardized si ( mol / l ) sd  =  5.731.24 ( 1.051.47)1.25 ( 1.031.51)1.32 ( 0.901.94)quartiles of si ( mol / l )  < 1442,480 ( 19.27)22 ( 15.83)1.00 ( ref)1.00 ( ref)1.00 ( ref )  141862,092 ( 28.16)45 ( 32.37)1.23 ( 0.741.06)1.33 ( 0.742.39)1.16 ( 0.393.49 )  1822590,675 ( 26.79)40 ( 28.78)1.20 ( 0.712.02)1.33 ( 0.732.41)0.95 ( 0.293.17 )  22568,676 ( 25.79)32 ( 23.02)1.23 ( 0.712.14)1.28 ( 0.692.41)1.51 ( 0.474.82)p value for trend0.560.530.60standardized tibc ( mol / l ) sd  =  0.111.04 ( 0.871.25)1.11 ( 0.921.35)0.72 ( 0.441.17)quartiles of tibc ( mol / l )  < 4247,458 ( 21.52)31 ( 22.30)1.00 ( ref)1.00 ( ref)1.00 ( ref )  425453,213 ( 24.12)36 ( 25.90)1.08 ( 0.671.75)1.09 ( 0.641.87)1.08 ( 0.363.23 )  546761,068 ( 27.69)39 ( 28.06)1.12 ( 0.701.80)1.00 ( 0.581.72)1.62 ( 0.594.44 )  6758,764 ( 26.65)33 ( 23.74)1.23 ( 0.752.01)1.47 ( 0.872.48)n / ap value for trend0.420.210.41p for interaction for si and tibc0.85p for interaction for si and crp levels0.86respiratory cancer219,947695n cancer  =  548n cancer  =  147standardized si ( mol / l ) sd  =  5.731.03 ( 0.951.12)1.04 ( 0.951.14)0.99 ( 0.841.17)quartiles of si ( mol / l )  < 1442,360 ( 19.26)142 ( 20.43)1.00 ( ref)1.00 ( ref)1.00 ( ref )  141861,950 ( 28.17)187 ( 26.91)0.80 ( 0.641.00)0.85 ( 0.661.09)0.64 ( 0.401.02 )  182258,923 ( 26.79)184 ( 26.47)0.84 ( 0.681.05)0.87 ( 0.671.12)0.80 ( 0.511.26 )  2256,716 ( 25.79)182 ( 26.19)1.04 ( 0.841.30)1.07 ( 0.821.38)1.00 ( 0.641.56)p value for trend0.440.440.82standardized tibc ( mol / l ) sd  =  0.111.02 ( 0.941.10)0.99 ( 0.901.08)1.17 ( 0.971.40)quartiles of tibc ( mol / l )  < 4247,324 ( 21.52)244 ( 25.66)1.00 ( ref)1.00 ( ref)1.00 ( ref )  425453,083 ( 24.13)231 ( 24.29)0.93 ( 0.751.16)0.97 ( 0.771.24)0.79 ( 0.491.29 )  546760,900 ( 27.69)274 ( 28.81)1.10 ( 0.901.36)1.09 ( 0.871.38)1.17 ( 0.751.81 )  6758,640 ( 22.59)202 ( 21.24)1.07 ( 0.861.34)0.99 ( 0.771.28)1.49 ( 0.932.39)p value for trend0.270.760.04p for interaction for si and tibc0.003p for interaction for si and crp levels0.31kidney cancer220,442200n cancer  =  155n cancer =  45standardized si ( mol / l ) sd  =  5.731.01 ( 0.871.17)1.03(0.871.23)0.94(0.691.28)quartiles of si ( mol / l )  < 1442,474 ( 19.27)28 ( 14.00)1.00 ( ref)1.00 ( ref)1.00 ( ref )  141862,058 ( 28.15)79 ( 39.50)1.73 ( 1.122.67)1.77 ( 1.062.30)1.70 ( 0.763.80 )  182259,059 ( 26.79)46 ( 23.00)1.07 ( 0.671.72)1.17 ( 0.672.03)0.82 ( 0.312.17 )  2256,852 ( 25.79)47 ( 23.50)1.34 ( 0.842.15)1.40 ( 0.802.45)1.21 ( 0.493.02)p value for trend0.990.910.81standardized tibc ( mol / l ) sd  =  0.111.07 ( 0.921.24)1.04 ( 0.881.23)1.22 ( 0.881.69)quartiles of tibc ( mol / l )  < 4247,442 ( 21.52)47 ( 23.50)1.00 ( ref)1.00 ( ref)1.00 ( ref )  425453,204 ( 24.14)45 ( 22.50)0.90 ( 0.591.35)0.93 ( 0.581.49)0.80 ( 0.341.85 )  546761,052 ( 27.70)55 ( 27.50)1.04 ( 0.701.53)1.11 ( 0.711.73)0.81 ( 0.351.90 )  6758,744 ( 26.65)53 ( 26.50)1.27 ( 0.86189)1.18 ( 0.741.86)1.80 ( 0.814.00)p value for trend0.180.360.21p for interaction for si and tibc0.74p for interaction for si and crp levels0.31prostate cancer113,3421,505n cancer  =  1,201n cancer  =  304standardized si ( mol / l ) sd  =  5.731.00 ( 0.951.06)1.01 ( 0.951.08)0.98(0.871.10)quartiles of si ( mol / l )  < 1416,502 ( 14.56)231 ( 15.35)1.00 ( ref)1.00 ( ref)1.00 ( ref )  141831,712 ( 27.98)441 ( 29.30)0.99 ( 0.841.16)0.98 ( 0.821.18)0.99 ( 0.711.36 )  182232,906 ( 29.03)462 ( 30.70)1.02 ( 0.871.19)1.01 ( 0.841.21)1.05 ( 0.761.44 )  2232,222 ( 28.43)371 ( 24.65)0.99 ( 0.841.17)1.02 ( 0.841.23)0.85 ( 0.601.20)p value for trend0.550.710.47standardized tibc ( mol / l ) sd  =  0.111.05 ( 0.991.11)1.05 ( 0.991.12)0.96 ( 0.871.07)quartiles of tibc ( mol / l )  < 4227,159 ( 23.96)388 ( 25.78)1.00 ( ref)1.00 ( ref)1.00 ( ref )  425429,897 ( 26.38)417 ( 27.71)1.06 ( 0.921.21)1.07 ( 0.911.25)1.02 ( 0.761.37 )  546732,328 ( 28.52)411 ( 27.31)1.08 ( 0.941.24)1.12 ( 0.961.31)0.95 ( 0.701.29 )  6723,958 ( 21.14)289 ( 19.20)1.15 ( 0.991.34)1.17 ( 0.961.39)1.08 ( 0.751.55)p value for trend0.080.060.91p for interaction for si and tibc0.84p for interaction for si and crp levels0.80stomach220,466176n cancer  =  144n cancer  =  32standardized si ( mol / l ) sd  =  5.731.11 ( 0.951.30)0.99 ( 0.831.19)1.65(1.252.17)quartiles of si ( mol / l )  < 1442,469 ( 19.26)33 ( 18.75)1.00 ( ref)1.00 ( ref)1.00 ( ref )  141862,085 ( 28.16)52 ( 29.55)0.92 ( 0.591.43)0.86 ( 0.541.36)1.50 ( 0.366.30 )  182259,063 ( 26.79)42 ( 23.86)0.80 ( 0.501.26)0.62 ( 0.381.03)3.32 ( 0.9112.14 )  2256,849 ( 25.79)49 ( 27.84)1.17 ( 0.751.84)0.87 ( 0.531.42)5.76 ( 1.6320.36)p value for trend0.550.360.0008standardized tibc ( mol / l ) sd  =  0.111.11 ( 0.951.30)1.10 ( 0.931.31)1.08 ( 0.721.63)quartiles of tibc ( mol / l )  < 4247,451 ( 21.52)38 ( 21.59)1.00 ( ref)1.00 ( ref)1.00 ( ref )  425453,207 ( 24.13)42 ( 23.86)1.03 ( 0.671.60)0.89 ( 0.541.45)1.87 ( 0.655.40 )  546761,059 ( 27.70)48 ( 27.27)1.13 ( 0.741.73)1.00 ( 0.621.60)1.84 ( 0.635.33 )  6758,749 ( 26.65)48 ( 27.27)1.46 ( 0.952.25)1.43 ( 0.902.25)1.32 ( 0.374.69)p value for trend0.070.110.64p for interaction for si and tibc0.41p for interaction for si and crp levels0.05breast cancer ( pre - menopausal women)75,3791,108n cancer  =  949n cancer  =  159standardized si ( mol / l ) sd  =  5.730.99 ( 0.931.06)0.99 ( 0.921.06)1.01 ( 0.861.18)quartiles of si ( mol / l )  < 1419,040 ( 25.26)198 ( 26.90)1.00 ( ref)1.00 ( ref)1.00 ( ref )  141820,140 ( 26.62)295 ( 26.62)0.91 ( 0.761.08)0.91 ( 0.751.11)0.84 ( 0.521.36 )  182217,501 ( 22.74)252 ( 22.74)0.90 ( 0.751.09)0.88 ( 0.721.09)0.99 ( 0.621.59 )   2218,698 ( 24.81)263 ( 23.74)1.00 ( 0.831.20)0.99 ( 0.811.22)1.03 ( 0.651.63)p value for trend0.940.850.79standardized tibc ( mol / l ) sd  =  0.111.02 ( 0.961.08)1.05 ( 0.991.11)0.95 ( 0.801.14)quartiles of tibc ( mol / l )  < 4212,864 ( 17.07)209 ( 18.86)1.00 ( ref)1.00 ( ref)1.00 ( ref )  425415,283 ( 20.27)249 ( 22.47)1.12 ( 0.911.38)1.11 ( 0.931.33)1.01 ( 0.621.64 )  546719,883 ( 26.38)307 ( 27.71)1.10 ( 0.901.34)1.11 ( 0.921.42)0.90 ( 0.551.46 )  6727,349 ( 36.28)343 ( 30.96)1.06 ( 0.871.29)1.10 ( 0.881.36)0.85 ( 0.511.42)p value for trend0.750.560.46p for interaction for si and tibc0.31p for interaction for si and crp levels0.95breast cancer ( postmenopausal women)106,6932,130n cancer  =  1,792n cancer  =  338standardized si ( mol / l ) sd  =  5.731.09 ( 1.021.15)1.09 ( 1.021.16)1.08 ( 0.941.23)quartiles of si ( mol / l )  < 1426,214 ( 24.57)495 ( 23.24)1.00 ( ref)1.00 ( ref)1.00 ( ref )  141830,228 ( 28.33)621 ( 29.15)1.02 ( 0.871.20)1.01 ( 0.851.20)1.09 ( 0.751.57 )  182225,829 ( 24.21)544 ( 25.54)1.11 ( 0.951.31)1.09 ( 0.911.30)1.22 ( 0.841.78 )  2224,422 ( 22.89)470 ( 22.07)1.24 ( 1.051.47)1.25 ( 1.041.50)1.20 ( 0.801.80)p value for trend0.0060.010.28standardized tibc ( mol / l ) sd  =  0.111.05 ( 0.991.11)1.05 ( 0.991.11)1.05 ( 0.901.22)quartiles of tibc ( mol / l )  < 4220,232 ( 18.96)422 ( 19.81)1.00 ( ref)1.00 ( ref)1.00 ( ref )  425423,066 ( 21.62)527 ( 24.74)1.16 ( 0.981.36)1.11 ( 0.931.33)1.39 ( 0.942.06 )  546728,587 ( 26.79)583 ( 27.37)1.03 ( 0.871.21)0.98 ( 0.821.17)1.31 ( 0.881.95 )  6734,808 ( 32.62)598 ( 28.08)1.13 ( 0.961.33)1.12 ( 0.931.33)1.15 ( 0.741.80)p value for trend0.390.510.61p for interaction for si and tibc0.18p for interaction for si and crp levels0.11all models were adjusted for age , sex , ses , history of lung diseases , and crp ( unless stratified by levels of crp)also adjusted for tibc as a continuous variablealso adjusted for si as a continuous variablemeasured in men ; not adjusted for gendermeasured in women ; not adjusted for gender hazard ratios and 95  % confidence intervals for the risk of specific types of cancer for quartiles , and standardized values of si levels and tibc all models were adjusted for age , sex , ses , history of lung diseases , and crp ( unless stratified by levels of crp ) also adjusted for tibc as a continuous variable also adjusted for si as a continuous variable measured in men ; not adjusted for gender measured in women ; not adjusted for gender overall , we found an inverse association between tibc and cancer risk particularly in colon cancer . no statistically significant association between si and cancer risk was observed except for postmenopausal breast cancer , where a positive association was observed . for many years , it has been suggested that iron overload plays a role in carcinogenesis . this was originally described in experimental systems where the injection of iron dextran led to the development of soft tissue sarcoma . more recently , it has been demonstrated that excess iron can promote protein and genomic alterations mirrored in human cancers   and this may occur via iron - induced persistent oxidative stress . also in epidemiological studies , the role of iron in risk of cancer has emerged ; ellervik and colleagues showed a statistically significant positive association between transferrin saturation , a marker of iron overload , and risk of all cancers . moreover , when studying the iron metabolism in relation to cancer , it is important to take markers of inflammation into account . during inflammation , normal iron homeostatic mechanisms are disturbed leading to the redistribution of iron , resulting in the accumulation of iron in liver , spleen , and at sites of inflammation while concomitantly reducing the iron present in the bone marrow , leading to anaemia of chronic disease ( acd ) . this process is initiated by hepcidin , an antimicrobial peptide that mediates the internalization and destruction of the iron exporter ferroportin-1 and which is under the control of pro - inflammatory cytokines . therefore , under conditions of inflammation , iron availability for proliferating cells is increased and may contribute to the pathogenesis of cancer . our study however suggests that apart from postmenopausal breast cancer , there is no association with total si and cancer and in fact suggests the opposite as there is a positive association with tibc and cancer . however , this association was influenced by the inflammatory state of the patient , as increased crp levels weakened the association . this may reflect acd where hepcidin production in response to inflammatory cytokines will result in low tibc . nevertheless , it is of note that the small number of cases in some types of cancer resulted in limited power of our analyses . the major strength of this analysis lies in the large number of subjects with prospective measurements of si , tibc , and crp in amoris , all measured at the same clinical laboratory . to our knowledge , this is the only prospective study on cancer risk with information on si , tibc , as well as information on inflammation . this database provided complete follow - up for each person as well as linkage to other registers allowing for detailed information on cancer diagnosis , time of death , and emigration . the amoris population was selected by analysing blood samples from health check - ups in non - hospitalized individuals . the amoris cohort is similar to the general working population of stockholm county in terms of ses and ethnicity . during the study period , all - cause mortality was about 14  % lower in the amoris population than in the general population of stockholm county when taking age , gender , and calendar year into account . this selection of a healthy cohort does however not affect the internal validity of our study . a restriction of this study is that there was no information available on tumour grade , stage , or histology , making it impossible to assess the association between iron metabolism and tumour severity , nor did we have information on other important serum iron markers such as ferritin which is widely accepted as a more definitive marker , especially of acd   or potential confounders such as smoking status and body mass index . however , even though we used history of lung disease as a proxy for smoking , some confounding effects may remain . the effect of using hscrp instead of non - hscrp in the context of inflammation and cancer risk has not been investigated in detail yet , but it is likely that low - grade inflammation is not captured by using this cut - off resulting in an underestimation of the association between crp and cancer . however , the cut - off value of 10  mg / l is thought to be satisfactory for the purpose of medical events such as ischemic necrosis [ 1921 ] . this large population - based epidemiological study adds to the existing pre - clinical studies on serum iron and development of specific cancer types . as opposed to previous studies , we found an inverse relation between iron metabolism and risk of cancer , as clearly shown for colon cancer . the positive link found with post - menopausal breast cancer emphasizes the need to address the specific tumour types and clinical features when assessing iron metabolism in the context of cancer . although no statistically significant interaction between inflammatory markers and iron metabolism was observed , the borderline interaction in relation to stomach cancer indicates a potential role of inflammation in specific cancer development .
objectivespre - clinical studies have shown that iron can be carcinogenic , but few population - based studies investigated the association between markers of the iron metabolism and risk of cancer while taking into account inflammation . 
 we assessed the link between serum iron ( si ) , total - iron binding capacity ( tibc ) , and risk of cancer by levels of c - reactive protein ( crp ) in a large population - based study ( n  =  220,642).methodsfrom the swedish apolipoprotein mortality risk ( amoris ) study , we selected all participants ( > 20  years old ) with baseline measurements of serum si , tibc , and crp . 
 multivariate cox proportional hazards regression was carried out for standardized and quartile values of si and tibc . 
 similar analyses were performed for specific cancers ( pancreatic , colon , liver , respiratory , kidney , prostate , stomach , and breast cancer ) . to avoid reverse causation , we excluded those with follow - up <3 
 years.resultswe found a positive association between standardized tibc and overall cancer [ hr 1.03 ( 95  % ci 1.011.05 ) ] . 
 no statistically significant association was found between si and cancer risk except for postmenopausal breast cancer [ hr for standardized si 1.09 ( 95  % ci 1.021.15 ) ] . 
 the association between tibc and specific cancer was only statistically significant for colon cancer [ i.e. , hr for standardized tibc : 1.17 ( 95  % ci 1.081.28 ) ] . a borderline interaction between si and levels of crp was observed only in stomach cancer.conclusionsas opposed to pre - clinical findings for serum iron and cancer , this population - based epidemiological study showed an inverse relation between iron metabolism and cancer risk . minimal role of inflammatory markers observed warrants further study focusing on developments of specific cancers .