The authors have declared that no competing interests exist.
Conceived and designed the experiments: SS ME JM TS TB WB CH AE GN MA RS ST HC GH HJ PS HU. Analyzed the data: SS ME HJ HU. Contributed reagents/materials/analysis tools: SS ME JM TS TB WB CH AE GN MA RS ST HC GH HJ PS HU. Wrote the paper: SS ME JM TS TB WB CH AE GN MA RS ST HC GH HJ PS HU.
To investigate the association between total serum cholesterol (TSC) and cancer incidence in the Metabolic syndrome and Cancer project (Me-Can).
Me-Can consists of seven cohorts from Norway, Austria, and Sweden including 289,273 male and 288,057 female participants prospectively followed up for cancer incidence (n = 38,978) with a mean follow-up of 11.7 years. Cox regression models with age as the underlying time metric were used to estimate hazard ratios (HR) and their 95% confidence intervals (CI) for quintiles of cholesterol levels and per 1 mmol/l, adjusting for age at first measurement, body mass index (BMI), and smoking status. Estimates were corrected for regression dilution bias. Furthermore, we performed lag time analyses, excluding different times of follow-up, in order to check for reverse causation.
In men, compared with the 1st quintile, TSC concentrations in the 5th quintile were borderline significantly associated with decreasing risk of total cancer (HR = 0.94; 95%CI: 0.88, 1.00). Significant inverse associations were observed for cancers of the liver/intrahepatic bile duct (HR = 0.14; 95%CI: 0.07, 0.29), pancreas cancer (HR = 0.52, 95% CI: 0.33, 0.81), non-melanoma of skin (HR = 0.67; 95%CI: 0.46, 0.95), and cancers of the lymph−/hematopoietic tissue (HR = 0.68, 95%CI: 0.54, 0.87). In women, hazard ratios for the 5th quintile were associated with decreasing risk of total cancer (HR = 0.86, 95%CI: 0.79, 0.93) and for cancers of the gallbladder (HR = 0.23, 95%CI: 0.08, 0.62), breast (HR = 0.70, 95%CI: 0.61, 0.81), melanoma of skin (HR = 0.61, 95%CI: 0.42, 0.88), and cancers of the lymph−/hematopoietic tissue (HR = 0.61, 95%CI: 0.44, 0.83).
TSC was negatively associated with risk of cancer overall in females and risk of cancer at several sites in both males and females. In lag time analyses some associations persisted, suggesting that for these cancer sites reverse causation did not apply.
Since the 1980s several epidemiological studies have reported an association between higher total serum cholesterol (TSC) levels and lower overall or site-specific cancer incidence and mortality
It has been suggested that the observed inverse associations have to be attributed to an effect of preclinical cancer or disease on cholesterol levels (i.e. metabolic depression or increased utilization of cholesterol during carcinogenesis
More recent studies
Assessment of cholesterol levels on a single occasion results in a substantial random error due to variability in the measurement process or real but short-term biological variability. Such inaccuracy in exposure measurement may lead to underestimation
Motivated by the inconsistency in the literature and the failure to account for regression dilution, the aim of this study was to investigate the association between TSC and the overall and site-specific cancer incidence in a large study population containing seven European cohorts.
The Metabolic syndrome and Cancer project (Me-Can) includes data from population-based cohorts from Norway, Austria, and Sweden, and aims at investigating associations between metabolic factors and cancer risk.
A detailed description of the project has been published previously
Anthropometric measurements were conducted in a similar way in all Me-Can cohorts, with participants wearing light indoor clothes and no shoes. Regarding smoking habits, participants were asked to fill in a questionnaire except in VHM&PP where respective questions were asked by the examining physician and the information was entered directly into a database. Participants were classified as never, former, and current smokers.
Fasting time before blood was drawn varied across the different cohorts
In the Oslo and the Norwegian Counties study serum levels of total cholesterol were measured applying a non-enzymatic method, whereas in all other cohorts an enzymatic method was used. Measurements obtained by a non-enzymatic method have been transformed according to 0.92×(cholesterol level) - 0.03 and are presented in mmol/l
Incident cancer cases were identified through linkages with national cancer registries of the respective countries and categorized according to the International Classification of Diseases, seventh revision. Follow-up ended at the date of the first primary cancer diagnosis, emigration, death or December 31, 2003 (in Austria), 2005 (in Norway), or 2006 (in Sweden), whichever occurred first.
Cox proportional hazard regression analyses were applied for men and women separately to investigate the association between TSC levels and site-specific cancer incidence. Subjects were followed until the date of first cancer diagnosis or were censored as described above. When analyzing a specific cancer site, this site was regarded as an event whereas all other sites were censored. Hazard ratios (HR) and respective 95% confidence intervals (CI) were estimated for TSC levels in quintiles (with cut-off levels determined separately for each sex, cohort, and fasting time category) and as a continuous variable (HRs per 1 mmol/l increment).
Age was utilized as the underlying time metric and all estimates were stratified by cohort, fasting time, and categories of birth year (before 1929, 1930–1939, 1940–1949, 1950–1959, 1960–1969, 1970 and later). Additionally, all analyses included adjustment for age at baseline (continuous), body mass index (BMI categories <22.5, 22.5–<25.0, 25.0–<27.5, 27.5–<30.0, 30.0–<32.5, ≥32.5- kg/m2), and smoking status (categories never, former, current smoker). Linear tests for trend were performed including TSC quintiles as an ordinal variable.
The proportionality assumption was checked applying a test based on Schoenfeld residuals. For some cancer sites there was an indication of violation of the proportionality assumption for BMI or smoking status. Additional models stratified for the respective variable were fitted, however estimates of hazard ratios for TSC did not change markedly. To check for reverse causation, various lag-time analyses were carried out, leaving out the first year, the first 5 years, and the first 10 years of follow-up.
In the main analyses hazard ratios were corrected for random error in TSC measurements using a method involving calculation of regression dilution ratio (RDR), similar to that described by Wood et al.
To assess whether statin prescription had an effect on the association between TSC and cancer incidence, additional analyses were performed with only baseline measurements that had been obtained before 1994. This timepoint was selected as the Scandinavian Simvastatin Study published in 1994
Statistical analyses were performed with Stata (version 10, StataCorp LP, College Station, Texas) and R (version 2.7.2, used for RDR calculation). Two-sided P values lower than 0.05 were considered statistically significant.
The study was approved by The Research Review Board of Umeå, Sweden, the Regional Committee for Medical and Health Research Ethics, Southeast Norway and the Ethikommission of the Land Vorarlberg, Austria. Participants from Sweden and Austria provided written informed consent to participate in this study. In Norway, the participants were invited to come to the health survey and a questionnaire was sent together with the invitation. An attendance to the health examination where the participants delivered their filled in questionnaire, has been accepted by the Data Inspectorate as an informed consent, but not a written consent. Written consent was obtained from 1994.
In
Oslo | NCS | CONOR | 40-y | VHM&PP | VIP | MPP | |
Inclusion period | 1972–1973 | 1974–1983 | 1995–2003 | 1994–1999 | 1988–2002 | 1985–2005 | 1974–1992 |
Number (%) | 16,760 (2.90) | 51,024 (8.84) | 109,868 (19.03) | 128,887 (22.32) | 159,280 (27.59) | 78,818 (13.65) | 32,693 (5.66) |
Baseline age, years (mean (SD)) | 44.1 (5.6) | 40.3 (7.0) | 47.5 (15.0) | 41.5 (1.9) | 42.7 (15.4) | 45.6 (9.6) | 45.6 (7.4) |
Smoking status, (n(%)) | |||||||
Never smoker | 3,303 (19.7) | 18,022 (35.3) | 48,859 (44.5) | 24,042 (18.7) | 105,328 (66.1) | 45,756 (58.1) | 12,170 (37.2) |
Ex-smoker | 3,975 (23.7) | 9,185 (18.0) | 28,255 (25.7) | 80,959 (42.8) | 13,960 (8.8) | 16,292 (20.7) | 5,882 (18.0) |
Current smoker | 9,482 (56.6) | 23,817 (46.7) | 32,754 (29.8) | 23,886 (18.5) | 39,992 (25.1) | 15,291 (19.4) | 14,589 (44.6) |
Missing | 0 | 0 | 0 | 0 | 0 | 1,479 (1.8) | 52 (0.2) |
BMI, kg/m2 (mean (SD)) | 26.6 (2.9) | 24.6 (3.5) | 26.1 (4.1) | 25.5 (3.8) | 24.8 (4.2) | 25.8 (4.0) | 24.6 (3.6) |
Cholesterol, mmol/l, (mean(SD)) | 6.33 (1.19) | 6.21 (1.26) | 5.70 (1.18) | 5.54 (1.01) | 5.55 (1.19) | 5.64 (1.19) | 5.66 (1.08) |
Quintiles, (mean (SD)) | |||||||
1 | 4.83 (0.47) | 4.66 (0.42) | 4.26 (0.41) | 4.28 (0.40) | 4.06 (0.41) | 4.12 (0.49) | 4.29 (0.40) |
2 | 5.75 (0.18) | 5.51 (0.20) | 5.03 (0.20) | 4.99 (0.23) | 4.88 (0.18) | 5.00 (0.20) | 5.07 (0.18) |
3 | 6.33 (0.16) | 6.11 (0.20) | 5.61 (0.19) | 5.47 (0.25) | 5.46 (0.18) | 5.71 (0.20) | 5.60 (0.17) |
4 | 6.92 (0.19) | 6.77 (0.26) | 6.26 (0.23) | 6.00 (0.30) | 6.10 (0.22) | 6.19 (0.25) | 6.16 (0.21) |
5 | 8.08 (0.83) | 8.05 (0.98) | 7.46 (0.74) | 7.01 (0.73) | 7.32 (0.82) | 7.39 (0.79) | 7.24 (0.76) |
Hypercholesterolemia, (n (%)) >6.2 mmol/l | 8,409 (50.2) | 23,575 (46.2) | 33,101 (30.1) | 30,178 (23.4) | 42,611 (26.8) | 22,674 (28.8) | 9,244 (28.3) |
Fasting | |||||||
<4 h | 13,642 (81.4) | 39,800 (78.0) | 85,533 (77.9) | 101,142 (78.5) | 0 (0.0) | 2,680 (3.4) | 0 (0.0) |
4 h–8 h | 1,700 (10.1) | 9,831 (19.27) | 18,208 (16.57) | 22,172 (17.20) | 0 (0.0) | 5,601 (7.1) | 0 (0.0) |
>8 h | 1,418 (8.5) | 1,393 (2.7) | 6,127 (5.6) | 5,573 (4.3) | 159,280 (100.0) | 70,537 (89.5) | 32,693 (100.0) |
Measurement method | Non- enzymatic | Non- enzymatic,Enzymatic from year 1980 | Enzymatic | Enzymatic | Enzymatic | Enzymatic | Enzymatic |
Follow-up, years (mean (SD)) | 26.0 (8.0) | 25.8 (6.2) | 6.1 (2.4) | 7.4 (1.6) | 10.4 (4.5) | 7.5 (4.2) | 21.1 (6.3) |
Categories, (n) | |||||||
<1 | 69 | 183 | 902 | 364 | 458 | 6600 | 190 |
1–<5 | 447 | 1,087 | 42,663 | 2,083 | 27,978 | 23,381 | 1,035 |
5–<10 | 659 | 1,411 | 67,205 | 123,035 | 37,354 | 30,581 | 1,353 |
10– | 15,654 | 48,546 | 0 | 3,769 | 93,948 | 24,856 | 30,305 |
Cancer cases, (n) | 4,382 | 7,916 | 4,610 | 2,714 | 8,524 | 4,163 | 6,639 |
Abbreviations: BMI, body mass index; CONOR, Cohort of Norway; MPP, Malmö Preventive Project; NCS, Norwegian Counties Study; Oslo, Oslo study I; SD, standard deviation; VHM&PP, Vorarlberg Heath Monitoring and Prevention Programme; VIP, Västerbotten Intervention Project; 40-y, Age 40-programme.
Hazard ratios corrected for regression dilution bias for total and site-specific cancer incidence by quintiles and per unit increment of TSC are presented in
Quintile | |||||||||||||
Site (ICD-7 code) | 2 | 3 | 4 | 5 | per 1 unit | (mmol/l) | |||||||
n cases | HR | 95% CI | HR | 95% CI | HR | HR | 95% CI | HR | 95% CI | ||||
Total cancer | 23,142 | 0.95 | 0.89, 1.02 | 0.94 | 0.88, 1.00 | 0.94 | 0.88, 1.01 | 0.94 | 0.88, 1.00 | 0.11 | 0.98 | 0.97,1.00 | |
Lip, oral cavity, pharynx (140–149) | 588 | 1.04 | 0.67, 1.61 | 0.93 | 0.60, 1.44 | 0.90 | 0.58, 1.40 | 1.38 | 0.91, 2.10 | 0.18 | 1.07 | 0.96, 1.19 | |
Oesophagus (150) | 248 | 0.95 | 0.48, 1.86 | 0.83 | 0.42, 1.63 | 0.79 | 0.40, 1.55 | 1.12 | 0.59, 2.12 | 0.79 | 0.99 | 0.84, 1.18 | |
Stomach (151) | 858 | 0.85 | 0.60, 1.22 | 0.78 | 0.55, 1.11 | 0.92 | 0.66, 1.30 | 0.71 | 0.50, 1.01 | 0.14 | 0.92 | 0.84, 1.01 | |
Colon (153) | 1,806 | 0.94 | 0.72, 1.22 | 1.19 | 0.93, 1.53 | 1.19 | 0.93, 1.52 | 1.18 | 0.92, 1.51 | 0.04 | 1.05 | 0.99, 1.12 | |
Rectum, anus (154) | 1,158 | 1.12 | 0.82, 1.53 | 0.97 | 0.71, 1.33 | 0.96 | 0.70, 1.31 | 1.09 | 0.81, 1.48 | 0.92 | 1.01 | 0.93, 1.09 | |
Liver, intrahepatic bile ducts (155.0) | 194 | 0.33 | 0.17, 0.63 | 0.22 | 0.11, 0.43 | 0.26 | 0.13, 0.49 | 0.14 | 0.07, 0.29 | <0.01 | 0.58 | 0.46, 0.71 | |
Gallbladder, biliary tract (155.1–155.3) | 98 | 1.16 | 0.38, 3.56 | 1.35 | 0.46, 3.98 | 1.03 | 0.34, 3.10 | 1.27 | 0.44, 3.69 | 0.80 | 1.10 | 0.84, 1.45 | |
Pancreas (157) | 520 | 0.63 | 0.41, 0.98 | 0.75 | 0.49, 1.14 | 0.63 | 0.41, 0.97 | 0.52 | 0.33, 0.81 | 0.01 | 0.86 | 0.76, 0.97 | |
Larynx, trachea/bronchus/lung (161,162) | 2,922 | 1.01 | 0.83, 1.24 | 1.09 | 0.90, 1.33 | 0.97 | 0.80, 1.18 | 1.15 | 0.95, 1.40 | 0.22 | 1.03 | 0.98, 1.08 | |
Prostate (177) | 6,884 | 1.00 | 0.88, 1.14 | 1.05 | 0.93, 1.20 | 1.01 | 0.89 1.14 | 0.99 | 0.88, 1.13 | 0.86 | 0.99 | 0.96, 1.03 | |
Testis (178) | 278 | 0.80 | 0.46, 1.39 | 1.11 | 0.64, 1.93 | 1.34 | 0.76, 2.36 | 0.81 | 0.42, 1.56 | 0.77 | 0.97 | 0.81, 1.16 | |
Kidney, renal cell (180.0–180.9) | 691 | 1.26 | 0.84, 1.88 | 0.99 | 0.66, 1.29 | 1.23 | 0.83, 1.83 | 1.06 | 0.71, 1.58 | 0.94 | 1.00 | 0.90, 1.11 | |
Bladder (181) | 1,573 | 1.27 | 0.97, 1.65 | 0.90 | 0.68, 1.18 | 1.04 | 0.80 1.35 | 1.11 | 0.85, 1.44 | 0.96 | 1.01 | 0.95, 1.09 | |
Melanoma of skin (190) | 1,074 | 0.87 | 0.64, 1.16 | 0.77 | 0.57, 1.04 | 0.76 | 0.56, 1.03 | 0.82 | 0.61, 1.11 | 0.15 | 0.93 | 0.85, 1.02 | |
Non-melanoma of skin (191) | 782 | 0.77 | 0.54 1.10 | 0.70 | 0.49, 1.01 | 0.79 | 0.56, 1.13 | 0.67 | 0.46, 0.95 | 0.07 | 0.91 | 0.82, 1.01 | |
Brain, nervous tissue (193) | 427 | 0.91 | 0.56, 1.47 | 0.97 | 0.60, 1.55 | 0.82 | 0.50 1.33 | 0.86 | 0.53, 1.41 | 0.48 | 0.98 | 0.86, 1.12 | |
Thyroid gland (194) | 128 | 1.03 | 0.44, 2.40 | 0.77 | 0.32, 1.88 | 1.01 | 0.43, 2.40 | 0.64 | 0.25, 1.62 | 0.40 | 0.94 | 0.74, 1.21 | |
Lymph/hematopoietic tissue (200–209) | 1,790 | 0.76 | 0.60, 0.97 | 0.75 | 0.59, 0.95 | 0.85 | 0.67, 1.07 | 0.68 | 0.54, 0.87 | 0.02 | 0.91 | 0.85, 0.97 | |
Other cancer | 1,123 | 0.94 | 0.69, 1.27 | 0.83 | 0.61, 1.13 | 0.85 | 0.63, 1.15 | 0.87 | 0.64, 1.18 | 0.31 | 0.96 | 0.89, 1.05 |
Abbreviations: CI, confidence interval; HR, hazard ratio; ICD-7, International Classification of Diseases, seventh revision.
HRs estimated from Cox proportional hazard regression models with age as the time scale, stratified by cohort, fasting status, and birth year categories, adjusted for baseline age, body mass index categories, and smoking status. HRs corrected for random error by regression dilution ratio (RDR); conversion into uncorrected HR = exp(ln(HR)*RDR), where RDR = 0.644.
Quintile | |||||||||||||
Site (ICD-7 code) | n cases | 2 | 3 | 4 | 5 | per 1 unit | (mmol/l) | ||||||
HR | 95% CI | HR | 95% CI | HR | 95% CI | HR | 95% CI | HR | 95% CI | ||||
Total cancer | 15,836 | 0.95 | 0.87, 1.03 | 0.93 | 0.85, 1.01 | 0.94 | 0.86, 1.02 | 0.86 | 0.79, 0.93 | <0.01 | 0.95 | 0.93, 0.97 | |
Lip, oral cavity, pharynx (140–149) | 186 | 1.19 | 0.53, 2.68 | 0.75 | 0.32, 1.74 | 1.26 | 0.58, 2.75 | 1.13 | 0.51, 2.48 | 0.68 | 1.11 | 0.92, 1.34 | |
Oesophagus (150) | 47 | 1.17 | 0.17, 7.98 | 1.10 | 0.17, 7.21 | 3.29 | 0.61, 17.81 | 1.51 | 0.26, 8.83 | 0.35 | 1.02 | 0.70, 1.49 | |
Stomach (151) | 416 | 0.96 | 0.55, 1.68 | 0.62 | 0.35, 1.09 | 0.98 | 0.57, 1.64 | 0.84 | 0.50, 1.42 | 0.72 | 0.96 | 0.85, 1.09 | |
Colon (153) | 1,336 | 1.05 | 0.75, 1.48 | 1.19 | 0.86, 1.64 | 1.17 | 0.85, 1.61 | 1.23 | 0.90, 1.69 | 0.15 | 1.03 | 0.96, 1.10 | |
Rectum, anus (154) | 635 | 1.11 | 0.68, 1.81 | 1.43 | 0.90, 2.26 | 1.50 | 0.95, 2.35 | 1.48 | 0.94, 2.32 | 0.49 | 1.09 | 0.99, 1.21 | |
Liver, intrahepatic bile ducts (155.0) | 71 | 2.87 | 0.69, 11.83 | 1.08 | 0.24, 4.86 | 1.09 | 0.25, 4.70 | 0.96 | 0.22, 4.07 | 0.24 | 0.73 | 0.53, 1.02 | |
Gallbladder, biliary tract (155.1–155.3) | 104 | 0.94 | 0.35, 2.51 | 0.38 | 0.13, 1.09 | 0.47 | 0.18, 1.25 | 0.23 | 0.08, 0.62 | <0.01 | 0.66 | 0.50, 0.86 | |
Pancreas (157) | 324 | 0.86 | 0.45, 1.67 | 0.76 | 0.40, 1.45 | 0.97 | 0.53, 1.80 | 1.08 | 0.60, 1.97 | 0.44 | 1.06 | 0.92, 1.23 | |
Larynx, trachea/bronchus/lung (161,162) | 947 | 0.83 | 0.56, 1.21 | 1.10 | 0.77, 1.57 | 1.04 | 0.73, 1.49 | 1.24 | 0.88, 1.76 | 0.05 | 1.03 | 0.95, 1.12 | |
Breast (170) | 5,228 | 0.93 | 0.81, 1.07 | 0.91 | 0.79, 1.04 | 0.84 | 0.73, 0.96 | 0.70 | 0.61, 0.81 | <0.01 | 0.90 | 0.86, 0.93 | |
Cervix (171) | 477 | 1.02 | 0.66, 1.59 | 0.97 | 0.62, 1.52 | 1.07 | 0.68, 1.67 | 1.05 | 0.66, 1.67 | 0.79 | 1.02 | 0.90, 1.16 | |
Other parts of uterus (172,174) | 1,081 | 0.83 | 0.59, 1.16 | 0.87 | 0.63, 1.20 | 0.70 | 0.51, 0.97 | 0.74 | 0.54, 1.02 | 0.04 | 0.91 | 0.84, 0.99 | |
Ovary (175.0) | 733 | 1.06 | 0.71, 1.60 | 1.32 | 0.89, 1.95 | 1.42 | 0.96, 2.09 | 1.27 | 0.86, 1.89 | 0.12 | 1.06 | 0.96, 1.17 | |
Kidney, renal cell (180.0–180.9) | 321 | 0.74 | 0.37, 1.48 | 1.12 | 0.60, 2.11 | 0.95 | 0.51, 1.79 | 1.13 | 0.61, 2.07 | 0.40 | 1.05 | 0.91, 1.21 | |
Bladder (181) | 325 | 0.74 | 0.39, 1.40 | 0.81 | 0.44, 1.49 | 0.70 | 0.38, 1.28 | 0.91 | 0.51, 1.62 | 1.00 | 0.95 | 0.82, 1.10 | |
Melanoma of skin (190) | 777 | 0.96 | 0.68, 1.34 | 0.68 | 0.48, 0.98 | 0.98 | 0.70, 1.38 | 0.61 | 0.42, 0.88 | 0.03 | 0.88 | 0.79, 0.98 | |
Non-melanoma of skin (191) | 396 | 1.67 | 0.88, 3.16 | 1.12 | 0.59, 2.14 | 1.47 | 0.80, 2.72 | 1.52 | 0.83, 2.78 | 0.32 | 1.10 | 0.97, 1.25 | |
Brain, nervous tissue (193) | 258 | 0.74 | 0.40, 1.39 | 0.56 | 0.29, 1.08 | 0.92 | 0.50, 1.68 | 0.70 | 0.37, 1.31 | 0.54 | 0.95 | 0.80, 1.13 | |
Thyroid gland (194) | 259 | 1.17 | 0.64, 2.13 | 0.90 | 0.48, 1.67 | 0.93 | 0.50, 1.72 | 0.85 | 0.56, 1.30 | 0.31 | 0.88 | 0.73, 1.05 | |
Lymph/hematopoietic tissue (200–209) | 1,094 | 0.77 | 0.56, 1.07 | 0.81 | 0.59, 1.11 | 0.77 | 0.57, 1.05 | 0.61 | 0.44, 0.83 | 0.01 | 0.85 | 0.78, 0.92 | |
Other cancer | 821 | 1.13 | 0.77, 1.65 | 1.10 | 0.75, 1.60 | 1.06 | 0.73, 1.54 | 0.94 | 0.64, 1.37 | 0.51 | 1.01 | 0.92, 1.11 |
Abbreviations: CI, confidence interval; HR, hazard ratio; ICD-7, International Classification of Diseases, seventh revision.
HRs estimated from Cox proportional hazard regression models with age as the time scale, stratified by cohort, fasting status, and birth year categories, adjusted for baseline age, body mass index categories, and smoking status. HRs corrected for random error by regression dilution ratio (RDR); conversion into uncorrected HR = exp(ln(HR)*RDR), where RDR = 0.660.
Among men, compared with the first quintile, TSC concentrations in the fifth quintile were borderline significantly associated with decreasing risk of total cancer (HR = 0.94; 95%CI: 0.88, 1.00) and significant inverse associations were observed for cancers of the liver/intrahepatic bile duct (HR = 0.14; 95%CI: 0.07, 0.29), pancreas cancer (HR = 0.52, 95% CI: 0.33, 0.81), non-melanoma of skin (HR = 0.67; 95%CI: 0.46, 0.95), and cancers of the lymph/hematopoietic tissue (HR = 0.68, 95%CI: 0.54, 0.87). Similar associations were observed when one unit increments of TSC were considered (
In women, the hazard ratio for the fifth quintile was associated with decreasing risk of total cancer (HR = 0.86, 95%CI: 0.79, 0.93) and furthermore for cancers of the gallbladder (HR = 0.23, 95%CI: 0.08, 0.62), breast (HR = 0.70, 95%CI: 0.61, 0.81), melanoma of skin (HR = 0.61, 95%CI: 0.42, 0.88) and cancers of the lymph−/hematopoietic tissue (HR = 0.61, 95%CI: 0.44, 0.83). Hazard ratios per one unit TSC increment showed similar inverse associations. Additionally, a borderline significant association was observed for cancers of other parts of uterus (HR = 0.91, 95%CI: 0.84, 0.99).
Considering males, comparing the fifth to the first quintile in lag-time analyses, after leaving out the first year of follow-up significant inverse associations persisted for cancers of the liver/intrahepatic bile ducts (HR = 0.15, 95%CI: 0.08, 0.31) and pancreas cancer (HR = 0.54, 95%CI: 0.35, 0.85). Furthermore, a borderline positive association for colon cancer (HR = 1.30, 95%CI: 1.01, 1.68) was observed. Leaving out the first five years of follow-up, significant inverse associations were still observed for cancers of the liver/intrahepatic bile ducts (HR = 0.24, 95%CI: 0.11, 0.53), pancreas (HR = 0.48, 95%CI: 0.30, 0.78) and non-melanoma of skin (HR = 0.63, 95%CI: 0.42, 0.94). There was again a positive association of TSC with colon cancer (HR = 1.46, 95%CI: 1.10, 1.92). When the first ten years of follow-up were excluded, only associations with pancreas cancer (HR = 0.50, 95%CI: 0.29, 0.88) non-melanoma of skin (HR = 0.56, 95%CI: 0.36, 0.89) and colon cancer (HR = 1.44, 95%CI: 1.05, 1.98) remained.
In females, all reported associations comparing the fifth to the first quintile persisted, when the first year of follow-up was excluded (total cancer HR = 0.90, 95%CI: 0.83, 0.98; gallbladder HR = 0.25, 95%CI: 0.09, 0.71; breast HR = 0.72, 95%CI: 0.62, 0.83; melanoma of skin HR = 0.60, 95%CI: 0.41, 0.89; cancers of the lymph/hematopoietic tissue HR = 0.65, 95%CI: 0.47, 0.90). When the first 5 years were left out, significant associations with breast cancer (HR = 0.71, 95%CI: 0.60, 0.85) and melanoma of skin (HR = 0.54, 95%CI: 0.33, 0.87) were still observed, which also persisted when the first ten years of follow-up were excluded (breast cancer HR = 0.62, 95%CI: 0.49, 0.80; melanoma of skin HR = 0.46, 95%CI: 0.21, 0.96).
Results of the sub-analyses including cholesterol data before 1994 are presented in
In the present prospective cohort study, elevated TSC levels were significantly associated with decreased risk of cancer incidence in general and with several site-specific cancers in men and women. With the exception of male colon cancer we only found no or inverse relationships between TSC and cancer. Inverse relationships were found for cancers of the liver/intrahepatic bile duct, pancreas, non-melanoma of skin and lymph/hematopoietic tissue among men and for gallbladder, breast, melanoma of skin and lymph/hematopoietic tissue among women. From these, only associations of TSC with colon cancer, pancreas cancer, breast cancer, and skin cancer remained significant in the lag-time analysis. Restricting analyses to measurements before 1994, the onset of statin medication, revealed no major differences regarding the estimated associations.
In previous studies, the “preclinical cancer effect” hypothesis
Concerning site-specific cancers, reports on associations with colon cancer are controversial. Positive as well as negative associations have been observed
Regarding liver cancer, our results are in line with previously published results of the Me-Can study collaboration and other studies, where mostly negative associations have been reported that diminished with increasing lag-time periods
For gallbladder/biliary tract cancer Andreotti et al
The amount of literature on pancreatic cancer and its associations with cholesterol is limited. Two conducted studies found no significant associations
With regard to cancers of the lymph/hematopoietic tissue, leukemic blood and bone narrow cells have been reported to show an elevated low density lipoprotein-receptor activity that was inversely associated with plasma cholesterol levels which might explain hypocholesteraemia often seen in leukemic patients
Most investigations on breast cancer have not reported significant associations with TSC
Recently several authors reported positive associations between TSC levels and aggressive prostate cancer
Strengths of our study include the large sample size of over 500,000 participants from seven European population-based cohorts with virtually complete capture of cancer cases. We were also able to correct risk estimates for regression dilution bias, caused by random fluctuations in baseline measurements common to long-term prospective studies, which might lead to underestimation of the true risk. Furthermore, all analyses were adjusted for potential confounders such as BMI and smoking status and stratified by birth year, cohort and fasting time before measurement.
On the other hand, our study is limited by the lack of information of use of anti-hypercholesterol medication, such as statins, behavioural aspects like dietary habits, physical activity and alcohol consumption, as well as genetic variations that could have influenced both cholesterol levels and cancer. Furthermore, we did not have separate data on low and high density lipoprotein cholesterol subfractions or detailed information on tumor staging.
In summary, TSC levels were negatively associated with risk of cancer overall in females and risk of cancer at several sites in both males and females. Also, a positive relation was found for colon cancer in men. In the lag-time analysis some associations persisted, suggesting that although competing risks and reverse causation may explain the mainly inverse associations, some etiologic role for this lipid fraction cannot be ruled out.
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The authors thank, in Norway, the screening team at the former National Health Screening Service of Norway, now the Norwegian Institute of Public Health, the services of CONOR, and the contributing research centres delivering data to CONOR; in the Vorarlberg Health Monitoring and Prevention Programme, Elmar Stimpfl, the database manager, Karin Parschalk at the cancer registry; in the Västerbotten Intervention Project, Åsa Ågren, the project database manager at the Medical Biobank, Umeå University, Sweden; and in the Malmö Preventive Project, Anders Dahlin, the database manager.