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 
has received considerable attention as an explanation for some of the observed inverse associations. That is, the inverse relation between low TSC levels and cancer risk might be caused by cancers in preclinical stages, as malignant neoplasm are known to have protean physiological effect, which might include metabolic depression of blood cholesterol 
. Additional evidence for reverse causation comes from Trompet et al’s Mendelian randomization study 
and a review on clinical trials investigating the relationship of low cholesterol and disease activity 
. Furthermore, it has been suggested that inverse cancer-cholesterol relationships could be explained by competing risks, i.e that patients showing high TSC levels are more likely to be censored due to cardiovascular mortality before they were diagnosed with cancer 
Concerning site-specific cancers, reports on associations with colon cancer are controversial. Positive as well as negative associations have been observed 
. Our results indicate only a modest positive association among men and absence of a relation among women.
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 
. There seems to be a general consensus that, when hepatic inadequacy occurs because of liver cancer and chronic liver disease, form, esterification and evacuation of cholesterol are blocked, which causes changes in cholesterol levels 
For gallbladder/biliary tract cancer Andreotti et al 
reported a U-shaped association, with low levels as well as high levels of cholesterol being linked with excess risks of biliary tract cancers. This was not confirmed in our data; our results showed no significant association in males and a clear inverse association in females.
The amount of literature on pancreatic cancer and its associations with cholesterol is limited. Two conducted studies found no significant associations 
. Our results differed between males and females with inverse associations in males and non-significant associations in females 
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 
. This interpretation is in line with our data, where associations of blood cancer with TSC disappeared in the lag-time analysis.
Most investigations on breast cancer have not reported significant associations with TSC 
. However, our data showed a clear negative association (see also 
) that persisted even when the first 10 years of follow-up were excluded, indicating that reverse causation does not apply in this case. Further, Fagherazzi et al 
found a significantly decreased breast cancer risk among women using cholesterol-lowering drugs. Unfortunately, we do not have any data regarding statin prescription in the Me-Can project to confirm this finding. Associations of TSC with breast cancer were, however, similar in the pre-statin period before 1994 and in the total observation period. Associations of TSC with skin cancer where a debate is going on whether statin use affects skin cancer outcomes 
, were also similar in the two periods.
Recently several authors reported positive associations between TSC levels and aggressive prostate cancer 
, even when TSC was not associated with overall prostate cancer 
. Unfortunately, we did not have information regarding prostate cancer grading in our data, so we cannot contribute to this discussion.
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.