Our data reveal a previously undisclosed relationship between plasma PCT levels in apparently healthy individuals and the risk of future mortality. PCT presented gender-specific association patterns. In men, PCT was correlated with the incidence of total mortality and cancer mortality, independently of previously disclosed risk factors for cancer and CVD. Additionally, we found that higher PCT levels were related to increased incidence of colon cancer. However, the subsequent ROC analyses suggested that PCT probably has limited value as a clinical predictor of cancer morbidity and mortality in apparently healthy men. In women, PCT was associated with the risk of total mortality and CV mortality, but the associations lost statistical significance after taking possible confounders into account. In a comparative analysis adjusted for possible confounders and each other, PCT was associated with all-cause and cancer mortality and hsCRP with CV mortality in the entire study population and in men analyzed separately. Neither biomarker predicted mortality in women.
The value of PCT as a biomarker in certain types of cancer has previously been investigated. PCT has been shown to have both a diagnostic and a prognostic value in thyroid cancer, as it is mainly produced in the neuroendocrine C cells of the thyroid gland
. In patients with solid tumors who developed febrile neutropenia during chemotherapy, elevated PCT was associated with treatment failure, death and sepsis
. A recently published study demonstrated similar results in non-neutropenic cancer patients
All the studies performed so far on PCT and cancer included patients with already diagnosed disease. We are the first to report a link between higher plasma PCT levels in individuals with no previous history of cancer and increased risk of cancer mortality. The biological importance of PCT in vivo at low concentrations in healthy individuals has so far been unexplored. Chronic inflammation plays a pathogenic role in tumor initiation and progression
 and hsCRP has previously been shown to predict total cancer incidence and the incidence of certain types of cancer in healthy individuals
. It has been shown that all tissues, including the ubiquitously present adipose tissue, are able to produce PCT under the stimulation of inflammatory mediators and bacterial products
. However, the specific stimuli of PCT secretion in healthy individuals other than bacterial endotoxin are currently unknown. PCT presented distinct association patterns with cancer and CV disease compared to hsCRP, suggesting that plasma PCT might reflect specific ongoing subclinical inflammatory processes rather than being a global marker of systemic inflammation, such as hsCRP.
Approximately 15% of malignancies worldwide are believed to be related to chronic infections
 through mechanisms involving chronic local inflammation leading to DNA damage and mutagenesis
. In sepsis PCT plays a dual role as a diagnostic and prognostic biomarker and as a disease mediator, due to its pro-inflammatory and immunosuppressive properties
. In experimental models of sepsis, administration of antibodies against PCT markedly increased survival of hamsters and pigs
 and PCT has been proposed as a therapeutic target in sepsis patients
. Clinically relevant doses of PCT, similar to those achieved in sepsis, induced the secretion of the pro-inflammatory cytokines TNFα, IL-1β and IL-6 in whole human blood cells in vitro. In turn, TNFα is a strong stimulator of PCT production and IL-1β and IL-6 have been linked with elevated PCT levels, thus creating potential pro-inflammatory positive feedback loops
[15, 33, 34]. TNFα, IL-6 and IL-17 are important links between chronic inflammation and tumor development
. Of note, although a monocyte chemoattractant in itself, PCT suppresses chemokine-induced human monocyte migration
 and inhibits human neutrophil mobility in vitro. Hypothetically, the high-responders, who have increased PCT levels under homeostatic conditions, may produce higher and more sustained amounts of PCT under bacterial and inflammatory stimulation. Subsequently, PCT may amplify the pro-carcinogenic inflammatory response and impair the anti-tumor immune mechanisms, thus acting as a disease mediator in cancer.
Although inflammation is thought to play an important role in the pathogenesis of cancer, not all types of cancer manifest the same pattern of association with inflammatory markers and mediators. CRP was previously shown to predict the incidence of cancer of any type, lung and colorectal cancer, but not breast or prostate cancer
. Here, we demonstrate a significant independent association between PCT levels in healthy individuals and the incidence of colon cancer. This relationship was only valid in men, who generally have higher plasma PCT concentrations than women
. Among the different types of cancer, colorectal cancer has one of the strongest documented associations with inflammation
. Patients suffering from local chronic inflammatory conditions such as Crohn’s disease and ulcerative colitis run a markedly increased risk of developing colorectal cancer, depending on the duration and the extent of the disease
. The PCT stimulators TNFα and IL-1β are actively involved in the pathogenesis of colon cancer and have been proposed as therapeutic targets for anti-cancer therapy
The main limitations of our study are related to the relatively low numbers of subjects within each individual cancer subtype group, except for prostate and breast cancer. Based on a population of 3,322 individuals from the general population, our study was underpowered for detecting relationships between PCT and individual cancer subtypes. The lack of association between PCT and the other considered tumor subtypes does not rule out with certainty the hypothesis that such relationships might exist. Larger and more specifically powered studies are needed in order to detect whether particular cancer subtypes, potentially those related to infectious and inflammatory conditions, drive the demonstrated association between PCT and cancer mortality. PCT measurements in healthy men using the ProCa-S assay are robust, as most PCT values in this population lie above the reported functional sensitivity of the assay of 17 pg/mL. However, exact determinations of plasma PCT concentrations in healthy women are less reliable due to the generally lower PCT levels in this group. Subsequently, we cannot exclude with certainty that this limitation of the assay might have contributed to the observed lack of correlation between plasma PCT and mortality in women.