Inflammatory biomarkers and risk of cancer in 84,000 individuals from the general population

Inflammation and cancer are tightly linked. This study tests the hypothesis that an inflammatory score based on plasma levels of C‐reactive protein (CRP) and fibrinogen and whole blood leukocyte count is associated with risk of colorectal, lung, breast and prostate cancer. A score ranging from none through three elevated biomarkers was constructed in 84,000 individuals from the Danish general population. During a median follow‐up time of 4.8 years, 4,081 incident cancers occurred. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) of incident cancer. Multifactor‐adjusted HRs for colorectal cancer were 1.28 (95% CI, 1.01 to 1.62), 1.79 (95% CI, 1.41 to 2.27) and 2.18 (95% CI, 1.67 to 2.86) for individuals with elevated levels of one, two and three inflammatory biomarkers compared to individuals with none elevated biomarkers. A similar stepwise increasing risk was observed for lung and breast cancer with HRs of 3.03 (95% CI, 2.25 to 4.08) and 1.42 (95% CI, 1.11 to 1.80) for three versus none elevated biomarkers. HRs were highest within the first years of follow‐up. Absolute 5‐year risk of lung cancer was 7.8 (95% CI, 6.1 to 10)% among older smokers with three elevated biomarkers compared to 3.8 (95% CI, 2.6 to 5.6)% among those with none elevated biomarkers. In conclusion, simultaneously elevated CRP, fibrinogen and leukocyte count are associated with an increased risk of colorectal, lung and breast cancer. Cancer as a promoter of inflammation may be more likely to account for our findings than low‐grade inflammation promoting cancer development.     

Circulating prediagnostic interleukin‐6 and C‐reactive protein and prostate cancer incidence and mortality

Interleukin‐6 (IL‐6) and C‐reactive protein (CRP) are elevated in prostate cancer patients, but the role of prediagnostic levels of these inflammatory mediators on prostate cancer outcomes is unclear. We undertook a large, prospective case‐control study to evaluate the relation between prediagnostic levels of IL‐6 and CRP and prostate cancer incidence and mortality. We also investigated the role of the IL‐6 (?174 G/C) polymorphism in relation to circulating levels of IL‐6 and CRP, as well as cancer risk and mortality. We used unconditional logistic regression that adjusted for matching factors to analyze prostate cancer risk. For analyses of prostate cancer mortality, we conducted survival analyses in cases. Because of the strong link between inflammatory markers and body mass index (BMI), we assessed interactions between BMI and plasma levels on prostate cancer outcomes. Neither IL‐6 nor CRP plasma levels varied significantly by IL‐6 genotype. Genotype was not associated with prostate cancer risk or survival. Though neither IL‐6 nor CRP was associated with prostate cancer incidence overall, we observed a statistically significant interaction between IL‐6 and BMI on prostate cancer incidence (p_interaction < 0.01). Increasing IL‐6 levels were positively associated with risk in healthy weight men, but inversely associated with risk in overweight men. Further, prediagnostic IL‐6 was associated with time to prostate cancer progression/death among healthy weight prostate cancer cases (p_trend = 0.02). Adjusted hazard ratios were 1.73 (95% CI: 0.86, 3.51) comparing the highest to lowest IL‐6 level. Our study suggests that IL‐6 may potentially be involved in the development or progression of prostate cancer. © 2008 Wiley‐Liss, Inc.     

C-reactive protein as a prognostic marker for men with androgen-independent prostate cancer: results from the ASCENT trial

BACKGROUND.

Studies of cancer risk and molecular carcinogenesis suggest a role for inflammation in cancer development and progression. The authors sought to determine whether specific blood proteins associated with inflammation predict for outcomes in men with metastatic androgen‐independent prostate cancer (AIPC) who are initiating docetaxel‐based chemotherapy.

METHODS.

Baseline plasma samples were stored (?80°C) from 160 of 250 patients enrolled in the AIPC Study of Calcitriol ENhancing Taxotere (ASCENT) trial, a randomized, placebo‐controlled trial comparing weekly docetaxel plus high‐dose calcitriol with weekly docetaxel. Multiplex immunoassays measured 16 cytokine, chemokine, cardiovascular, or inflammatory markers. The Cox proportional hazards model was used to assess associations between baseline biomarkers, clinical characteristics, and survival. Logistic regression was used for analyses of associations with prostate‐specific antigen (PSA) decline.

RESULTS.

C‐reactive protein (CRP) was found to be significantly predictive of a shorter overall survival (hazards ratio [HR] of 1.41 for each natural logarithm [ln] [CRP] increase; 95% confidence interval [95% CI], 1.20–1.65 [P < .0001]). When CRP (continuous) was entered into a multivariate model using 13 baseline clinical variables, only elevated CRP remained a significant predictor (P < .0001) of shorter overall survival. When categorized as normal (≤8 mg/L) or abnormal (>8 mg/L), elevated CRP was found to be a significant predictor of shorter overall survival (HR of 2.96; 95% CI, 1.52–5.77 [P = .001]), as was hemoglobin (P = .007). Elevated CRP was also associated with a lower probability of PSA decline (odds ratio of 0.74 for each ln(CRP) increase; 95% CI, 0.60–0.92 [P = .007]).

CONCLUSIONS.

Elevated plasma CRP concentrations appear to be a strong predictor of poor survival and lower probability of PSA response to treatment in patients with AIPC who are receiving docetaxel‐based therapy. Cancer 2008. © 2008 American Cancer Society.     

Risk of prostate cancer is not associated with levels of C-reactive protein and other commonly used markers of inflammation

Most population-based studies studied the association between inflammation and prostate cancer (PCa) by assessing C-reactive protein (CRP). As these findings have shown inconsistent results, we aimed to also study different markers that have been commonly taken as indications of inflammation. A cohort based on four groups of men (n = 34,891), according to age at cohort entry (45, 55, 65 and 75 years), with measurements of glucose, triglycerides, total cholesterol, haptoglobin, albumin, hemoglobin and leukocytes were selected from the Apolipoprotein Mortality Risk database. A total of 17,937 men had measurements of non-high-sensitive CRP. Multivariate Cox proportional hazard models were used to analyze associations between inflammatory markers and PCa. A total of 49 of 12,063 men developed PCa in the age 45 group, whereas 207 of 9,940, 472 of 8,266 and 276 of 3,618 were diagnosed in the age 55, 65 and 75 groups, respectively. Mean follow-up time was 7.5 years (SD: 3.9). No markers showed an association with PCa risk, nor was there a trend by quartiles or an indication for different PCa risks by strata of hypercholesterolemia, hyperglycemia and hypertriglyceridemia status. The studied markers were not found to be associated with PCa risk. These null findings might be due to methodological issues; however, it is unlikely that strong and long-lasting associations between inflammation and PCa risk were missed as this was a large database with long follow-up. This indicates need for international consensus on appropriate inflammatory markers in the context of cancer that may be practically applied in large studies.     

Prediagnostic plasma IGFBP‐1, IGF‐1 and risk of prostate cancer

Insulin‐like growth factor (IGF)?1 is associated with a higher risk of prostate cancer. IGF‐binding protein (IGFBP)?1, a marker for insulin activity, also binds IGF‐1 and inhibits its action. Data on IGFBP‐1 and prostate cancer risk are sparse and whether the IGF and insulin axes interact to affect prostate cancer carcinogenesis is unknown. We evaluated the independent and joint influence of prediagnostic plasma levels of IGFBP‐1 (fasting) and IGF‐1 on risk of prostate cancer among 957 cases and 1,021 controls with fasting levels of IGFBP‐1 and 1,709 cases and 1,778 controls with IGF‐1 nested within the Health Professionals Follow‐up Study. Unconditional logistic regression adjusting for matching factors was used to estimate the odds ratio (OR) and 95% confidence interval (CI). Higher prediagnostic fasting IGFBP‐1 levels were associated with lower risk of prostate cancer (highest vs. lowest quartile OR = 0.67, 95% CI 0.52–0.86, p_trend = 0.003), which remained similar after adjusting for IGF‐1. Prediagnostic IGF‐1 was associated with increased risk of prostate cancer (highest vs. lowest quartile OR = 1.28, 95% CI = 1.05–1.56, p_trend = 0.01). The associations with each marker were primarily driven by lower‐grade and non‐advanced prostate cancer. Being low in IGFBP‐1 and high in IGF‐1 did not confer appreciable additional risk (p_interaction = 0.42). In summary, prediagnostic fasting IGFBP‐1 may influence prostate cancer carcinogenesis. Being low in IGFBP‐1 or high in IGF‐1 is sufficient to elevate the risk of prostate cancer.     

Joint effects of inflammation and androgen metabolism on prostate cancer severity

Multiple pathways of prostate carcinogenesis have been proposed, including those involving androgen metabolism and inflammation. These pathways are not independent, and may act together in prostate cancer etiology: androgens promote both inflammatory processes and serve as mitogens in prostate tumor growth. To explore the possible joint effects of these pathways in prostate cancer severity, we studied 1,090 Caucasian prostate cancer cases to evaluate whether tumor severity is influenced by a history of benign prostatic hyperplasia (BPH) interacting with genotypes involved in inflammation or androgen metabolism including MSR1, RNASEL, AR, CYP3A4, CYP3A43, CYP3A5 and SRD5A2. We observed a statistically significant interaction between a number of genotypes and BPH. After considering the potential for false positive associations, the only remaining significant associations involved CYP3A43 P340A genotypes and history of BPH on both Gleason grade (interaction p-value = 0.026) and tumor stage (interaction p-value = 0.017). These results suggest that androgen metabolism may act in concert with inflammatory phenotypes such as BPH in determining prostate cancer severity.     

Biomarkers of inflammation are associated with colorectal cancer risk in women but are not suitable as early detection markers

Initial studies have investigated the association between inflammation and colorectal cancer (CRC) using C‐reactive protein (CRP) as a proinflammatory biomarker and have noted inconsistent results among women. We here report the findings from a large prospective study with repeat measurements of CRP, as well as serum amyloid A (SAA), an additional biomarker of inflammation, and risk of CRC. In the Women's Health Initiative Observational Study, we examined associations of CRP and SAA with CRC using repeat assessments (baseline and 3‐year follow‐up) among 953 matched case–control pairs for CRP and 966 pairs for SAA. Multivariate‐adjusted conditional‐logistic regression models were used with two‐sided tests of significance. Receiver operating characteristic (ROC) curve analysis assessed their utility as early detection markers. Colon cancer risk (odds ratio [OR] and 95% confidence intervals) among women in the highest quintiles of CRP or SAA compared to those in the lowest quintiles was OR_colon/CRP = 1.37 (0.95–1.97, p‐trend = 0.04) and OR_colon/SAA = 1.26 (0.88–1.80, p‐trend = 0.10), respectively. Women with elevated concentrations of both CRP and SAA had an increased risk of OR_colon = 1.50 (1.12–2.00, p‐value = 0.006) compared to those with low concentrations. No positive associations were observed with rectal cancer and weaker associations for CRC overall. Temporal changes in biomarkers more than 3 years did not predict risk. The area under the 6‐month ROC curve for CRP+SAA was 0.62 (95% confidence interval = 0.55–0.68). Elevated inflammatory biomarkers are associated with an increased risk of CRC, mainly colon cancer. Nevertheless, changes in the biomarkers over time do not suggest that they merit consideration as early detection markers for CRC.     

Alcohol consumption,finasteride, and prostate cancer risk

BACKGROUND:

Current research is inconclusive regarding the relation between alcohol consumption and prostate cancer risk. In this study, the authors examined the associations of total alcohol, type of alcoholic beverage, and drinking pattern with the risk of total, low‐grade, and high‐grade prostate cancer.

METHODS:

Data for this study came from the 2129 participants in the Prostate Cancer Prevention Trial (PCPT) who had cancer detected during the 7‐year trial and 8791 men who were determined by biopsy to be free of cancer at the trial end. Poisson regression was used to calculate relative risks (RRs) and 95% confidence intervals (95% CIs) for associations of alcohol intake with prostate cancer risk.

RESULTS:

Associations of drinking with high‐grade disease did not differ by treatment arm. In combined arms, heavy alcohol consumption (≥50 g of alcohol daily) and regular heavy drinking (≥4 drinks daily on ≥5 days per week) were associated with increased risks of high‐grade prostate cancer (RR, 2.01 [95% CI, 1.33‐3.05] and 2.17 [95% CI, 1.42‐3.30], respectively); less heavy drinking was not associated with risk. Associations of drinking with low‐grade cancer differed by treatment arm. In the placebo arm, there was no association of drinking with risk of low‐grade cancer. In the finasteride arm, drinking ≥50 g of alcohol daily was associated with an increased risk of low‐grade disease (RR, 1.89; 95% CI, 1.39‐2.56); this finding was because of a 43% reduction in the risk of low‐grade cancer attributable to finasteride treatment in men who drank <50g of alcohol daily and the lack of an effect of finasteride in men who drank ≥50 g of alcohol daily (P_interaction = .03).

CONCLUSIONS:

Heavy, daily drinking increased the risk of high‐grade prostate cancer. Heavy drinking made finasteride ineffective for reducing prostate cancer risk. Cancer 2009. © 2009 American Cancer Society.     

C-reactive protein and colorectal cancer risk: a systematic review of prospective studies

C-reactive protein is a sensitive but nonspecific systemic marker of inflammation. Several prospective studies have investigated the association of prediagnostic circulating C-reactive protein concentrations with the development of colorectal cancer, but the results have been inconsistent. We performed a systematic review of prospective studies of the association between prediagnostic measurements of circulating high-sensitivity C-reactive protein and development of invasive colorectal cancer. Authors of original studies were contacted to acquire uniform data. We combined relative risks (RR) for colorectal cancer associated with a one unit change in natural logarithm-transformed high-sensitivity C-reactive protein using inverse variance weighted random effects models. We identified eight eligible studies, which included 1,159 colorectal cancer cases and 37,986 controls. The summary RR per one unit change in natural log-transformed high-sensitivity C-reactive protein was 1.12 (95% confidence intervals [CI], 1.01-1.25) for colorectal cancer, 1.13 (95% CI, 1.00-1.27) for colon cancer, and 1.06 (95% CI, 0.86-1.30) for rectal cancer. The association was stronger in men (RR, 1.18; 95% CI, 1.04-1.34) compared to women (RR, 1.09; 95% CI, 0.93-1.27) but this difference was sensitive to the findings from a single study. Prediagnostic high-sensitivity C-reactive protein concentrations were weakly associated with an increased risk for colorectal cancer. More work is needed to understand the extent to which circulating high-sensitivity C-reactive protein or other blood inflammatory markers are related to colonic inflammation.     

Prediagnostic circulating follicle stimulating hormone concentrations and ovarian cancer risk

Gonadotropins have been indicted in ovarian carcinogenesis but direct evidence has been limited and inconsistent. The aim of this study was to determine the association between prediagnostic levels of follicle stimulating hormone (FSH) and subsequent development of invasive epithelial ovarian cancer. A nested case‐control study was conducted using cases and controls drawn from three cohorts: CLUE I and CLUE II of Washington County, MD, and the Island of Guernsey Study, United Kingdom. In total, 67 incident invasive epithelial ovarian cancer cases were each matched to 1 to 2 controls on age, menopausal status, time since last menstrual period, current hormone use and other relevant factors. FSH concentrations were classified into ranked thirds of low, medium or high based on the distribution among controls. Conditional logistic regression was used to estimate the odds ratio (OR) across increasing thirds of FSH concentrations. Results of the analysis showed that ovarian cancer risk decreased with higher FSH concentrations (p‐trend = 0.005). Compared with the lowest third of FSH concentrations, the OR among those in the middle and highest thirds were 0.45 [95% Confidence Interval (CI): 0.20–1.00] and 0.26 (95% CI: 0.10–0.70), respectively. Associations persisted after excluding cases diagnosed within 5 years of follow‐up. In conclusion, a reduction in subsequent risk of invasive epithelial ovarian cancer was observed among women with higher circulating FSH concentrations. These findings contradict the hypothesized role of FSH as a risk factor in ovarian carcinogenesis. © 2009 UICC     

Fibre intake and prostate cancer risk

Dietary fibre has been reported to protect from several neoplasms, but the issue remains controversial. No previous study considered in depth the topic of fibres and prostate cancer. A multicentre case-control study was conducted in Italy from 1991 to 2002, including 1,294 men with incident, histologically confirmed prostate cancer and 1,451 controls admitted to the same network of hospitals as cases with acute nonmalignant conditions. Multivariate odds ratios (OR) and 95% confidence intervals (CI) were obtained after allowance for major identified confounding factors, including total energy intake. Compared to the lowest quintile, the OR of prostate cancer for the highest quintile of total fibre intake was 0.93 (95% CI 0.71-1.22). The risk was inversely related with soluble fibre (OR = 0.89, 95% CI 0.78-1.02, for a difference between 80th and 20th percentile), cellulose (OR = 0.88, 95% CI 0.78-1.01) and vegetable fibre (OR = 0.82, 95% CI 0.73-0.93). These relationships were consistent across strata of age, family history of prostate cancer, body mass index and education. Vegetable fibres appear, therefore, to have a favourable association with prostate cancer risk.     

Lifetime physical activity and prostate cancer risk

The purpose of our study was to investigate the relation in between physical activity in different periods of life at work and in leisure-time and prostate cancer risk. We conducted a case-control study on prostate cancer in Italy between 1991 and 2002, which included 1,294 incident cases of histologically confirmed prostate cancer below 75 years of age and 1,451 controls, who were admitted to hospital for acute nonneoplastic conditions. Odds ratios (OR) of prostate cancer according to physical activity in different periods of life were obtained by unconditional multiple logistic regression models, including terms for age, study centre, education, social class, body mass index, energy intake, family history and other selected covariates. Compared to the lowest level of occupational physical activity, the multivariate ORs for prostate cancer for the highest level were 0.94 (95% confidence interval, CI, 0.75-1.17) at age 15-19, 0.78 (95% CI, 0.63-0.97) at age 30-39 and 0.75 (95% CI, 0.61-0.93) at age 50-59. A significant inverse trend in risk was found for activity at work at ages 30-39 and 50-59. The inverse associations were consistent in strata of age at diagnosis, body mass index, education and social class. No significant association was found for leisure-time physical activity. The inverse association between occupational physical activity and prostate cancer risk may reflect favorable hormonal correlates of physical activity, but residual confounding by socioeconomic covariates cannot be excluded.     

Relative risk of prostate cancer for men with affected relatives: systematic review and meta-analysis

An increased risk of prostate cancer associated with a family history of prostate cancer has been documented in multiple published reports. Risk has been shown to vary by degree of relationship and age of onset of disease in the affected relative. Several studies, using various designs, have estimated the relative risk (RR) for these associations. The purpose of our study was to identify and summarize published reports on the relationship between risk of prostate cancer and family history, which is defined as having a father, brother, any first- or second-degree relative or other relative affected with prostate cancer. A Medline and manual search from 1982 to 2000 identified 24 studies that reported RR and confidence intervals (CI) and satisfied inclusion criteria. Pooled RR estimates based upon a weighted average model were as follows: any affected family member RR = 1.93, CI 1.65-2.26; affected first-degree relative RR = 2.22, CI 2.06-2.40; affected second-degree relative RR = 1.88, CI 1.54-2.30; father with prostate cancer RR = 2.12, CI 1.82-2.51; and brother with prostate cancer RR = 2.87, CI 2.21-3.73). Statistical comparison of pooled data demonstrated that the RR is significantly higher for affected brother than for affected father (p < 0.03). A sensitivity analysis demonstrated that these results are robust with respect to population bias. This meta-analysis confirms that risk of prostate cancer is associated with family history of disease and improves the quantification of this risk.     

Chromosome 8q24 markers: risk of early-onset and familial prostate cancer

Recent admixture mapping and linkage/association studies have implicated an approximately 1 Mb region on chromosome 8q24 in prostate cancer susceptibility. In a subsequent follow-up investigation, Haiman et al. (Nat Genet 2007;39:638-44) observed significant, independent associations between 7 markers within this region and sporadic prostate cancer risk in a multi-ethnic sample. To clarify the risk associated with hereditary prostate cancer, we tested for prostate cancer association with 6 of these 7 markers in a sample of 1,015 non-Hispanic white men with and without prostate cancer from 403 familial and early-onset prostate cancer families. Single nucleotide polymorphisms (SNPs) rs6983561 and rs6983267 showed the strongest evidence of prostate cancer association. Using a family-based association test, the minor ("C") allele of rs6983561 and the major ("G") allele of rs6983267 were preferentially transmitted to affected men (p < 0.05), with estimated odds ratios (ORs) of 2.26 (95% confidence interval of 1.06-4.83) and 1.30 (95% confidence interval of 0.99-1.71), respectively, for an additive model. Notably, rs6983561 was significantly associated with prostate cancer among men diagnosed at an early (<50 years) but not later age (p = 0.03 versus p = 0.21). Similarly, the association with rs6983267 was (not) statistically significant among men with(out) clinically aggressive disease (p = 0.007 versus p = 0.34). Our results confirm the association of prostate cancer with several of the SNPs on chromosome 8q24 initially reported by Haiman et al. In addition, our results suggest that the increased risk associated with these SNPs is approximately doubled in individuals predisposed to develop early onset or clinically aggressive disease.     

前列腺癌干细胞相关肿瘤标志物的研究进展

前列腺癌(prostate cancer,PCa)是男性常见的恶性肿瘤。内分泌治疗是晚期前列腺癌的主要治疗方法,但该方法易使其发展成为激素难治性前列腺癌,且暂无切实有效的治疗方法。近年来的研究发现,前列腺癌干细胞在前列腺癌的发生、发展和转移中起着关键作用,因此前列腺癌干细胞的靶向治疗可能是根治前列腺癌的有效途径。靶向前列腺癌干细胞治疗需首先明确前列腺癌干细胞标志物,尤其是其特异标志物,才能更好地开展前列腺癌根治方案的研究。目前前列腺癌干细胞标志物的研究主要集中于CD44和CD133,但随着研究的不断深入其开始受到质疑,且发现了更多新的标志物,本文主要对前列腺癌干细胞领域研究较广和较新发现的肿瘤标志物进行综述。      

Associations of circulating 25-hydroxyvitamin D with prostate cancer diagnosis, stage and grade

Epidemiological studies suggest that vitamin D protects against prostate cancer, although evidence is limited and inconsistent. We investigated associations of circulating total 25-hydroxyvitamin D (25(OH)D) with prostate specific antigen-detected prostate cancer in a case-control study nested within the prostate testing for cancer and treatment (ProtecT) trial. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) quantifying the association between circulating total 25(OH)D and prostate cancer. In case-only analyses, we used unconditional logistic regression to quantify associations of total 25(OH)D with stage (advanced vs. localized) and Gleason grade (high-grade (≥7) vs. low-grade (<7)). Predetermined categories of total 25(OH)D were defined as: high: ≥30 ng/mL; adequate: 20-<30 ng/mL; insufficient: 12-<20 ng/mL; deficient: <12 ng/mL. Fractional polynomials were used to investigate the existence of any U-shaped relationship. We included 1,447 prostate cancer cases (153 advanced, 469 high-grade) and 1,449 healthy controls. There was evidence that men deficient in vitamin D had a 2-fold increased risk of advanced versus localized cancer (OR for deficient vs. adequate total 25(OH)D=2.33, 95% CI: 1.26, 4.28) and high-grade versus low-grade cancer (OR for deficient vs. adequate total 25(OH)D=1.78, 95% CI: 1.15, 2.77). There was no evidence of a linear association between total 25(OH)D and prostate cancer (p=0.44) or of an increased risk of prostate cancer with high and low vitamin D levels. Our study provides evidence that lower 25(OH)D concentrations were associated with more aggressive cancers (advanced versus localized cancers and high- versus low-Gleason grade), but there was no evidence of an association with overall prostate cancer risk.