We investigated the associations of estimated free and total circulating testosterone and sex hormone‐binding globulin (SHBG) with cancer risk in men and postmenopausal women, using a pan‐cancer ...approach, including 19 cancers in UK Biobank. Risk was estimated using multivariable‐adjusted Cox regression in up to 182 608 men and 122 112 postmenopausal women who were cancer‐free at baseline. Participants diagnosed with cancer within 2 years of baseline were excluded. Hazard ratios (HRs) and confidence intervals (CIs) were corrected for regression dilution bias using repeat measurements. We accounted for multiple testing using the false discovery rate. In men, higher free testosterone was associated with higher risks of melanoma and prostate cancer (HR per 50 pmol/L increase = 1.35, 95% CI 1.14‐1.61 and 1.10, 1.04‐1.18, respectively). Higher total testosterone was associated with an elevated risk of liver cancer (HR per 5 nmol/L = 2.45, 1.56‐3.84), and higher SHBG was associated with a higher risk of liver cancer (HR per 10 nmol/L = 1.56, 1.31‐1.87) and a lower risk of prostate cancer (0.93, 0.91‐0.96); the associations with liver cancer were partially attenuated after excluding men diagnosed within 4.7 years from baseline. In postmenopausal women, free and total testosterone and SHBG were associated with risks of endometrial (HR per 10 pmol/L = 1.59, 1.32‐1.90; HR per 0.5 nmol/L = 1.34, 1.18‐1.52 and HR per 25 nmol/L = 0.78, 0.67‐0.91, respectively) and breast cancer (1.32, 1.22‐1.43; 1.24, 1.17‐1.31 and 0.88, 0.83‐0.94, respectively). We report a novel association of free testosterone with malignant melanoma in men, and confirm known associations between testosterone and risks for prostate, breast and endometrial cancers. The association with liver cancer in men may be attributable to reverse causation.
What's new?
Significant differences exist in serum androgen regulation and quantity between men and postmenopausal women, implying key differences in risk of hormone‐associated cancers. Previous studies, however, have been limited in their ability to assess relationships between androgens and many site‐specific cancers. Here, analysis of circulating free and total testosterone and sex hormone‐binding globulin in a cohort of men and postmenopausal women reveals positive associations between free testosterone and risk of prostate cancer and melanoma in men and breast and endometrial cancer in postmenopausal women. Sex‐ and site‐specific associations with testosterone do not support a general role for testosterone in cancer risk.
Numerous epidemiological studies have investigated the role of blood lipids in prostate cancer (PCa) risk, though findings remain inconclusive to date. The ongoing research has mainly involved ...observational studies, which are often prone to confounding. This study aimed to identify the relationship between genetically predicted blood lipid concentrations and PCa.
Data for low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides (TG), apolipoprotein A (apoA) and B (apoB), lipoprotein A (Lp(a)), and PCa were acquired from genome-wide association studies in UK Biobank and the PRACTICAL consortium, respectively. We used a two-sample summary-level Mendelian randomisation (MR) approach with both univariable and multivariable (MVMR) models and utilised a variety of robust methods and sensitivity analyses to assess the possibility of MR assumptions violation. No association was observed between genetically predicted concentrations of HDL, TG, apoA and apoB, and PCa risk. Genetically predicted LDL concentration was positively associated with total PCa in the univariable analysis, but adjustment for HDL, TG, and Lp(a) led to a null association. Genetically predicted concentration of Lp(a) was associated with higher total PCa risk in the univariable (ORweighted median per standard deviation (SD) = 1.091; 95% CI 1.028 to 1.157; P = 0.004) and MVMR analyses after adjustment for the other lipid traits (ORIVW per SD = 1.068; 95% CI 1.005 to 1.134; P = 0.034). Genetically predicted Lp(a) was also associated with advanced (MVMR ORIVW per SD = 1.078; 95% CI 0.999 to 1.163; P = 0.055) and early age onset PCa (MVMR ORIVW per SD = 1.150; 95% CI 1.015,1.303; P = 0.028). Although multiple estimation methods were utilised to minimise the effect of pleiotropy, the presence of any unmeasured pleiotropy cannot be excluded and may limit our findings.
We observed that genetically predicted Lp(a) concentrations were associated with an increased PCa risk. Future studies are required to understand the underlying biological pathways of this finding, as it may inform PCa prevention through Lp(a)-lowering strategies.
Insulin‐like growth factor‐I (IGF‐I) and testosterone may be related to prostate cancer risk. Acromegaly is associated with clinically high IGF‐I concentrations. Klinefelter's syndrome, testicular ...hypofunction and hypopituitarism are associated with clinically low testosterone concentrations. We aimed to investigate whether diagnosis with these conditions was associated with subsequent prostate cancer diagnosis and mortality. We used linked English national Hospital Episode Statistics and mortality data from 1999 to 2017 to construct and follow‐up cohorts of men aged ≥35 years diagnosed with (i) acromegaly (n = 2,495) and (ii) hypogonadal‐associated diseases (n = 18,763): Klinefelter's syndrome (n = 1,992), testicular hypofunction (n = 8,086) and hypopituitarism (n = 10,331). We estimated adjusted hazard ratios (HRs) and confidence intervals (CIs) for prostate cancer diagnosis and death using Cox regression in comparison with an unexposed reference cohort of 4.3 million men, who were admitted to hospital for a range of minor surgeries and conditions (n observed cases = 130,000, n prostate cancer deaths = 30,000). For men diagnosed with acromegaly, HR for prostate cancer diagnosis was 1.33 (95% CI 1.09–1.63; p = 0.005; n observed cases = 96), HR for prostate cancer death was 1.44 (95% CI 0.92–2.26; p = 0.11; n deaths = 19). Diagnosis with Klinefelter's syndrome was associated with a lower prostate cancer risk (HR = 0.58, 95% CI 0.37–0.91; p = 0.02; n observed cases = 19) and hypopituitarism was associated with a reduction in prostate cancer death (HR = 0.53, 95% CI 0.35–0.79; p = 0.002; n deaths = 23). These results support the hypothesised roles of IGF‐I and testosterone in prostate cancer development and/or progression. These findings are important because they provide insight into prostate cancer aetiology.
What's new?
Although the incidence rates of prostate cancer vary globally, little is known about modifiable risk factors. Previous studies have shown insulin‐like growth factor‐I (IGF‐I) and testosterone may be related to prostate cancer risk. Using national hospital admission data, the authors examined whether these associations are consistent across clinical extremes in comparison with a reference cohort. Men diagnosed with acromegaly (characterised by high IGF‐I) had an increased risk of incident prostate cancer, while men diagnosed with diseases characterised by low testosterone had a lower risk of prostate cancer mortality. The findings support the role of IGF‐I and testosterone in prostate cancer pathogenesis.
Epidemiologic studies examining the association between specific fatty acids and colorectal cancer (CRC) risk are inconclusive. We investigated the association between dietary estimates and plasma ...levels of individual and total saturated (SFA), monounsaturated (MUFA), industrial‐processed trans (iTFA), and ruminant‐sourced trans (rTFA) fatty acids, and CRC risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Baseline fatty acid intakes were estimated in 450 112 participants (6162 developed CRC, median follow‐up = 15 years). In a nested case‐control study, plasma phospholipid fatty acids were determined by gas chromatography in 433 colon cancer cases and 433 matched controls. Multivariable‐adjusted hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were computed using Cox and conditional logistic regression, respectively. Dietary total SFA (highest vs lowest quintile, HRQ5vsQ1 = 0.80; 95%CI:0.69‐0.92), myristic acid (HRQ5vsQ1 = 0.83, 95%CI:0.74‐0.93) and palmitic acid (HRQ5vsQ1 = 0.81, 95%CI:0.70‐0.93) were inversely associated with CRC risk. Plasma myristic acid was also inversely associated with colon cancer risk (highest vs lowest quartile, ORQ4vsQ1 = 0.51; 95%CI:0.32‐0.83), whereas a borderline positive association was found for plasma stearic acid (ORQ4vsQ1 = 1.63; 95%CI:1.00‐2.64). Dietary total MUFA was inversely associated with colon cancer (per 1‐SD increment, HR1‐SD = 0.92, 95%CI: 0.85‐0.98), but not rectal cancer (HR1‐SD = 1.04, 95%CI:0.95‐1.15, Pheterogeneity = 0.027). Dietary iTFA, and particularly elaidic acid, was positively associated with rectal cancer (HR1‐SD = 1.07, 95%CI:1.02‐1.13). Our results suggest that total and individual saturated fatty acids and fatty acids of industrial origin may be relevant to the aetiology of CRC. Both dietary and plasma myristic acid levels were inversely associated with colon cancer risk, which warrants further investigation.
What's new?
The role of specific fatty acids in cancer development is not fully understood. In this large, prospective European study of colorectal cancer (CRC) risk, the authors found that dietary myristic and palmitic acids from dairy were inversely associated with CRC risk, as were total saturated (SFA) and monounsaturated (MUFA) fatty acids. Dietary industrially‐processed trans fatty acids (iTFA) were positively associated with rectal cancer. These results suggest that total and individual saturated fatty acids may be relevant to the aetiology of CRC.
Timothy J Key and colleagues describe the evidence linking diet and nutrition to cancer risk, concluding that obesity and alcohol are the most important factors
Metabolomics may reveal novel insights into the etiology of prostate cancer, for which few risk factors are established. We investigated the association between patterns in baseline plasma metabolite ...profile and subsequent prostate cancer risk, using data from 3,057 matched case–control sets from the European Prospective Investigation into Cancer and Nutrition (EPIC). We measured 119 metabolite concentrations in plasma samples, collected on average 9.4 years before diagnosis, by mass spectrometry (AbsoluteIDQ p180 Kit, Biocrates Life Sciences AG). Metabolite patterns were identified using treelet transform, a statistical method for identification of groups of correlated metabolites. Associations of metabolite patterns with prostate cancer risk (OR1SD) were estimated by conditional logistic regression. Supplementary analyses were conducted for metabolite patterns derived using principal component analysis and for individual metabolites. Men with metabolite profiles characterized by higher concentrations of either phosphatidylcholines or hydroxysphingomyelins (OR1SD = 0.77, 95% confidence interval 0.66–0.89), acylcarnitines C18:1 and C18:2, glutamate, ornithine and taurine (OR1SD = 0.72, 0.57–0.90), or lysophosphatidylcholines (OR1SD = 0.81, 0.69–0.95) had lower risk of advanced stage prostate cancer at diagnosis, with no evidence of heterogeneity by follow‐up time. Similar associations were observed for the two former patterns with aggressive disease risk (the more aggressive subset of advanced stage), while the latter pattern was inversely related to risk of prostate cancer death (OR1SD = 0.77, 0.61–0.96). No associations were observed for prostate cancer overall or less aggressive tumor subtypes. In conclusion, metabolite patterns may be related to lower risk of more aggressive prostate tumors and prostate cancer death, and might be relevant to etiology of advanced stage prostate cancer.
What's new?
This prospective study is the largest investigation of metabolite profile and prostate cancer risk, to date. We found that patterns in plasma metabolite profile (characterized by higher concentrations of phosphatidylcholines and hydroxysphingomyelins; specific acylcarnitines, amino acids and a biogenic amine; and lysophosphatidylcholines, respectively) were associated with subsequent lower risk of more aggressive tumor subtypes and prostate cancer death. Moreover, the results suggest that metabolite profile may be relevant to the etiology of advanced stage disease.
Bile acids (BAs) play different roles in cancer development. Some are carcinogenic and BA signaling is also involved in various metabolic, inflammatory and immune-related processes. The liver is the ...primary site of BA synthesis. Liver dysfunction and microbiome compositional changes, such as during hepatocellular carcinoma (HCC) development, may modulate BA metabolism increasing concentration of carcinogenic BAs. Observations from prospective cohorts are sparse. We conducted a study (233 HCC case-control pairs) nested within a large observational prospective cohort with blood samples taken at recruitment when healthy with follow-up over time for later cancer development. A targeted metabolomics method was used to quantify 17 BAs (primary/secondary/tertiary; conjugated/unconjugated) in prediagnostic plasma. Odd ratios (OR) for HCC risk associations were calculated by multivariable conditional logistic regression models. Positive HCC risk associations were observed for the molar sum of all BAs (OR
= 2.30, 95% confidence intervals CI: 1.76-3.00), and choline- and taurine-conjugated BAs. Relative concentrations of BAs showed positive HCC risk associations for glycoholic acid and most taurine-conjugated BAs. We observe an association between increased HCC risk and higher levels of major circulating BAs, from several years prior to tumor diagnosis and after multivariable adjustment for confounders and liver functionality. Increase in BA concentration is accompanied by a shift in BA profile toward higher proportions of taurine-conjugated BAs, indicating early alterations of BA metabolism with HCC development. Future studies are needed to assess BA profiles for improved stratification of patients at high HCC risk and to determine whether supplementation with certain BAs may ameliorate liver dysfunction.
To examine the association between the Mediterranean lifestyle and all-cause, cancer, and cardiovascular disease (CVD) mortality in a British population.
We studied 110,799 individuals 40 to 75 years ...of age from the UK Biobank cohort, free of CVD or cancer between 2009 and 2012 who were followed-up to 2021. The Mediterranean lifestyle was assessed at baseline through the Mediterranean Lifestyle (MEDLIFE) index, derived from the lifestyle questionnaire and diet assessments and comprising three blocks: (1) "Mediterranean food consumption," (2) "Mediterranean dietary habits," and (3) "physical activity, rest, social habits, and conviviality." Death information was retrieved from death register records. Cox regression models were used to analyze the study associations.
During a median 9.4-year follow-up, 4247 total deaths, 2401 cancer deaths, and 731 CVD deaths were identified. Compared with the first quartile of the MEDLIFE index, increasing quartiles had HRs of 0.89 (95% CI, 0.81 to 0.97), 0.81 (95% CI, 0.74 to 0.89), and 0.71 (95% CI, 0.65 to 0.78) (P-trend<.001 for all-cause mortality). For cancer mortality, the quartiles had HRs of 0.90 (95% CI, 0.80 to 1.01), 0.83 (95% CI, 0.74 to 0.93), and 0.72 (95% CI, 0.64 to 0.82) (P-trend<.001). All MEDLIFE index blocks were independently associated with lower risk of all-cause and cancer death, and block 3 was associated with lower CVD mortality.
Higher adherence to the Mediterranean lifestyle was associated with lower all-cause and cancer mortality in British middle-aged and older adults in a dose-response manner. Adopting a Mediterranean lifestyle adapted to the local characteristics of non-Mediterranean populations may be possible and part of a healthy lifestyle.
Obesity is a risk factor for several major cancers. Associations of weight change in middle adulthood with cancer risk, however, are less clear. We examined the association of change in weight and ...body mass index (BMI) category during middle adulthood with 42 cancers, using multivariable Cox proportional hazards models in the European Prospective Investigation into Cancer and Nutrition cohort. Of 241 323 participants (31% men), 20% lost and 32% gained weight (>0.4 to 5.0 kg/year) during 6.9 years (average). During 8.0 years of follow‐up after the second weight assessment, 20 960 incident cancers were ascertained. Independent of baseline BMI, weight gain (per one kg/year increment) was positively associated with cancer of the corpus uteri (hazard ratio HR = 1.14; 95% confidence interval: 1.05‐1.23). Compared to stable weight (±0.4 kg/year), weight gain (>0.4 to 5.0 kg/year) was positively associated with cancers of the gallbladder and bile ducts (HR = 1.41; 1.01‐1.96), postmenopausal breast (HR = 1.08; 1.00‐1.16) and thyroid (HR = 1.40; 1.04‐1.90). Compared to maintaining normal weight, maintaining overweight or obese BMI (World Health Organisation categories) was positively associated with most obesity‐related cancers. Compared to maintaining the baseline BMI category, weight gain to a higher BMI category was positively associated with cancers of the postmenopausal breast (HR = 1.19; 1.06‐1.33), ovary (HR = 1.40; 1.04‐1.91), corpus uteri (HR = 1.42; 1.06‐1.91), kidney (HR = 1.80; 1.20‐2.68) and pancreas in men (HR = 1.81; 1.11‐2.95). Losing weight to a lower BMI category, however, was inversely associated with cancers of the corpus uteri (HR = 0.40; 0.23‐0.69) and colon (HR = 0.69; 0.52‐0.92). Our findings support avoiding weight gain and encouraging weight loss in middle adulthood.
What's new?
Obesity is well known as a risk factor for multiple cancers. What about gaining or losing weight mid‐life? Here, the authors investigated the association between cancer and change in weight and BMI category during mid‐life. Among 241,323 people, about a third gained weight and 20% lost weight during the study. Independent of starting weight, gaining weight was associated with several obesity‐related cancers including cancers of the gallbladder, uterus, ovary, kidney, thyroid, breast after the menopause and in men pancreas. Losing weight was inversely associated with obesity‐related cancers overall, and specifically colon and uterine cancer. The authors conclude that public health interventions to support weight loss in middle age could help reduce cancer incidence.
Insulin‐like growth factor‐I (IGF‐I) and testosterone have been implicated in prostate cancer aetiology. Using data from a large prospective full‐cohort with standardised assays and repeat blood ...measurements, and genetic data from an international consortium, we investigated the associations of circulating IGF‐I, sex hormone‐binding globulin (SHBG), and total and calculated free testosterone concentrations with prostate cancer incidence and mortality. For prospective analyses, risk was estimated using multivariable‐adjusted Cox regression in 199 698 male UK Biobank participants. Hazard ratios (HRs) were corrected for regression dilution bias using repeat hormone measurements from a subsample. Two‐sample Mendelian randomisation (MR) analysis of IGF‐I and risk used genetic instruments identified from UK Biobank men and genetic outcome data from the PRACTICAL consortium (79 148 cases and 61 106 controls). We used cis‐ and all (cis and trans) SNP MR approaches. A total of 5402 men were diagnosed with and 295 died from prostate cancer (mean follow‐up 6.9 years). Higher circulating IGF‐I was associated with elevated prostate cancer diagnosis (HR per 5 nmol/L increment = 1.09, 95% CI 1.05‐1.12) and mortality (HR per 5 nmol/L increment = 1.15, 1.02‐1.29). MR analyses also supported the role of IGF‐I in prostate cancer diagnosis (cis‐MR odds ratio per 5 nmol/L increment = 1.34, 1.07‐1.68). In observational analyses, higher free testosterone was associated with a higher risk of prostate cancer (HR per 50 pmol/L increment = 1.10, 1.05‐1.15). Higher SHBG was associated with a lower risk (HR per 10 nmol/L increment = 0.95, 0.94‐0.97), neither was associated with prostate cancer mortality. Total testosterone was not associated with prostate cancer. These findings implicate IGF‐I and free testosterone in prostate cancer development and/or progression.
What's new?
Testosterone, insulin‐like growth factor‐I (IGF‐I), and sex hormone‐binding globulin (SHBG) all have been associated with prostate‐cancer risk. In this large, prospective study, the authors analyzed how these circulating hormones might impact mortality as well as risk. They found that men with higher IGF‐I had a higher risk of both prostate‐cancer diagnosis and mortality. Men with higher free testosterone had an increased risk of prostate cancer, while men with higher SHBG had a decreased risk. These results support the roles of IGF‐I and testosterone in prostate cancer development.
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