Fangfang Song

Background The classic cardiovascular disease (CVD) risk scores perform poorly in predicting CVD in cancer survivors. This study aimed to identify proteins associated with major CVDs risk and explore their roles in risk prediction for major CVDs in cancer survivors. Methods We included 4225 cancer survivors from the UK Biobank with available plasma proteomic data and no major CVDs at recruitment. Associations between proteins and risks of major CVDs (heart failure, atrial fibrillation, myocardial infarction, angina, peripheral vascular disease, and stroke) were estimated using Cox proportional hazards models, followed by enrichment analysis. Candidate protein biomarkers were further identified through random forest model, and classification performance was evaluated using area under the receiver operating characteristic curve (AUC), net reclassification index (NRI), and integrated discrimination improvement index (IDI). Results This study identified 182 proteins, the majority of which were positively associated with major CVDs risk in cancer survivors (HRs:1.11-1.93), especially NTproBNP, NPC2, TNFRSF12A, LMNB2, and EDA2R, mainly involved in biological processes of immune, inflammatory, and angiogenesis. Further, a panel of 23 proteins derived from a random forest model demonstrated moderate predictive performance for major, 5-year, and 10-year CVDs in the test set (AUCs: 0.646–0.665), outperforming several classic CVD risk scores. Incorporating the protein panel into CVD risk scores significantly improved discrimination (AUCs: 0.647–0.705) and 5-year risk reclassification (NRI: 0.245–0.327; IDI: 0.055–0.060). Conclusions Certain plasma proteins were associated with major CVD risk and may serve as promising biomarkers for risk prediction in cancer survivors, but these require further investigation.

Background: Individuals with metabolic dysfunction‐associated steatotic liver disease (MASLD) have a higher mortality risk, and physical activity is important to MASLD management. However, a comprehensive exploration of associations of volume and intensity of physical activity and rest‐activity rhythm (RAR) based on an accelerometer with all‐cause and cause‐specific mortality in MASLD individuals was scarce.Methods: We included 10,143 individuals with MASLD from the UK Biobank. Volume and intensity of physical activity [low‐intensity physical activity (LPA), moderate‐to‐vigorous‐intensity physical activity (MVPA) and sedentary time] and RAR (amplitude, mesor, pseudo‐F statistics and acrophase) were computed from accelerometer data. The Cox proportional hazards model was used to estimate the relationships of volume and intensity of physical activity and RAR with all‐cause, cardiovascular disease (CVD) and cancer mortality risk in individuals with MASLD and further in common subtypes of cardiometabolic abnormalities. The population attributable risk and relative importance of physical activity were estimated.Results: Higher LPA, MVPA and normal RAR (amplitude and mesor) were associated with decreased risk of all‐cause and CVD mortality among individuals with MASLD (HRs: 0.712–0.805), especially of all‐cause mortality in those with common subtypes of more than two metabolic abnormalities (overweight/obesity‐elevated blood pressure‐hyperlipidemia and all the four abnormalities). Furthermore, we found MVPA and amplitude represented relatively important contributors to all‐cause and CVD mortality risk in individuals with MASLD.Conclusions: In individuals with MASLD, a higher volume and intensity of physical activity, as well as normal RAR supported lower all‐cause and CVD mortality risk, which provided insights for management guidelines.

Background: There existed bidirectional associations of cardiovascular disease (CVD) and type 2 diabetes (T2D) with cancer, partly attributed to their shared risk factors. We aimed to explore the role of cardiovascular health (CVH) in bidirectional transitions between CVD, T2D, and cancer. Methods: Based on the UK Biobank, we used 2 subcohorts: a disease‐free cohort of 277 997 individuals without cancer, CVD, and T2D; and a disease survivor cohort consisting of 61 971 cases with cancer, CVD, and T2D at baseline. The CVH was assessed on the basis of Life's Essential 8 score. We conducted the multistate model and Cox proportional hazards model to explore the role of CVH in bidirectional transitions between CVD, T2D, and cancer in disease‐free and disease survivor cohorts, respectively. Results: High CVH was significantly associated with a lower transition risk from CVD to cancer (hazard ratio, 0.822 [95% CI, 0.693–0.975]). On the other hand, increased CVH was related to reduced risks of progression from cancer to CVD and T2D (both P for trend10% lower cancer risk in CVD and T2D cases, and a 16% and 42% reduction in the risk of incident CVD and T2D among cancer survivors, respectively. Conclusions: High CVH was related to a decreased risk of bidirectional transitions between CVD, T2D, and cancer. This highlighted the significance of maintaining high CVH throughout the life span for the primary prevention of CVD, T2D, and cancer.

Background: Few studies focused on the effects of sarcopenia on lung cancer in general population and optimizing nutritional intake may be a feasible way to manage sarcopenia. We sought to systematically investigate the associations of sarcopenia symptoms with lung cancer incidence and mortality in general population, and whether dietary patterns could modify these risks. Methods: A total of 361,763 participants (mean age: 56.2 years; and men: 46.7%) were included in this prospective UK Biobank study. Sarcopenia symptoms (low handgrip strength, low muscle mass and slow walking pace) were determined according to European Working Group of Sarcopenia in Older People 2 (EWGSOP2) criteria. Individuals without any of the three sarcopenia symptoms were classified as the normal control group. Based on baseline data from Food Frequency Questionnaires, primary dietary patterns were identified through principal component analysis. Cox proportional hazards models were used to examine associations between sarcopenia symptoms as well as dietary patterns and lung cancer. Then we explored the joint effects of sarcopenia symptoms and dietary patterns on lung cancer risk. Results: A total of 3,532 incident lung cancer cases and 2,073 deaths were documented during a median follow-up of 12 years. All the sarcopenia symptoms were associated with a higher risk of lung cancer incidence than normal control group, especially in people aged P_interactionQ4vsQ1: 0.71, 95% CI: 0.65-0.79) and mortality (HR_Q4vsQ1: 0.68, 95% CI: 0.60-0.77). The joint analysis demonstrated that the risk of lung cancer-related outcomes associated with low handgrip strength gradually reduced as the quartile of Wholegrain pattern scores increased (P_trend<0.05). Conclusions: Our study indicated that individuals with sarcopenia symptoms suffered a higher risk of lung cancer incidence and mortality even in younger age. A diet abundant in whole grains may help to improve sarcopenia symptoms and reduce adverse lung cancer-related outcomes associated with low handgrip strength.

Background: Fatty liver disease may be associated with increased risks of intrahepatic and extrahepatic cancers. Our objective was to investigate associations between new subcategories of steatotic liver disease (SLD) recently proposed by nomenclature consensus group and cancer risk. Methods: A total of 283 238 participants from the UK Biobank were included. Based on information on cardiometabolic factors, alcohol consumption and the specific aetiology of SLD, individuals were categorized into four groups: no SLD ( n = 170 885), metabolic dysfunction‐associated steatotic liver disease (MASLD, n = 74 510), MASLD with increased alcohol intake (MetALD, n = 23 320) and other SLD ( n = 6718). Outcomes were overall incident cancer ( n = 39 352) and 21 site‐specific cancers. The Cox proportional hazards model was used to estimate relationships between subcategories of SLD and cardiometabolic factors in MASLD with cancer risk. Population attributable risk (PAR) of cancer associated with SLD was estimated. Results: MASLD was the most prevalent SLD in the general population. All SLD subcategories were associated with elevated risks of overall cancer, digestive system cancers (except gastric cancer) and breast cancer (HRs 1.079–4.663). Additionally, MASLD was associated with increased risks of renal cancer, endometrial cancer and Hodgkin lymphoma. Compared to MetALD and other SLDs, MASLD has a higher PAR% for the majority of aforementioned cancers. This could be largely explained by its common metabolic abnormalities, dominantly characterized by overweight/obesity and elevated blood pressure, concomitant with hyperglycaemia and hyperlipidaemia. Conclusions: All subcategories of SLD, particularly MASLD with multiple metabolic abnormalities, were associated with increased risks of multiple cancers, providing a new perspective for cancer prevention.

Gut microbiota and associated metabolites have been linked to breast carcinogenesis. Evidences demonstrate blood microbiota primarily originates from the gut and may act as a biomarker for breast cancer. We aimed to characterize the microbiota–gut microbial metabolites cross-talk in blood and develop a composite diagnostic panel for breast cancer. We performed 16S rRNA gene sequencing and metabolomics profiling on blood samples from 107 breast cancer cases and 107 age-paired controls. We found that the alpha diversity of the blood microbiota was decreased in breast cancer compared to controls. There were significantly different profiles of microbiota and gut microbial metabolites in blood between these two groups, with nine bacterial genera and four gut microbial metabolites increased in patients, while thirty-nine bacterial genera and two gut microbial metabolites increased in controls. Some breast cancer-associated gut microbial metabolites were linked to differential blood microbiota, and a composite microbiota–metabolite diagnostic panel was further developed with an area under the curve of 0.963 for breast cancer. This study underscored the pivotal role of microbiota and gut microbial metabolites in blood and their interactions for breast carcinogenesis, as well as the potential of a composite diagnostic panel as a non-invasive biomarker for breast cancer. IMPORTANCE: Our integrated analysis demonstrated altered profiles of microbiota and gut microbial metabolites in blood for breast cancer patients. The extensive correlation between microbiota and gut microbial metabolites in blood assisted the understanding of the pathogenesis of breast cancer. The good performance of a composite microbiota–gut microbial metabolites panel in blood suggested a non-invasive approach for breast cancer detection and a novel strategy for better diagnosis and prevention of breast cancer in the future.

Scope: The association between a planetary and sustainable EAT‐Lancet diet and lung cancer remains inconclusive, with limited exploration of the role of genetic susceptibility and inflammation.Methods and results: The study includes 175 214 cancer‐free participants in the UK Biobank. Fourteen food components are collected from a 24‐h dietary recall questionnaire. A polygenic risk score is constructed through capturing the overall risk variants for lung cancer. Sixteen inflammatory biomarkers are assayed in blood samples. Participants with the highest EAT‐Lancet diet scores (≥12) have a lower risk of lung cancer incidence (hazard ratio [HR] = 0.64, 95% confidence interval [CI]: 0.51–0.80) and mortality (HR = 0.65, 95% CI: 0.48–0.88), compared to those with the lowest EAT‐Lancet diet scores (≤8). Interestingly, there is a significantly protective trend against both lung adenocarcinoma and lung squamous cell carcinoma with higher EAT‐Lancet diet scores. Despite no significant interactions, a risk reduction trend for lung cancer is observed with increasing EAT‐Lancet diet scores and decreasing genetic risk. Ten inflammatory biomarkers partially mediate the association between the EAT‐Lancet diet and lung cancer risk.Conclusion: The study depicts a lower risk of lung cancer conferred by the EAT‐Lancet diet associated with lower inflammation levels among individuals with diverse genetic predispositions.

Sex disparity between metabolic-obesity (defined by body mass index, BMI) phenotypes and obesity-related cancer (ORC) remains unknown. Considering BMI reflecting overall obesity but not fat distribution, we aimed to systematically assess the association of our newly proposed metabolic-anthropometric phenotypes with risk of overall and site-specific ORC by sex. A total of 141,579 men (mean age: 56.37 years, mean follow-up time: 12.04 years) and 131,047 women (mean age: 56.22 years, mean follow up time: 11.82 years) from the UK Biobank was included, and designated as metabolic-anthropometric phenotypes based on metabolic status (metabolically healthy/unhealthy), BMI (non-obesity/obesity) and body shape (pear/slim/apple/wide). The sex-specific association of different phenotypes with overall and site-specific ORC was assessed by hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional hazards regression models. We found metabolically unhealthy and/or obesity phenotypes conveyed a higher risk in men than in women for overall ORC and colorectal cancer compared with metabolically healthy non-obesity phenotype (Pinteraction < 0.05). Of note, metabolically healthy obesity phenotype contributed to increased risks of most ORC in men (HRs: 1.58 ~ 2.91), but only correlated with higher risks of endometrial (HR = 1.89, 95% CI: 1.54–2.32) and postmenopausal breast cancers (HR = 1.17, 95% CI: 1.05–1.31) in women. Similarly, even under metabolically healthy, men carrying apple and wide shapes phenotypes (metabolically healthy apple/wide and metabolically healthy non-obesity apple/wide) suffered an increased risk of ORC (mainly colorectal, liver, gastric cardia, and renal cancers, HRs: 1.20 ~ 3.81) in comparison with pear shape or non-obesity pear shape. There was a significant sex disparity between metabolic-anthropometric phenotypes and ORC risk. We advised future ORC prevention and control worth taking body shape and sex disparity into account.