Many risk factors have been identified for breast cancer. The potential causality for some of them remains uncertain, and few studies have comprehensively investigated these associations by molecular ...subtypes. We performed a two‐sample Mendelian randomization (MR) study to evaluate potential causal associations of 23 known and suspected risk factors and biomarkers with breast cancer risk overall and by molecular subtypes using data from the Breast Cancer Association Consortium. The inverse‐variance weighted method was used to estimate odds ratios (OR) and 95% confidence interval (CI) for association of each trait with breast cancer risk. Significant associations with breast cancer risk were found for 15 traits, including age at menarche, age at menopause, body mass index, waist‐to‐hip ratio, height, physical activity, cigarette smoking, sleep duration, and morning‐preference chronotype, and six blood biomarkers (estrogens, insulin‐like growth factor‐1, sex hormone‐binding globulin SHBG, telomere length, HDL‐cholesterol and fasting insulin). Noticeably, an increased circulating SHBG was associated with a reduced risk of estrogen receptor (ER)‐positive cancer (OR = 0.83, 95% CI: 0.73‐0.94), but an elevated risk of ER‐negative (OR = 1.12, 95% CI: 0.93‐1.36) and triple negative cancer (OR = 1.19, 95% CI: 0.92‐1.54) (Pheterogeneity = 0.01). Fasting insulin was most strongly associated with an increased risk of HER2‐negative cancer (OR = 1.94, 95% CI: 1.18‐3.20), but a reduced risk of HER2‐enriched cancer (OR = 0.46, 95% CI: 0.26‐0.81) (Pheterogeneity = 0.006). Results from sensitivity analyses using MR‐Egger and MR‐PRESSO were generally consistent. Our study provides strong evidence supporting potential causal associations of several risk factors for breast cancer and suggests potential heterogeneous associations of SHBG and fasting insulin levels with subtypes of breast cancer.
What's new?
Many risk factors have been identified for breast cancer in observational studies. But the potential causality for some of these associations has not yet been established, and few studies have comprehensively investigated these associations by molecular subtype. This large two‐sample Mendelian randomization study supports potential causal associations for 15 risk factors and blood biomarkers with the risk of breast cancer. The results also show that the association of breast cancer risk with certain risk factors and biomarkers may differ by estrogen receptor status and intrinsic subtype, highlighting the heterogeneous nature of this disease.
Oral microbiome may play an important role in cancer pathogenesis. However, no study has prospectively investigated the association of the oral microbiome with subsequent risk of developing ...colorectal cancer (CRC). We conducted a nested case–control study including 231 incident CRC cases and 462 controls within the Southern Community Cohort Study with 75% of the subjects being African‐Americans. The controls were individually matched to cases based on age, ethnic group, smoking, season‐of‐study enrollment and recruitment method. Oral microbiota were assessed using 16S rRNA gene sequencing in pre‐diagnostic mouth rinse samples. Multiple bacterial taxa showed an association with CRC risk at p <0.05. Oral pathogens Treponema denticola and Prevotella intermedia were associated with an increased risk of CRC, with odds ratios (ORs) and 95% confidence intervals (CIs) of 1.76(1.19–2.60) and 1.55(1.08–2.22), respectively, for the individuals carrying these bacteria compared to non‐carriers. In the phylum Actinobacteria, Bifidobacteriaceae was more abundant among CRC patients than among controls. In the phylum Bacteroidetes, Prevotella denticola and Prevotella sp. oral taxon 300 were associated with an increased CRC risk, while Prevotella melaninogenica was associated with a decreased risk of CRC. In the phylum Firmicutes, Carnobacteriaceae, Streptococcaceae, Erysipelotrichaceae, Streptococcus, Solobacterium, Streptococcus sp. oral taxon 058 and Solobacterium moorei showed associations with a decreased risk of CRC. Most of these associations were observed among both African‐ and European‐Americans. Most of the associations were not significant after Bonferroni correction for multiple testing, which may be conservative. Our study suggests that the oral microbiome may play a significant role in CRC etiology.
What's new?
Oral microbiome composition is of special interest in research on colorectal cancer risk, owing in part to evidence that certain oral microbes cause chronic inflammation. In this prospective investigation of participants in the Southern Community Cohort Study in the United States, multiple oral bacterial taxa were associated with risk of developing colorectal cancer. Among the taxa, two species, Treponema denticola and Prevotella intermedia, previously were described as pathogenic in the oral cavity. The findings suggest that oral microbiome composition influences colorectal cancer risk, warranting further investigation for the possible use of oral microbiota in colorectal cancer detection and prevention.
The association between metformin use and risk of prostate cancer remains controversial, while data from randomized trials is lacking. We aim to evaluate the association of genetically proxied ...metformin effects with prostate cancer risk using a drug‐target Mendelian randomization (MR) approach. Summary statistics for prostate cancer were obtained from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome Consortium (79,148 cases and 61,106 controls). Cis‐expression quantitative trait loci (cis‐eQTL) variants in the gene targets of metformin were identified in the GTEx project and eQTLGen consortium. We also obtained male‐specific genome‐wide association study data for type 2 diabetes, body mass index (BMI), total testosterone, bioavailable testosterone, estradiol, and sex hormone binding globulin for mediation analysis. Inverse‐variance weighted (IVW) regression, weighted median, MR‐Egger regression, and MR‐PRESSO were performed in the main MR analysis. Multivariable MR was used to identify potential mediators and genetic colocalization analysis was performed to assess any shared genetic basis between two traits of interest. We found that genetically proxied metformin effects (1‐SD HbA1c reduction, equivalent to 6.75 mmol/mol) were associated with higher risk of prostate cancer (odds ratioIVW ORIVW: 1.55, 95% confidence interval, CI: 1.23–1.96, p = 3.0 × 10−3). Two metformin targets, mitochondrial complex I (ORIVW: 1.48, 95% CI: 1.07–2.03, p = 0.016) and gamma‐secretase complex (ORIVW: 2.58, 95%CI :1.47–4.55, p = 0.001), showed robust associations with prostate cancer risk, and their effects were partly mediated through BMI (16.4%) and total testosterone levels (34.3%), respectively. These results were further supported by colocalization analysis that expressions of NDUFA13 and BMI, APH1A, and total testosterone may be influenced by shared genetic factors, respectively. In summary, our study indicated that genetically proxied metformin effects may be associated with an increased risk of prostate cancer. Repurposing metformin for prostate cancer prevention in general populations is not supported by our findings.
Background
Although racial disparities in prostate cancer survival are well documented, the relative importance of contributing factors remains unclear. Few studies have examined the disparity ...between Whites and Hispanics or between Whites and Asian Americans and Pacific Islanders (AAPIs).
Methods
Using data from the National Cancer Database for 526,690 patients with prostate cancer who underwent radical prostatectomy between 2004 and 2014, this study systematically evaluated the impact of clinical characteristics and factors related to access to care on survival by race. Included in the analysis were 432,640 White patients (82.1%), 63,602 Black patients (12.1%), 8990 AAPI patients (1.7%), and 21,458 Hispanic patients (4.1%). Multivariable Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals to measure racial survival disparities. Inverse probability weighting was used to adjust for imbalances of prognostic factors.
Results
When adjustments were made for age and year of diagnosis only, Blacks had 51% higher mortality, AAPIs had 22% lower mortality, and Hispanics had 6% lower mortality than Whites. Overall, with adjustments for all clinical factors and nonclinical factors, the Black‐White survival disparity narrowed to 20%, whereas the AAPI‐White disparity increased to 35%. Among the controlled‐for factors, education, median household income, and insurance status contributed the most to the racial disparity.
Conclusions
The overall survival disparity among men undergoing radical prostatectomy was significantly decreased, but not eliminated, for Blacks and significantly increased for AAPIs in comparison with Whites after adjustments for a number of clinical factors and factors related to access to care.
The overall survival disparity among men undergoing radical prostatectomy is significantly decreased, but not eliminated, for Blacks and significantly increased for Asian Americans and Pacific Islanders in comparison with Whites after adjustments for a number of clinical factors and factors related to access to care. Further research is needed to address how these factors and modifiable lifestyle factors contribute to racial disparities in the overall survival of patients with prostate cancer.
Colonization of specific bacteria in the human mouth was reported to be associated with gastric cancer risk. However, previous studies were limited by retrospective study designs and low taxonomic ...resolutions. We performed a prospective case‐control study nested within three cohorts to investigate the relationship between oral microbiome and gastric cancer risk. Shotgun metagenomic sequencing was employed to characterize the microbiome in prediagnostic buccal samples from 165 cases and 323 matched controls. Associations of overall microbial richness and abundance of microbial taxa, gene families and metabolic pathways with gastric cancer risk were evaluated via conditional logistic regression. Analyses were performed within each cohort, and results were combined by meta‐analyses. We found that overall microbial richness was associated with decreased gastric cancer risk, with an odds ratio (OR) per standard deviation (SD) increase in Simpson's reciprocal index of 0.77 (95% confidence interval CI = 0.61‐0.99). Nine taxa, 38 gene families and six pathways also showed associations with gastric cancer risk at P < .05. Neisseria mucosa and Prevotella pleuritidis were enriched, while Mycoplasma orale and Eubacterium yurii were depleted among cases with ORs and 95% CIs per SD increase in centered log‐ratio transformed taxa abundance of 1.31 (1.03‐1.67), 1.26 (1.00‐1.57), 0.74 (0.59‐0.94) and 0.80 (0.65‐0.98), respectively. The top two gene families (P = 3.75 × 10−4 and 3.91 × 10−4) and pathways (P = 1.75 × 10−3 and 1.53 × 10−3) associated with gastric cancer were related to the decreased risk and are involved in hexitol metabolism. Our study supports the hypothesis that oral microbiota may play a role in gastric cancer etiology.
What's new?
Previous studies of oral microbiome and gastric cancer risk were mainly conducted in Asians and were limited by retrospective designs and low taxonomic resolutions. This study is the first multi‐racial study to prospectively investigate the relationship between oral microbiome and gastric cancer risk, utilizing shotgun metagenomic sequencing to assess the microbiome in pre‐diagnostic buccal samples. Decreased overall microbial richness, altered abundance of several microbial taxa, and multiple microbial functional markers were found to be associated with gastric cancer risk. The study supports the hypothesis that oral microbiota may play a role in gastric cancer etiology.
High nut consumption is associated with reduced total and certain cause‐specific mortality in general populations. However, its association with cancer outcomes among long‐term breast cancer ...survivors remains unknown. We examined the associations of nut consumption (including peanuts and tree nuts), assessed at 5‐year postdiagnosis, with overall survival (OS) and disease‐free survival (DFS) among 3449 long‐term breast cancer survivors from the Shanghai Breast Cancer Survival Study, applying Cox regression analysis. During a median follow‐up of 8.27 years post dietary assessment, there were 374 deaths, including 252 breast cancer deaths. Among 3274 survivors without previous recurrence at the dietary assessment, 209 developed breast cancer‐specific events, that is, recurrence, metastasis or breast cancer mortality. At 5‐year post dietary assessment (ie, 10‐year postdiagnosis), regular nut consumers had higher OS (93.7% vs 89.0%) and DFS (94.1% vs 86.2%) rates. After multivariable adjustment, nut consumption was positively associated with OS (Ptrend = .022) and DFS (Ptrend = .003) following a dose‐response pattern, with hazard ratios (95% confidence interval) of 0.72 (0.52‐1.05) for OS and 0.48 (0.31‐0.73) for DFS, for participants with greater than median nut intake compared with nonconsumers. The associations did not vary by nut type. Stratified analyses showed that the associations were more evident among participants with a higher total energy intake for OS (Pinteraction = .02) and among participants with early stage (I‐II) breast cancers for DFS (Pinteraction = .04). The nut‐DFS associations were not modified by estrogen receptor/progesterone receptor status or other known prognostic factors. In conclusion, nut consumption was associated with better survival, particularly DFS, among long‐term breast cancer survivors.
What's new?
High nut consumption has been associated with reduced all‐cause and cause‐specific mortality. However, to date, nut intake has not been investigated for associations with survival outcomes among breast cancer patients. This large cohort study found that nut consumption among long‐term breast cancer survivors was associated with a 52% reduced risk of recurrence or breast cancer mortality following a dose‐response pattern. The association was stronger for survivors with stage I‐II breast cancer than those with stage III‐IV breast cancer. This study provides evidence for promoting nut consumption as a modifiable lifestyle factor among breast cancer survivors.
Evidence suggests that Helicobacter pylori plays a role in gastric cancer (GC) initiation. However, epidemiologic studies on the specific role of other bacteria in the development of GC are lacking. ...We conducted a case‐control study of 89 cases with gastric intestinal metaplasia (IM) and 89 matched controls who underwent upper gastrointestinal endoscopy at three sites affiliated with NYU Langone Health. We performed shotgun metagenomic sequencing using oral wash samples from 89 case‐control pairs and antral mucosal brushing samples from 55 case‐control pairs. We examined the associations of relative abundances of bacterial taxa and functional pathways with IM using conditional logistic regression with and without elastic‐net penalty. Compared with controls, oral species Peptostreptococcus stomatis, Johnsonella ignava, Neisseria elongata and Neisseria flavescens were enriched in cases (odds ratios ORs = 1.29‐1.50, P = .004‐.01) while Lactobacillus gasseri, Streptococcus mutans, S parasanguinis and S sanguinis were under‐represented (ORs = 0.66‐0.76, P = .006‐.042) in cases. Species J ignava and Filifactor alocis in the gastric microbiota were enriched (ORs = 3.27 and 1.43, P = .005 and .035, respectively), while S mutans, S parasanguinis and S sanguinis were under‐represented (ORs = 0.61‐0.75, P = .024‐.046), in cases compared with controls. The lipopolysaccharide and ubiquinol biosynthesis pathways were more abundant in IM, while the sugar degradation pathways were under‐represented in IM. The findings suggest potential roles of certain oral and gastric microbiota, which are correlated with regulation of pathways associated with inflammation, in the development of gastric precancerous lesions.
What's new?
There's not much evidence for how gut bacteria, besides H. pylori, contribute to gastric cancer risk. Here, the authors used metagenome sequencing to characterize the differences in bacterial microbiota in gastric precancerous lesion cases compared with healthy controls. In gastric intestinal metaplasias, they found higher proportions of several species related to periodontal disease as well as opportunistic pathogens, but lower levels of certain commensals and probiotic species. Metagenomic analysis revealed pathways that were associated with gastric intestinal metaplasias, suggesting a possible mechanism for how the bacteria influence disease risk.
Both genetic and lifestyle factors play an etiologic role in colorectal cancer (CRC).
We evaluated potential gene–environment interactions in CRC risk.
We used data from 346,297 participants in the ...UK Biobank cohort. Healthy lifestyle scores (HLSs) were constructed using 8 lifestyle factors, primarily according to the American Cancer Society guidelines, and were categorized into unhealthy, intermediate, and healthy groups. A polygenic risk score (PRS) was created using 95 genetic risk variants identified by genome-wide association studies of CRC and was categorized by tertile. Cox models were used to estimate the HRs and 95% CIs of CRC risk associated with the HLS and PRS.
During a median follow-up of 5.8 y, 2066 incident cases of CRC were identified. Healthier HLSs were associated with reduced risk of CRC in a dose–response manner. The risk reduction was more apparent among those with high PRS (HRhealthy vs. unhealthy HLS1: 0.58; 95% CI: 0.43, 0.79 for men and 0.71; 0.58, 0.85 for men and women combined) than those with low PRS. Although no multiplicative interactions were identified, the HLS1 and PRS showed a significant additive interaction (P = 0.02 for all participants combined, 0.04 for men). In analyses including all participants, the adjusted CRC cumulative risk from age 40 to 75 y was 6.40% for those with high PRS/unhealthy HLS1, with a relative excess risk due to interaction of 0.58 (95% CI: 0.06, 1.10), compared with 2.09% among those with low PRS/healthy HLS1. This pattern was more apparent among those who reported not having received any bowel screening before baseline.
Although the observational nature of the study precludes proof of causality, our findings suggest that individuals with a high genetic susceptibility could benefit more substantially than those with a low genetic risk from lifestyle modification in reducing CRC risk.
Few prospective studies, and none in Asians, have systematically evaluated the relationship between blood metabolites and colorectal cancer risk. We conducted a nested case–control study to search ...for risk‐associated metabolite biomarkers for colorectal cancer in an Asian population using blood samples collected prior to cancer diagnosis. Conditional logistic regression was performed to assess associations of metabolites with cancer risk. In this study, we included 250 incident cases with colorectal cancer and individually matched controls nested within two prospective Shanghai cohorts. We found 35 metabolites associated with risk of colorectal cancer after adjusting for multiple comparisons. Among them, 12 metabolites were glycerophospholipids including nine associated with reduced risk of colorectal cancer and three with increased risk odds ratios per standard deviation increase of transformed metabolites: 0.31–1.98; p values: 0.002–1.25 × 10−10. The other 23 metabolites associated with colorectal cancer risk included nine lipids other than glycerophospholipid, seven aromatic compounds, five organic acids and four other organic compounds. After mutual adjustment, nine metabolites remained statistically significant for colorectal cancer. Together, these independently associated metabolites can separate cancer cases from controls with an area under the curve of 0.76 for colorectal cancer. We have identified that dysregulation of glycerophospholipids may contribute to risk of colorectal cancer.
What's new?
Blood metabolites have emerged as novel biomarkers for various cancers but few studies have focused on colorectal cancer. In this prospective study, the authors identified 35 metabolites associated with colorectal cancer risk. The majority of risk‐associated metabolites were lipids, especially glycerophospholipids, pointing to a mechanistic connection between colorectal cancer and dysregulation of glycerophospholipid biology.
Using a metabolomics approach, we systematically searched for circulating metabolite biomarkers for pancreatic cancer risk in a case‐control study nested within two prospective Shanghai cohorts. ...Included in our study were 226 incident pancreatic cancer cases and their individually‐matched controls. Untargeted mass spectrometry platforms were used to measure metabolites in blood samples collected prior to cancer diagnosis. Conditional logistic regression was performed to assess the associations of metabolites with pancreatic cancer risk. We identified 10 metabolites associated with pancreatic cancer, after accounting for multiple comparisons (the Benjamini‐Hochberg false discovery rate <0.05). The majority of the identified metabolites were glycerophospholipids (ORs per SD increase: 0.44–2.32; p values: 7.2 × 10−4 to 1.0 × 10−6), six of which were associated with decreased risk and one with increased risk. Additionally, levels of coumarin (OR = 1.96, p = 3.7 × 10−6) and picolinic acid (OR = 2.53, p = 5.0 × 10−5) were positively associated with pancreatic cancer risk, while tetracosanoic acid was inversely associated with risk (OR = 0.48, p = 7.16 × 10−7). Four metabolites remained statistically significant after mutual adjustment. Our study provides novel evidence that the dysregulation of glycerophospholipids may play an important role in pancreatic cancer development.
What's new?
Despite the lack of reliable biomarkers for risk assessment and early diagnosis, to date few metabolomics studies have been conducted to identify biomarkers for pancreatic cancer risk. In this nested case‐control study using pre‐diagnostic plasma samples, the authors identified ten metabolites associated with risk of pancreatic cancer after adjusting for multiple comparisons. Seven of these metabolites were glycerophospholipids, the majority of which were inversely associated with pancreatic cancer risk, providing novel evidence that glycerophospholipids dysregulation may be related to pancreatic cancer. The new metabolite biomarkers may be useful in identifying high‐risk individuals for screening and chemoprevention for this deadly malignancy.
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