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Background: Physical activity is an established protective factor for colorectal cancer (CRC), but it is unclear if genetic variants modify this effect. To investigate this possibility, we conducted a genome-wide gene–physical activity interaction analysis.

Methods: Using logistic regression (1-d.f), two-step screening and testing method (EDGE), and joint tests (3-d.f), we analyzed interactions between common genetic variants across the genome and physical activity in relation to CRC risk. Self-reported physical activity levels were categorized as active (≥ 8.75 MET-h/wk) vs. inactive (< 8.75 MET-h/wk; 39,992 participants) and as study- and sex-specific quartiles of activity (42,602 participants).

Results: Physical activity was inversely associated with CRC risk overall (OR [active vs. inactive] = 0.85; 95% CI = 0.81–0.90). The two-step EDGE method identified an interaction between rs4779584, an intergenic variant near the GREM1 and SCG5 genes, and physical activity for CRC risk (p-interaction = 2.6 × 10−8). Stratification by genotype at this locus showed a significant reduction in CRC risk by 20% in active vs. inactive participants with the CC genotype (OR = 0.80; 95% CI = 0.75–0.85), but no significant physical activity–CRC associations among CT or TT carriers. When physical activity was modeled as quartiles, the 1-d.f. test identified that rs56906466, an intergenic variant near the KCNG1 gene, modified the association between physical activity and CRC (p-interaction = 3.5 × 10−8). Stratification at this locus showed that an increase in physical activity (highest vs. lowest quartile) was associated with a lower CRC risk solely among TT carriers (OR = 0.77; 95% CI = 0.72–0.82).

Conclusions: In summary, we identified two genetic variants that modified the association between physical activity and CRC risk. One of them, related to GREM1 and SCG5, suggests that the bone morphogenetic protein (BMP)-related, inflammatory, and/or insulin signaling pathways may be involved in the protective association between physical activity and colorectal carcinogenesis.

Background: Identifying significantly mutated genes in tumors aids in understanding disease etiology and survival and may aid in the discovery of new drug targets. We aimed to detect and characterize mutated genes from a large, well-characterized group of colorectal cancers.

Methods: In tumor and paired normal samples from 6,111 colorectal patients, we sequenced 199 genes identified from whole exome sequencing of over 1,100 tumors. Analyses focused on non-silent mutations. We classified significantly mutated genes after stratification by hypermutation status, and estimated associations of mutated genes/pathways with disease-specific (DS)-survival using Cox regression, adjusting for age, sex, mutation burden, hypermutation status, and study while accounting for multiple comparisons (n = 4,874).

Results: We identified 57 genes that were significantly mutated in colorectal cancer, including 9 that were not previously reported. Among individual genes, only BRAF p.V600E mutations were significantly associated with poorer survival after correction for multiple testing (HR 1.96, P = 2.07 × 10− 10), with a more pronounced association among those with non-hypermutated tumors (HR 2.24, P = 1.79 × 10− 12). We also observed statistically significant associations with survival for four mutated pathways: TP53/ATM (HR 1.24, P = 7.96 × 10− 4), RTK/RAS (HR 1.33, P = 3.81 × 10− 6), TGF-beta (HR 1.25, P = 1.85 × 10− 3), and WNT (HR 0.81, P = 2.52 × 10− 03).

Conclusions: We identified 9 significantly mutated genes, some of which are known drug targets. Among individual genes, only the BRAF p.V600E mutation was significantly associated with DS-survival, suggesting a limited survival impact from mutations driving colorectal cancer development.

Background: The chemical exposome includes exposure to numerous environmental and endogenous molecules, many of which have been linked to reproductive outcomes due to their endocrine-disrupting properties. As several breast cancer risk factors, including age and parity, are related to reproduction, it is imperative to investigate the interplay between such factors and the chemical exposome prior to conducting large scale exposome-based breast cancer studies.

Objective: This pilot study aimed to provide an overview of the chemical exposome in plasma samples from healthy women and identify associations between environmental exposures and three risk factors for breast cancer: age, parity, and age at menarche.

Material and methods: Plasma samples (n = 161), were selected based on reproductive history from 100 women participating in the Northern Sweden Health and Disease Study, between 1987 and 2006. Samples were analyzed by liquid chromatography high-resolution mass spectrometry (LC-HRMS) for 77 priority target analytes including contaminants and hormones, with simultaneous untargeted profiling of the chemical exposome and metabolome. Linear mixed effects models were applied to test associations between risk factors and chemical levels.

Results: Fifty-five target analytes were detected in at least one individual and over 94,000 untargeted features were detected across all samples. Among untargeted features, 430 could be annotated and were broadly classified as environmental (246), endogenous (167) or ambiguous (17). Applying mixed effect models to features detected in at least 70% of the samples (16,778), we found seven targeted analytes (including caffeine and various per- and poly-fluoroalkyl substances) and 38 untargeted features, positively associated with age. The directionality of these associations reversed for parity, decreasing with increasing births. Seven separate targeted analytes were associated with age at menarche.

Significance: This study demonstrates how a comprehensive chemical exposome approach can be used to inform future research prioritization regarding associations between known and unknown substances, reproduction, and breast cancer risk.

Impact statement: This study illustrates how chemical exposomics of long-term stored blood samples offers valuable insights to discover chemical exposures and their potential links to disease in humans, particularly those related to reproduction and breast cancer risk factors.

Key features: 

• The Northern Sweden Health and Disease Study (NSHDS) was initiated in the mid-1980s. The NSHDS is a population-based prospective longitudinal cohort comprising >140 000 participants in the two northernmost regions in Sweden, Norrbotten and Västerbotten, with >240 000 blood samples and 1.5 million person-years of follow-up.
• The NSHDS includes three sub-cohorts: the Västerbotten Intervention Programme (VIP), the expanded Northern Sweden Monitoring of Trends and Determinants of Cardiovascular Disease (MONICA) Study, and the Mammography Screening Project (MSP). The VIP is both a community-based cardiometabolic intervention programme encouraging healthy lifestyle (targeting individuals 40, 50, and 60 years of age), and a corresponding research cohort. The MONICA is an observational study focusing on cardiovascular disease and its associated risk factors, recruiting individuals aged 25–74 years. The MSP recruited women attending mammography during 1995–2006. The NSHDS median participation age is 50 years (53% women).
• Most participants contribute data on health, lifestyle, anthropometric measures, blood pressure, blood lipids, and glucose tolerance, along with research blood samples that are fractionated, frozen within an hour of collection, and stored at –80°C. Linkage to registries, clinical cohorts, and biological tissue archives facilitates studies of well-characterized participants (often combined with intervention studies).
• Collaborations are encouraged. Additional information can be found at: info.brs@umu.se; https://www.umu.se/en/biobank

Background: Air pollution has been linked to breast cancer risk, but previous studies have seldom considered specific exposure windows, like pregnancy. During pregnancy the breast undergoes substantial changes and exposures may have a stronger impact than if they occurred during other time periods. This study aims to identify associations between ambient air pollution exposure during pregnancy and risk of early-onset breast cancer.

Methods: Using nationwide data from Swedish registers, we constructed a cohort consisting of all cancer-free women in Sweden giving birth to their first child between 1991 and 2015. Residential exposure to nitrogen dioxide (NO2), particulate matter < 10 μm (PM10) and < 2.5 μm (PM2.5) were modelled based on air pollution concentrations from 2019. Particulate matter between 2.5 and 10 μm (PMcoarse) was calculated separately. Detailed data on residential addresses (including exact moving dates) were available for the entire study period, allowing for spatial variation in the exposure dataset. Mean air pollution levels were assessed at first pregnancy, last pregnancy, 35 years of age, and 2 years after the last delivery. Associations were evaluated using Cox proportional hazards regression to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: Among 1,019,076 women, 12,085 (1.2%) were diagnosed with breast cancer and 65.2% moved at least once between their first pregnancy and two years after their last delivery. All exposures during pregnancy periods were positively associated with breast cancer, with the highest HR observed for exposure to PMcoarse during the last pregnancy (HRPMcoarse = 1.12 (95% CI = 1.04, 1.20) per 5 μg/m3 increase). The lowest HR were for NO2 levels estimated at 35 years of age, regardless of pregnancy status (HRNO2 = 1.03 (95% CI = 0.99, 1.06) per 10 μg/m3 increase). In analyses differentiating between invasive breast cancer and ductal carcinoma in situ, only invasive breast cancer was associated with air pollution exposure.

Conclusions: In this cohort study, air pollution exposure was consistently associated with increased risk of early-onset breast cancer.

Background:The impact of air pollution and road traffic noise on depression remains inconclusive. This study examined long-term residential exposure to air pollutants and road traffic noise in relation to dispensed antidepressant medications.

Methods:A cohort study was conducted using the Swedish Malmö Diet and Cancer Study, with the outcome defined as a first dispensed antidepressant (ATC: N06A) and/or a first clinical depression diagnosis (ICD-10: F32/F33) during follow-up (2007–2011). Exposure was assessed through modelled annual mean concentrations of particulate matter (PM2.5, PM10), nitrogen oxides (NOx), and road traffic noise (Lden). Cox proportional hazards regression was applied, adjusted for potential confounders including sociodemographic and lifestyle factors.

Results:A total of 18 373 individuals were included, among whom 2224 with the outcome (89 % had dispensed antidepressant, 6 % both clinical diagnosis and antidepressant, and 5 % clinical diagnosis) during follow-up. Increased hazard ratios (HRs) were observed in association with long-term air pollution exposure, but only among women. Increased but statistically non-significant HRs were found for road traffic noise in women, while no associations were found in men. For lag1-5 (1–5 years exposure window prior to the event) in women, HRs per 10-unit increase were: PM2.5, 1.29 (95 % CI, 1.09–1.52); PM10, 1.10 (1.03–1.17); NOx, 1.15 (1.04–1.26); and Lden, 1.06 (0.99–1.13). Similar patterns were found for lag1 and in the two-pollutant models.

Conclusion:Long-term exposure to air pollution was positively associated with dispensed antidepressant medications in women but not in men. For road traffic noise, evidence was less clear, but a potential link was seen in women. Though associations were seen only in women, the findings suggest that air quality improvements and possibly also noise reductions may help reduce health burdens related to depressive symptoms.

Background: Prenatal exposure to maternal asthma may influence DNA methylation patterns in offspring, potentially affecting their susceptibility to later diseases including asthma.

Objective: To investigate the relationship between parental asthma and newborn blood DNA methylation.

Methods: Epigenome-wide association analyses were conducted in 13 cohorts on 7433 newborns with blood methylation data from the Illumina450K or EPIC array. We used fixed effects meta-analyses to identify differentially methylated CpGs (DMCs) and comb-p to identify differentially methylated regions (DMRs) associated with maternal asthma during pregnancy and maternal asthma ever. Paternal asthma was analyzed for comparison. Models were adjusted for covariates and cell-type composition. We examined whether implicated sites related to gene expression analyses in publicly available data for childhood blood and adult lung.

Results: We identified 27 CpGs associated with maternal asthma during pregnancy at False Discovery Rate < 0.05 but none for maternal asthma ever. Two distinct CpGs were associated with paternal asthma. We observed 5 DMRs associated with maternal asthma during pregnancy 3 associated with maternal asthma ever and 13 DMRs associated with paternal asthma. Gene expression analysis using data in blood from 832 children and lung from 424 adults showed associations between identified DMCs using maternal asthma and expression of several genes, including HLA genes and HOXA5, previously implicated in asthma or lung function.

Conclusion: Parental asthma, especially maternal asthma during pregnancy, may be associated with alterations in newborn DNA methylation. These findings might shed light on underlying mechanisms for asthma susceptibility.

Transcriptomics is an important OMICs method that is often unavailable in biobank research. Frozen blood samples are routinely collected and stored in medical biobanks, but transcriptional studies have been limited due to technical difficulties of extracting high-quality RNA from blood frozen in standard tubes (without RNA preservatives). We aimed to determine whether biobanked buffy coat samples stored at -80°C for up to 23 years could be successfully used for mRNA sequencing. We used a CryoXtract CXT 350 to remove frozen sample cores, which were immersed in RNA preservative during thawing prior to RNA extraction. RNA sequencing was then performed on extractions from pooled samples as well as from 23 buffy coat samples from prospective colorectal cancer cases and 23 matched controls included in the population-based, prospective Northern Sweden Health and Disease Study (NSHDS). For all samples, two library preparation methods were used (Illumina TruSeq Stranded mRNA poly-A selection and Illumina Stranded Total RNA with Ribo-Zero Globin). RNA yields of over 1 µg were obtained from the majority of NSHDS samples (mean = 2.57 µg), and over 92% of samples had RIN values of ≥ 6, indicating suitability for downstream analyses. In conclusion, we developed a method for successfully extracting and sequencing high-quality mRNA from frozen buffy coat samples stored long term in tubes with no RNA preservative.

Multiple myeloma is preceded by monoclonal gammopathy of undetermined significance (MGUS). Only a minority of patients with MGUS will develop multiple myeloma, but precise prediction of progression is impossible using routine clinical biomarkers. Changes in the levels of blood immune markers can help predict disease progression. Data remain inconsistent for some markers of interest such as monocyte chemotactic protein-3 (MCP-3), macrophage inflammatory protein-1 alpha (MIP-1α), fibroblast growth factor-2 (FGF-2), vascular endothelial growth factor (VEGF), fractalkine, and transforming growth factor-alpha (TGF-α). We aimed to investigate the associations between the prediagnostic serum levels of these candidate biomarkers and future multiple myeloma risk, as well as to assess marker changes over time. We performed a nested case-control study using prospective samples from the Janus Serum Bank in Norway to investigate associations between multiple myeloma risk and prediagnostic serum levels of MCP-3, MIP-1α, FGF-2, VEGF, fractalkine, and TGF-α. The study included 293 future multiple myeloma cases with serum samples collected 20 years (median) before multiple myeloma diagnosis and 293 matched cancer-free controls. Patients with multiple myeloma had an additional prediagnostic sample collected up to 42 years before diagnosis to identify marker changes over time. Markers with >60% detection rate (MIP-1α, VEGF, and TGF-α) were included in the statistical analysis. We observed no statistically significant associations between multiple myeloma risk and serum levels of MIP-1α, VEGF, or TGF-α in samples collected 20 years before diagnosis. However, TGF-α levels decreased significantly closer to the diagnosis in patients with multiple myeloma (P < 0.001). The decrease in TGF-α levels may reflect subtle microenvironmental changes related to multiple myeloma progression.

PREVENTION RELEVANCE: This study observed a decline in TGF-α serum levels closer to multiple myeloma diagnosis, which may aid in predicting multiple myeloma progression and early detection, although validation in other longitudinal cohorts is needed.

Gut microbiota composition has been implicated in surgical site complications after colorectal cancer surgery. Antibiotics affect gut microbiota, but evidence for a role in surgical site complications is inconclusive. We aimed to investigate use of prescription antibiotics during the years before surgery in relation to the risk of surgical site infections, including anastomotic leakage, within 30 days after surgery. Cardiovascular/neurological complications and the urinary antiseptic methenamine hippurate, for which there is no clear link with the microbiota, were used as negative controls. We conducted a patient cohort study using complete population data from Swedish national registers between 2005 and 2020. The final study population comprised 26,527 colon cancer and 12,312 rectal cancer cases with a 4.5 year exposure window. In colon cancer patients, antibiotics use was associated with a higher risk of surgical site infections (adjusted odds ratio (aOR) for any versus no use = 1.20, 95% confidence interval (CI) 1.10–1.33) and anastomotic leakage in particular (aOR =1.19, 95% CI 1.03–1.36), both with dose–response relationships for increasing cumulative antibiotics use (Ptrend = <0.001 and Ptrend = 0.047, respectively). Conversely, associations in rectal cancer patients, as well as for the negative controls cardiovascular/neurological complications and methenamine hippurate, were null. In conclusion, prescription antibiotics use up to 4.5 years before colorectal cancer surgery is associated with a higher risk of surgical site infections, including anastomotic leakage, after colon cancer but not rectal cancer surgery. These findings support a role for antibiotics-induced intestinal dysbiosis in surgical site infections.