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The incidence of colorectal cancer (CRC) among individuals under age 50, or early-onset CRC (EOCRC), has been rising over the past few decades for unclear reasons, and the etiology of the disease remains largely unknown. Known genetic risk factors do not explain this increase, pointing to possible environmental and as-yet unidentified genetic contributors and their interactions. Previous research linked genetic variation on chromosome 6 to increased CRC risk. This region harbors multiple immune genes, including the gene encoding Major Histocompatibility Complex (MHC) class I polypeptide-related sequence A (MICA). MICA is a polygenic ligand for the Natural Killer Group 2D receptor (NKG2D), a receptor expressed on Natural Killer (NK) cells and other lymphocytes. Given that intra-tumoral NK cell infiltration correlates with favorable CRC outcomes, we hypothesized that germline genetic variation in MICA could influence CRC risk. In a discovery set of 40,125 cases and controls, we show that the minor G allele at Chr6:31373718C>G (hg19) is associated with increased risk for CRC (odds ratio (OR) = 1.09, 95% confidence interval (CI) 1.04 - 1.15, p = 0.0009). The effect is stronger in EOCRC (OR = 1.26, 95% CI 1.08 - 1.44, p = 0.0023) than in those 50 and over (OR = 1.07, 95% CI 1.02 - 1.13; p = 0.012) (Ratio of ORs = 1.32, 95% CI 1.14 - 1.52, p = 0.0002). In an independent validation set of 77,983 cases and controls, the adjusted interaction by age-of-onset was significant at OR = 1.15 (95% CI 1.03 - 1.34, p = 0.0150) with a higher risk in EOCRC. Expression quantitative trait locus analysis in normal colonic epithelia showed that MICA RNA expression decreases linearly with each additional copy of the minor G allele (p = 3.345 × 10e-18). Bulk RNA analysis of the tumor immune microenvironment revealed that tumors from patients with CG or GG genotypes have lower resting and activated NK cell infiltration as compared to tumors from patients with CC genotype. Multiplex immunofluorescence analysis demonstrated that patients with a G allele (i.e. CG or GG genotype, but not CC genotype) have a statistically significant decrease in the number of NK cells in tumor compared to adjacent normal colonic mucosa. Taken together, population-based epidemiologic, molecular, genetic, cellular and immunologic evidence demonstrate that MICA genotype is associated with increased risk of EOCRC and reduced number of NK cells in colorectal tumors, suggesting that patients with a G allele have altered NK cell-mediated immunosurveillance. These novel findings suggest that EOCRC may have a previously unrecognized innate immune-mediated etiology which merits further investigation.

Importance: Little is known about the causes of second primary cancers among individuals with a history of cancer. Descriptive studies have suggested that lifestyle factors, including excess body weight, may be important., Objective: To investigate whether excess body weight is associated with the risk of a second primary malignant neoplasm among cancer survivors., Design, Setting, and Participants: This cohort study of adults in 21 states in the US used data from the Cancer Prevention Study II Nutrition cohort, a large prospective study that invited participants to respond to a survey in 1992 and biennial surveys starting in 1997, and who were followed-up through 2017. Eligible participants included those who received a diagnosis of a first primary nonmetastatic invasive cancer between 1992 and 2015. Data analysis occurred from September 2023 to March 2024., Exposure: Body mass index (BMI), computed from self-reported height and weight at the time of the first primary cancer diagnosis (mean [SD] years to diagnosis, 1.7 [1.5] years)., Main Outcome and Measures: Main outcomes included a second primary cancer or an obesity-related second cancer. Cancer diagnoses were reported on biennial surveys and verified through medical record abstraction or linkage with state cancer registries., Results: This cohort included 26 894 participants who received a diagnosis of a first nonmetastatic primary cancer (mean [SD] age at first cancer diagnosis, 72.2 [6.5] years; 15 920 male [59.2%]). At the time of first diagnosis, 11 497 participants (42.8%) had overweight and 4684 (17.2%) had obesity. During a median (IQR) follow-up time of 7.9 (3.4-13.6) years, 3749 (13.9%) participants received a diagnosis of a second primary cancer, of which 1243 (33.2%) were obesity-related second primary cancers. Compared with cancer survivors whose BMI was in the normal range (18.5 to <25), there was 15% increased risk of any second primary cancer for those who had overweight (25 to <30; adjusted hazard ratio [aHR], 1.15; 95% CI, 1.07-1.25) and a 34% increased risk for those who had obesity (BMI ≥30; aHR, 1.34; 95% CI, 1.21-1.48), with greater risk for obesity-related second primary cancers, including a 40% increased risk for those with overweight (aHR, 1.40; 95% CI, 1.22,-1.61) and a 78% increased risk for those with obesity (aHR, 1.78; 95% CI, 1.51-2.11)., Conclusions and Relevance: In this cohort study of older survivors of nonmetastatic cancer, those who had overweight or obesity at the time of their first cancer diagnosis were at higher risk of developing a second cancer, especially an obesity-related second cancer. Given the high prevalence of overweight and obesity among cancer survivors, it is important to promote survivorship care guidelines recommending weight management and increase awareness of second cancers among physicians and cancer survivors.

Background: Folate is involved in multiple genetic, epigenetic, and metabolic processes, and inadequate folate intake has been associated with an increased risk of cancer., Objective: We examined whether folate intake is differentially associated with colorectal cancer (CRC) risk according to somatic mutations in genes linked to CRC using targeted sequencing., Design: Participants within 2 large CRC consortia with available information on dietary folate, supplemental folic acid, and total folate intake were included. Colorectal tumor samples from cases were sequenced for the presence of nonsilent mutations in 105 genes and 6 signaling pathways (IGF2/PI3K, MMR, RTK/RAS, TGF-β, WNT, and TP53/ATM). Multinomial logistic regression models were analyzed comparing mutated/nonmutated CRC cases to controls to compute multivariable-adjusted odds ratios (ORs) with 95% confidence interval (CI). Heterogeneity of associations of mutated compared with nonmutated CRC cases was tested in case-only analyses using logistic regression. Analyses were performed separately in hypermutated and nonhypermutated tumors, because they exhibit different clinical behaviors., Results: We included 4339 CRC cases (702 hypermutated tumors, 16.2%) and 11,767 controls. Total folate intake was inversely associated with CRC risk (OR = 0.93; 95% CI: 0.90, 0.96). Among hypermutated tumors, 12 genes (AXIN2, B2M, BCOR, CHD1, DOCK3, FBLN2, MAP3K21, POLD1, RYR1, TET2, UTP20, and ZNF521) showed nominal statistical significance (P < 0.05) for heterogeneity by mutation status, but none remained significant after multiple testing correction. Among these genetic subtypes, the associations between folate variables and CRC were mostly inverse or toward the null, except for tumors mutated for DOCK3 (supplemental folic acid), CHD1 (total folate), and ZNF521 (dietary folate) that showed positive associations. We did not observe differential associations in analyses among nonhypermutated tumors, or according to the signaling pathways., Conclusions: Folate intake was not differentially associated with CRC risk according to mutations in the genes explored. The nominally significant differential mutation effects observed in a few genes warrants further investigation., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Consumption of fibre, fruits and vegetables have been linked with lower colorectal cancer (CRC) risk. A genome-wide gene-environment (G × E) analysis was performed to test whether genetic variants modify these associations., Methods: A pooled sample of 45 studies including up to 69,734 participants (cases: 29,896; controls: 39,838) of European ancestry were included. To identify G × E interactions, we used the traditional 1--degree-of-freedom (DF) G × E test and to improve power a 2-step procedure and a 3DF joint test that investigates the association between a genetic variant and dietary exposure, CRC risk and G × E interaction simultaneously., Findings: The 3-DF joint test revealed two significant loci with p-value <5 × 10 -8 . Rs4730274 close to the SLC26A3 gene showed an association with fibre (p-value: 2.4 × 10 -3 ) and G × fibre interaction with CRC (OR per quartile of fibre increase = 0.87, 0.80, and 0.75 for CC, TC, and TT genotype, respectively; G × E p-value: 1.8 × 10 -7 ). Rs1620977 in the NEGR1 gene showed an association with fruit intake (p-value: 1.0 × 10 -8 ) and G × fruit interaction with CRC (OR per quartile of fruit increase = 0.75, 0.65, and 0.56 for AA, AG, and GG genotype, respectively; G × E -p-value: 0.029)., Interpretation: We identified 2 loci associated with fibre and fruit intake that also modify the association of these dietary factors with CRC risk. Potential mechanisms include chronic inflammatory intestinal disorders, and gut function. However, further studies are needed for mechanistic validation and replication of findings., Funding: National Institutes of Health, National Cancer Institute. Full funding details for the individual consortia are provided in acknowledgments., Competing Interests: Declaration of interests ESK is a co-investigator in a grant from National Institutes of Health (R01CA196569). JW is Stock shareholder of Gilead Sciences Inc. AK has received consulting fees for Illumina Inc., has participated on data safety monitoring boards or advisory boards of TensorBio, PatchBio, Serimmune, and OpenTargets, and has stock or stock options of Illumina, Freenome, Deep Genomics, Immunai, TensorBio, PatchBio, and Serimmune. MCS was a co-investigator in a grant from National Institutes of Health (R01CA201407). VM has received grant support from Instituto de Salud Carlos III and Fundacion Cientifica Asociación Española Contra el Cáncer. SBG is a co-founder of Brogent international LLC. JPL has received additional grant support (5P01CA196569, 6R01CA201407). The remaining authors declare that they have no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769 ), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047 ), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.

It remains unknown whether adiposity subtypes are differentially associated with colorectal cancer (CRC). To move beyond single-trait anthropometric indicators, we derived four multi-trait body shape phenotypes reflecting adiposity subtypes from principal components analysis on body mass index, height, weight, waist-to-hip ratio, and waist and hip circumference. A generally obese (PC1) and a tall, centrally obese (PC3) body shape were both positively associated with CRC risk in observational analyses in 329,828 UK Biobank participants (3728 cases). In genome-wide association studies in 460,198 UK Biobank participants, we identified 3414 genetic variants across four body shapes and Mendelian randomization analyses confirmed positive associations of PC1 and PC3 with CRC risk (52,775 cases/45,940 controls from GECCO/CORECT/CCFR). Brain tissue-specific genetic instruments, mapped to PC1 through enrichment analysis, were responsible for the relationship between PC1 and CRC, while the relationship between PC3 and CRC was predominantly driven by adipose tissue-specific genetic instruments. This study suggests distinct putative causal pathways between adiposity subtypes and CRC.

Background: The genotoxin colibactin causes a tumor single-base substitution (SBS) mutational signature, SBS88. It is unknown whether epidemiologic factors' association with colorectal cancer risk and survival differs by SBS88., Methods: Within the Genetic Epidemiology of Colorectal Cancer Consortium and Colon Cancer Family Registry, we measured SBS88 in 4,308 microsatellite stable/microsatellite instability low tumors. Associations of epidemiologic factors with colorectal cancer risk by SBS88 were assessed using multinomial regression (N = 4,308 cases, 14,192 controls; cohort-only cases N = 1,911), and with colorectal cancer-specific survival using Cox proportional hazards regression (N = 3,465 cases)., Results: 392 (9%) tumors were SBS88 positive. Among all cases, the highest quartile of fruit intake was associated with lower risk of SBS88-positive colorectal cancer than SBS88-negative colorectal cancer [odds ratio (OR) = 0.53, 95% confidence interval (CI) 0.37-0.76; OR = 0.75, 95% CI 0.66-0.85, respectively, Pheterogeneity = 0.047]. Among cohort studies, associations of body mass index (BMI), alcohol, and fruit intake with colorectal cancer risk differed by SBS88. BMI ≥30 kg/m2 was associated with worse colorectal cancer-specific survival among those SBS88-positive [hazard ratio (HR) = 3.40, 95% CI 1.47-7.84], but not among those SBS88-negative (HR = 0.97, 95% CI 0.78-1.21, Pheterogeneity = 0.066)., Conclusions: Most epidemiologic factors did not differ by SBS88 for colorectal cancer risk or survival. Higher BMI may be associated with worse colorectal cancer-specific survival among those SBS88-positive; however, validation is needed in samples with whole-genome or whole-exome sequencing available., Impact: This study highlights the importance of identification of tumor phenotypes related to colorectal cancer and understanding potential heterogeneity for risk and survival., (©2024 American Association for Cancer Research.)

Background: High red meat and/or processed meat consumption are established colorectal cancer risk factors. We conducted a genome-wide gene-environment (GxE) interaction analysis to identify genetic variants that may modify these associations., Methods: A pooled sample of 29,842 colorectal cancer cases and 39,635 controls of European ancestry from 27 studies were included. Quantiles for red meat and processed meat intake were constructed from harmonized questionnaire data. Genotyping arrays were imputed to the Haplotype Reference Consortium. Two-step EDGE and joint tests of GxE interaction were utilized in our genome-wide scan., Results: Meta-analyses confirmed positive associations between increased consumption of red meat and processed meat with colorectal cancer risk [per quartile red meat OR = 1.30; 95% confidence interval (CI) = 1.21-1.41; processed meat OR = 1.40; 95% CI = 1.20-1.63]. Two significant genome-wide GxE interactions for red meat consumption were found. Joint GxE tests revealed the rs4871179 SNP in chromosome 8 (downstream of HAS2); greater than median of consumption ORs = 1.38 (95% CI = 1.29-1.46), 1.20 (95% CI = 1.12-1.27), and 1.07 (95% CI = 0.95-1.19) for CC, CG, and GG, respectively. The two-step EDGE method identified the rs35352860 SNP in chromosome 18 (SMAD7 intron); greater than median of consumption ORs = 1.18 (95% CI = 1.11-1.24), 1.35 (95% CI = 1.26-1.44), and 1.46 (95% CI = 1.26-1.69) for CC, CT, and TT, respectively., Conclusions: We propose two novel biomarkers that support the role of meat consumption with an increased risk of colorectal cancer., Impact: The reported GxE interactions may explain the increased risk of colorectal cancer in certain population subgroups., (©2023 American Association for Cancer Research.)

Background: Obesity has been positively associated with most molecular subtypes of colorectal cancer (CRC); however, the magnitude and the causality of these associations is uncertain., Methods: We used Mendelian randomization (MR) to examine potential causal relationships between body size traits (body mass index [BMI], waist circumference, and body fat percentage) with risks of Jass classification types and individual subtypes of CRC (microsatellite instability [MSI] status, CpG island methylator phenotype [CIMP] status, BRAF and KRAS mutations). Summary data on tumour markers were obtained from two genetic consortia (CCFR, GECCO)., Findings: A 1-standard deviation (SD:5.1 kg/m 2 ) increment in BMI levels was found to increase risks of Jass type 1 MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype (odds ratio [OR]: 2.14, 95% confidence interval [CI]: 1.46, 3.13; p-value = 9 × 10 -5 ) and Jass type 2 non-MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype CRC (OR: 2.20, 95% CI: 1.26, 3.86; p-value = 0.005). The magnitude of these associations was stronger compared with Jass type 4 non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-wildtype CRC (p-differences: 0.03 and 0.04, respectively). A 1-SD (SD:13.4 cm) increment in waist circumference increased risk of Jass type 3 non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-mutated (OR 1.73, 95% CI: 1.34, 2.25; p-value = 9 × 10 -5 ) that was stronger compared with Jass type 4 CRC (p-difference: 0.03). A higher body fat percentage (SD:8.5%) increased risk of Jass type 1 CRC (OR: 2.59, 95% CI: 1.49, 4.48; p-value = 0.001), which was greater than Jass type 4 CRC (p-difference: 0.03)., Interpretation: Body size was more strongly linked to the serrated (Jass types 1 and 2) and alternate (Jass type 3) pathways of colorectal carcinogenesis in comparison to the traditional pathway (Jass type 4)., Funding: Cancer Research UK, National Institute for Health Research, Medical Research Council, National Institutes of Health, National Cancer Institute, American Institute for Cancer Research, Brigham and Women's Hospital, Prevent Cancer Foundation, Victorian Cancer Agency, Swedish Research Council, Swedish Cancer Society, Region Västerbotten, Knut and Alice Wallenberg Foundation, Lion's Cancer Research Foundation, Insamlingsstiftelsen, Umeå University. Full funding details are provided in acknowledgements., Competing Interests: Declaration of interests AB has received a Scholar-in-Training Award from AACR for 2023. VM has received grants from Instituto de Salud Carlos III and FC AECC. BML has received support from Uppsala University as a part of a presentation in the Svedberg Seminar Series, and she was the president of the Australasian Epidemiological Association (2020–2023). BVG has received support grant from World Cancer Research Fund for a separate project within the same research field. AET has received an editorial board fee from NIH PDQ Cancer Genetics. MG has received research funding from Janssen and Servier, consulting fees from Nerviano Medical Sciences, Chromacode, and AstraZeneca and support to attend a meeting from Dava Oncology. JN has received research funding from Natera Inc and consulting fees from Leica Biosciences. MAJ has received an NIH funding. The remaining authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Background: Research on calcium intake as well as variants in the calcium sensor receptor ( CaSR) gene and their interaction in relation to CRC survival is still limited., Methods: Data from 18,952 CRC patients, were included. Associations between primarily pre-diagnostic dietary ( n  = 13.085), supplemental ( n  = 11,837), total calcium intake ( n  = 5970) as well as 325 single nucleotide polymorphisms (SNPs) of the CaSR gene ( n  = 15,734) in relation to CRC-specific and all-cause mortality were assessed using Cox proportional hazard models. Also interactions between calcium intake and variants in the CaSR gene were assessed., Results: During a median follow-up of 4.8 years (IQR 2.4-8.4), 6801 deaths occurred, of which 4194 related to CRC. For all-cause mortality, no associations were observed for the highest compared to the lowest sex- and study-specific quartile of dietary (HR 1.00, 95%CI 0.92-1.09), supplemental (HR 0.97, 95%CI 0.89-1.06) and total calcium intake (HR 0.99, 95%CI 0.88-1.11). No associations with CRC-specific mortality were observed either. Interactions were observed between supplemental calcium intake and several SNPs of the CaSR gene., Conclusion: Calcium intake was not associated with all-cause or CRC-specific mortality in CRC patients. The association between supplemental calcium intake and all-cause and CRC-specific mortality may be modified by genetic variants in the CaSR gene., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2024.)

Background: Multimorbidity is associated with premature mortality and excess health care costs. The burden of multimorbidity is highest among patients with cancer, yet trends and determinants of multimorbidity over time are poorly understood., Methods: Via Medicare claims linked to Cancer Prevention Study II data, group-based trajectory modeling was used to compare National Cancer Institute comorbidity index score trends for cancer survivors and older adults without a cancer history. Among cancer survivors, multinomial logistic regression analyses evaluated associations between demographics, health behaviors, and comorbidity trajectories., Results: In 82,754 participants (mean age, 71.6 years [SD, 5.1 years]; 56.9% female), cancer survivors (n = 11,265) were more likely than older adults without a cancer history to experience the riskiest comorbidity trajectories: (1) steady, high comorbidity scores (remain high; odds ratio [OR], 1.36; 95% CI, 1.29-1.45), and (2) high scores that increased over time (start high and increase; OR, 1.51; 95% CI, 1.38-1.65). Cancer survivors who were physically active postdiagnosis were less likely to fall into these two trajectories (OR, 0.73; 95% CI, 0.64-0.84, remain high; OR, 0.42; 95% CI, 0.33-0.53, start high and increase) compared to inactive survivors. Cancer survivors with obesity were more likely to have a trajectory that started high and increased (OR, 2.83; 95% CI, 2.32-3.45 vs. normal weight), although being physically active offset some obesity-related risk. Cancer survivors who smoked postdiagnosis were also six times more likely to have trajectories that started high and increased (OR, 6.86; 95% CI, 4.41-10.66 vs. never smokers)., Conclusions: Older cancer survivors are more likely to have multiple comorbidities accumulated at a faster pace than older adults without a history of cancer. Weight management, physical activity, and smoking avoidance postdiagnosis may attenuate that trend., (© 2023 American Cancer Society.)

Background: The association of fitness with cancer risk is not clear., Methods: We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of lung, colorectal, endometrial, breast, and prostate cancer in a subset of UK Biobank participants who completed a submaximal fitness test in 2009-12 (N = 72,572). We also investigated relationships using two-sample Mendelian randomisation (MR), odds ratios (ORs) were estimated using the inverse-variance weighted method., Results: After a median of 11 years of follow-up, 4290 cancers of interest were diagnosed. A 3.5 ml O 2 ⋅min -1 ⋅kg -1 total-body mass increase in fitness (equivalent to 1 metabolic equivalent of task (MET), approximately 0.5 standard deviation (SD)) was associated with lower risks of endometrial (HR = 0.81, 95% CI: 0.73-0.89), colorectal (0.94, 0.90-0.99), and breast cancer (0.96, 0.92-0.99). In MR analyses, a 0.5 SD increase in genetically predicted O 2 ⋅min -1 ⋅kg -1 fat-free mass was associated with a lower risk of breast cancer (OR = 0.92, 95% CI: 0.86-0.98). After adjusting for adiposity, both the observational and genetic associations were attenuated., Discussion: Higher fitness levels may reduce risks of endometrial, colorectal, and breast cancer, though relationships with adiposity are complex and may mediate these relationships. Increasing fitness, including via changes in body composition, may be an effective strategy for cancer prevention., (© 2023. The Author(s).)

Background: Diabetes is an established risk factor for colorectal cancer. However, the mechanisms underlying this relationship still require investigation and it is not known if the association is modified by genetic variants. To address these questions, we undertook a genome-wide gene-environment interaction analysis., Methods: We used data from 3 genetic consortia (CCFR, CORECT, GECCO; 31,318 colorectal cancer cases/41,499 controls) and undertook genome-wide gene-environment interaction analyses with colorectal cancer risk, including interaction tests of genetics(G)xdiabetes (1-degree of freedom; d.f.) and joint testing of Gxdiabetes, G-colorectal cancer association (2-d.f. joint test) and G-diabetes correlation (3-d.f. joint test)., Results: Based on the joint tests, we found that the association of diabetes with colorectal cancer risk is modified by loci on chromosomes 8q24.11 (rs3802177, SLC30A8 - OR AA : 1.62, 95% CI: 1.34-1.96; OR AG : 1.41, 95% CI: 1.30-1.54; OR GG : 1.22, 95% CI: 1.13-1.31; p-value 3-d.f. : 5.46 × 10 -11 ) and 13q14.13 (rs9526201, LRCH1 - OR GG : 2.11, 95% CI: 1.56-2.83; OR GA : 1.52, 95% CI: 1.38-1.68; OR AA : 1.13, 95% CI: 1.06-1.21; p-value 2-d.f. : 7.84 × 10 -09 )., Discussion: These results suggest that variation in genes related to insulin signaling (SLC30A8) and immune function (LRCH1) may modify the association of diabetes with colorectal cancer risk and provide novel insights into the biology underlying the diabetes and colorectal cancer relationship., (© 2023. The Author(s).)

Background & Aims: Incidence rates of liver cancer in most populations are two to three times higher among men than women. The higher rates among men have led to the suggestion that androgens are related to increased risk whereas oestrogens are related to decreased risk. This hypothesis was investigated in the present study via a nested case-control analysis of pre-diagnostic sex steroid hormone levels among men in five US cohorts., Methods: Concentrations of sex steroid hormones and sex hormone-binding globulin were quantitated using gas chromatography-mass spectrometry and a competitive electrochemiluminescence immunoassay, respectively. Multivariable conditional logistic regression was used to calculate odds ratios (ORs) and 95% CIs for associations between hormones and liver cancer among 275 men who subsequently developed liver cancer and 768 comparison men., Results: Higher concentrations of total testosterone (OR per one-unit increase in log 2  = 1.77, 95% CI = 1.38-2.29), dihydrotestosterone (OR = 1.76, 95% CI = 1.21-2.57), oestrone (OR = 1.74, 95% CI = 1.08-2.79), total oestradiol (OR = 1.58, 95% CI=1.22-20.05), and sex hormone-binding globulin (OR = 1.63, 95% CI = 1.27-2.11) were associated with increased risk. Higher concentrations of dehydroepiandrosterone (DHEA), however, were associated with a 53% decreased risk (OR = 0.47, 95% CI = 0.33-0.68)., Conclusions: Higher concentrations of both androgens (testosterone, dihydrotestosterone) and their aromatised oestrogenic metabolites (oestrone, oestradiol) were observed among men who subsequently developed liver cancer compared with men who did not. As DHEA is an adrenal precursor of both androgens and oestrogens, these results may suggest that a lower capacity to convert DHEA to androgens, and their subsequent conversion to oestrogens, confers a lower risk of liver cancer, whereas a greater capacity to convert DHEA confers a greater risk., Impact and Implications: This study does not fully support the current hormone hypothesis as both androgen and oestrogen levels were associated with increased risk of liver cancer among men. The study also found that higher DHEA levels were associated with lower risk, thus suggesting the hypothesis that greater capacity to convert DHEA could be associated with increased liver cancer risk among men., Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details.

Background: Obesity is an established risk factor for colorectal cancer (CRC), but the evidence for the association is inconsistent across molecular subtypes of the disease., Methods: We pooled data on body mass index (BMI), tumor microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, and Jass classification types for 11 872 CRC cases and 11 013 controls from 11 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for covariables., Results: Higher BMI was associated with increased CRC risk (OR per 5 kg/m2 = 1.18, 95% CI = 1.15 to 1.22). The positive association was stronger for men than women but similar across tumor subtypes defined by individual molecular markers. In analyses by Jass type, higher BMI was associated with elevated CRC risk for types 1-4 cases but not for type 5 CRC cases (considered familial-like/Lynch syndrome microsatellite instability-H, CpG island methylator phenotype-low or negative, BRAF-wild type, KRAS-wild type, OR = 1.04, 95% CI = 0.90 to 1.20). This pattern of associations for BMI and Jass types was consistent by sex and design of contributing studies (cohort or case-control)., Conclusions: In contrast to previous reports with fewer study participants, we found limited evidence of heterogeneity for the association between BMI and CRC risk according to molecular subtype, suggesting that obesity influences nearly all major pathways involved in colorectal carcinogenesis. The null association observed for the Jass type 5 suggests that BMI is not a risk factor for the development of CRC for individuals with Lynch syndrome., (© The Author(s) 2022. Published by Oxford University Press.)

Cancer is a heterogeneous disease, and rapid progress in sequencing and -omics technologies has enabled researchers to characterize tumors comprehensively. This has stimulated an intensive interest in studying how risk factors are associated with various tumor heterogeneous features. The Cancer Prevention Study-II (CPS-II) cohort is one of the largest prospective studies, particularly valuable for elucidating associations between cancer and risk factors. In this paper, we investigate the association of smoking with novel colorectal tumor markers obtained from targeted sequencing. However, due to cost and logistic difficulties, only a limited number of tumors can be assayed, which limits our capability for studying these associations. Meanwhile, there are extensive studies for assessing the association of smoking with overall cancer risk and established colorectal tumor markers. Importantly, such summary information is readily available from the literature. By linking this summary information to parameters of interest with proper constraints, we develop a generalized integration approach for polytomous logistic regression model with outcome characterized by tumor features. The proposed approach gains the efficiency through maximizing the joint likelihood of individual-level tumor data and external summary information under the constraints that narrow the parameter searching space. We apply the proposed method to the CPS-II data and identify the association of smoking with colorectal cancer risk differing by the mutational status of APC and RNF43 genes, neither of which is identified by the conventional analysis of CPS-II individual data only. These results help better understand the role of smoking in the etiology of colorectal cancer.

Importance: The number of cancer survivors living in the US is projected to be 26.1 million by 2040. Cancer survivors may be at increased risk of bone fractures, but research is limited in several important ways., Objective: To investigate the associations of cancer diagnoses, including time since diagnosis and stage at diagnosis, with risks of pelvic, radial, and vertebral fractures (separately and combined) among older cancer survivors and compared with fracture risk among older adults without a history of cancer. Secondarily, to examine differences in risk of fracture stratified by modifiable behaviors, treatment, and cancer type., Design, Setting, and Participants: This longitudinal cohort study used data from 92 431 older adults in the US Cancer Prevention Study II Nutrition Cohort linked with 1999 to 2017 Medicare claims. Data were analyzed from July 15, 2021, to May 3, 2022., Exposures: Cancer history, time since cancer diagnosis, and stage at cancer diagnosis., Main Outcomes and Measures: Hazard ratios (HRs) and 95% CIs for the risk of pelvic, radial, vertebral, and total frailty-related fractures were estimated using multivariate Cox proportional hazards regression. Stratification was used for secondary aims., Results: Among 92 431 participants (mean [SD] age, was 69.4 [6.0] years, 51 820 [56%] women, and 90 458 [97.9%] White], 12 943 participants experienced a frailty-related bone fracture. Compared with participants without a history of cancer, cancer survivors who were diagnosed 1 to less than 5 years earlier with advanced stage cancer had higher risk of fracture (HR, 2.12; 95% CI, 1.75-2.58). The higher fracture risk in cancer survivors with recent advanced stage diagnosis (vs no cancer) was driven largely by vertebral (HR, 2.46; 95% CI, 1.93-3.13) and pelvic (HR, 2.46; 95% CI, 1.84-3.29) fracture sites. Compared with cancer survivors who did not receive chemotherapy, survivors who received chemotherapy were more likely to have a fracture; this association was stronger within 5 years of diagnosis (HR, 1.31; 95% CI, 1.09-1.57) than 5 or more years after diagnosis (HR, 1.22; 95% CI, 0.99-1.51). Although the HR for risk of fracture was lower among physically active cancer survivors 5 or more years after diagnosis (HR, 0.76; 95% CI, 0.54-1.07), this result was not statistically significant, whereas current smoking was significantly associated with higher risk of fracture (HR, 2.27; 95% CI, 1.55-3.33)., Conclusions and Relevance: Findings from this cohort study suggest that older adults with a history of cancer may benefit from clinical guidance on prevention of frailty-related fractures. If study findings are replicated, fracture prevention programs for survivors might include referrals for physical activity with cancer exercise professionals and smoking cessation programs.

Diabetes is an established risk factor for colorectal cancer. However, colorectal cancer is a heterogeneous disease and it is not well understood whether diabetes is more strongly associated with some tumor molecular subtypes than others. A better understanding of the association between diabetes and colorectal cancer according to molecular subtypes could provide important insights into the biology of this association. We used data on lifestyle and clinical characteristics from the Colorectal Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), including 9756 colorectal cancer cases (with tumor marker data) and 9985 controls, to evaluate associations between reported diabetes and risk of colorectal cancer according to molecular subtypes. Tumor markers included BRAF and KRAS mutations, microsatellite instability and CpG island methylator phenotype. In the multinomial logistic regression model, comparing colorectal cancer cases to cancer-free controls, diabetes was positively associated with colorectal cancer regardless of subtype. The highest OR estimate was found for BRAF-mutated colorectal cancer, n = 1086 (OR fully adj : 1.67, 95% confidence intervals [CI]: 1.36-2.05), with an attenuated association observed between diabetes and colorectal cancer without BRAF-mutations, n = 7959 (OR fully adj : 1.33, 95% CI: 1.19-1.48). In the case only analysis, BRAF-mutation was differentially associated with diabetes (P difference  = .03). For the other markers, associations with diabetes were similar across tumor subtypes. In conclusion, our study confirms the established association between diabetes and colorectal cancer risk, and suggests that it particularly increases the risk of BRAF-mutated tumors., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Colorectal cancer survivors often use multivitamins and other over-the-counter dietary supplements, but evidence is limited regarding their potential associations with mortality., Methods: This prospective analysis included women and men from the Cancer Prevention Study-II Nutrition Cohort who were cancer-free at baseline (1992 or 1993) and diagnosed with colorectal cancer through June 2015. Detailed information on multivitamin use, vitamin C supplements, and vitamin E supplements was self-reported on questionnaires at baseline, in 1997, and every 2 years thereafter. Pre- and postdiagnosis data were available for 3176 and 2006 colorectal cancer survivors, respectively, among whom 2116 (648 from colorectal cancer) and 1256 (242 from colorectal cancer) died. Multivariable-adjusted Cox proportional hazards regression models examined associations. All statistical tests were 2-sided., Results: Among colorectal cancer survivors, 49.7% and 58.5% reported multivitamin use before and after diagnosis, respectively (vitamin C use before and after diagnosis: 27.8% and 28.1%; vitamin E use before and after diagnosis: 27.5% and 29.4%, respectively). There were no statistically significant associations of pre- or postdiagnosis multivitamin use with all-cause, colorectal cancer-specific, or noncolorectal cancer mortality. Vitamin C was also not associated with any mortality outcomes. However, prediagnosis vitamin E use was associated with a non-statistically significant increased risk of all-cause mortality (multivariable adjusted hazard ratio = 1.08, 95% confidence intervals = 0.96 to 1.23) and all other noncolorectal cancer mortality (multivariable adjusted hazard ratio = 1.13, 95% confidence intervals = 0.97 to 1.31)., Conclusions: These results suggest that multivitamin use before or after diagnosis is not associated with mortality in colorectal cancer survivors. However, vitamin E use may be associated with increased risk of mortality and merits further investigation., (© The Author(s) 2022. Published by Oxford University Press.)

Self-reported type 2 diabetes mellitus (T2DM) is a risk factor for many cancers, suggesting its pathology relates to carcinogenesis. We conducted a case-cohort study to examine associations of hemoglobin A 1c (HbA 1c ) and c-peptide with cancers associated with self-reported T2DM. This study was drawn from a prospective cohort of 32,383 women and men who provided blood specimens at baseline: c-peptide and HbA 1c were assessed in 3,000 randomly selected participants who were cancer-free-at-baseline and an additional 2,281 participants who were cancer-free-at-baseline and subsequently diagnosed with incident colorectal, liver, pancreatic, female breast, endometrial, ovarian, bladder, or kidney cancers. Weighted-Cox regression models estimated hazards ratios (HRs) and 95% confidence intervals (CI), adjusted for covariates. C-peptide was associated with higher risk of liver cancer (per standard deviation (SD) HR: 1.80; 95%CI: 1.32-2.46). HbA 1c was associated with higher risk of pancreatic cancer (per SD HR: 1.21 95%CI 1.05-1.40) and with some suggestion of higher risks for all-cancers-of-interest (per SD HR: 1.05; 95%CI: 0.99-1.11) and colorectal (per SD HR: 1.09; 95%CI: 0.98-1.20), ovarian (per SD HR: 1.18; 95%CI 0.96-1.45) and bladder (per SD HR: 1.08; 95%CI 0.96-1.21) cancers. Compared to no self-reported T2DM and HbA 1c <6.5% (reference group), self-reported T2DM and HbA 1c <6.5% (i.e., T2DM in good glycemic control) was not associated with risk of colorectal cancer, whereas it was associated with higher risks of all-cancers-of-interest combined (HR: 1.28; 95%CI: 1.01-1.62), especially for breast and endometrial cancers. Additional large, prospective studies are needed to further explore the roles of hyperglycemia, hyperinsulinemia, and related metabolic traits with T2DM-associated cancers to better understand the mechanisms underlying the self-reported T2DM-cancer association and to identify persons at higher cancer risk., Competing Interests: Conflict of interest statement The authors declare that they have no conflicts of interest. The authors declare no potential conflicts of interest.

Background: Few prospective studies have examined biomarkers of glucose homeostasis or inflammation with prostate cancer risk by tumor stage or grade., Methods: We conducted a case-cohort study to examine associations of prediagnosis hemoglobin A1c (HbA1c), C-peptide, and C-reactive protein (CRP) with prostate cancer risk overall and stratified by tumor stage and grade. The study included 390 nonaggressive (T1-2, N0, M0, and Gleason score <8) and 313 aggressive cases (T3-4, or N1, or M1, or Gleason score 8-10) diagnosed after blood draw (1998-2001) and up to 2013, and a random subcohort of 1,303 cancer-free men at blood draw in the Cancer Prevention Study-II Nutrition Cohort. Prentice-weighted Cox proportional hazards regression models were used to estimate HRs and 95% confidence intervals (CI)., Results: In the multivariable-adjusted model without body mass index, HbA1c was inversely associated with nonaggressive prostate cancer (HR per unit increase, 0.89; 95% CI, 0.80-1.00; P = 0.04). Analyses stratified by tumor stage and grade separately showed that HbA1c was inversely associated with low-grade prostate cancer (HR per unit increase, 0.89; 95% CI, 0.80-1.00) and positively associated with high-grade prostate cancer (HR per unit increase, 1.15; 95% CI, 1.01-1.30). C-peptide and CRP were not associated with prostate cancer overall or by stage or grade., Conclusions: The current study suggests that associations of hyperglycemia with prostate cancer may differ by tumor grade and stage., Impact: Future studies need to examine prostate cancer by tumor stage and grade, and to better understand the role of hyperglycemia in prostate cancer progression., (©2022 American Association for Cancer Research.)

Objectives: Assess differences in movement behaviours within the 24-hour cycle, including light intensity physical activity (LPA), moderate-to-vigorous physical activity (MVPA), sedentary time and sleep, before and during the COVID-19 pandemic and assess these differences stratified by several relevant factors in a subcohort of the Cancer Prevention Study-3., Design and Setting: US-based longitudinal cohort study (2018-August 2020)., Participants: N=1992 participants, of which 1304 (65.5%) are women, and 1512 (75.9%) are non-Latino white, with a mean age 57.0 (9.8) years., Measures: Age, sex, race/ethnicity, education; self-reported LPA, MVPA, sedentary time and sleep duration collected before and during the pandemic; pandemic-related changes in work, childcare and living arrangement; COVID-19 health history., Results: Compared to 2018, participants spent an additional 104 min/day sedentary, 61 fewer min/day in LPA and 43 fewer min/day in MVPA during the pandemic. Time spent sleeping was similar at the two time points. Differences in movement behaviours were more pronounced among men, those with a higher level of education, and those who were more active before the pandemic., Conclusions: From 2018 to Summer 2020, during the COVID-19 pandemic, US adults have made significant shifts in daily time spent in LPA, MVPA and sedentary. There is an urgent need to promote more physical activity and less sedentary time during this public health crisis to avoid sustaining these patterns long-term., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Numerous studies have documented mental health challenges during the COVID-19 pandemic. Few studies included pre-pandemic levels of mental health or were comprehensive in assessing factors likely associated with longer-term mental health impacts., Methods: Analyses used prospective data from a subset of participants in the nationwide Cancer Prevention Study-3 (CPS-3) United States cohort (N=2,359; 1,534 women; 825 men) who completed surveys in 2018 and during the COVID-19 pandemic (July-September 2020). Logistic regressions examined associations of pandemic-related stressors, sociodemographic and other predictors with (i) overall psychological distress (PD) and depression and anxiety separately during the COVID-19 pandemic and (ii) change in PD from 2018 to during the pandemic (low/low; high to low; low to high; high/high)., Findings: During the pandemic, 10% of participants reported moderate-to-severe PD and almost half (42%) reported at least mild PD. Pandemic PD levels were associated with pre-pandemic PD (female OR=5.65; male OR=9.70), financial stressors (female OR=2.48; male OR=3.68), and work/life balance stressors (female OR=3.03; male OR=3.33) experienced since the pandemic began. These stressors also predicted an escalation from low PD in 2018 to high PD during the pandemic. Factors associated with high PD at both time points included younger age, female sex, and financial stressors., Interpretation: These results highlight the importance of regular mental health assessment and support among those with a history of mental health problems and those experiencing pandemic-related stressors, such as those with caregiving responsibilities or job changes., Funding: The American Cancer Society funds the creation, maintenance, and updating of the CPS-3., Competing Interests: The authors declare that they have no conflict of interest., (© 2021 The Authors. Published by Elsevier Ltd.)

Background: Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis., Objectives: The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC., Methods: We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (±20 kb) for a total of 412 SNPs., Results: The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association., Conclusions: Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association., (Published by Oxford University Press on behalf of the American Society for Nutrition 2021.)

Background: Cannabis use is increasing, including among smokers, an at-risk population for cancer. Research is equivocal on whether using cannabis inhibits quitting cigarettes. The current longitudinal study investigated associations between smoking cannabis and subsequently quitting cigarettes., Methods: Participants were 4,535 adult cigarette smokers from a cohort enrolled in the American Cancer Society's Cancer Prevention Study-3 in 2009-2013. Cigarette quitting was assessed on a follow-up survey in 2015-2017, an average of 3.1 years later. Rates of quitting cigarettes at follow-up were examined by retrospectively assessed baseline cannabis smoking status ( never, former, recent ), and by frequency of cannabis smoking among recent cannabis smokers ( low : ≤3 days/month; medium : 4-19 days/month; high : ≥20 days/month). Logistic regression models adjusted for sociodemographic factors, smoking- and health-related behaviors, and time between baseline and follow-up., Results: Adjusted cigarette quitting rates at follow-up did not differ significantly by baseline cannabis smoking status [never 36.2%, 95% confidence interval (CI), 34.5-37.8; former 34.1%, CI, 31.4-37.0; recent 33.6%, CI, 30.1-37.3], nor by frequency of cannabis smoking (low 31.4%, CI, 25.6-37.3; moderate 36.7%, CI, 30.7-42.3; high 34.4%, CI, 28.3-40.2) among recent baseline cannabis smokers. In cross-sectional analyses conducted at follow-up, the proportion of cigarette smokers intending to quit smoking cigarettes in the next 30 days did not differ by cannabis smoking status ( P = 0.83)., Conclusions: Results do not support the hypothesis that cannabis smoking inhibits quitting cigarette smoking among adults., Impact: Future longitudinal research should include follow-ups of >1 year, and assess effects of intensity/frequency of cannabis use and motivation to quit on smoking cessation., (©2021 The Authors; Published by the American Association for Cancer Research.)

Problem: The COVID-19 pandemic is associated with psychological distress. Decreased moderate-vigorous physical activity (MVPA) and increased sedentary time may be exacerbating pandemic-related symptoms of anxiety and depression, but existing studies exploring these associations are almost entirely cross-sectional., Methods: Reported data from 2018 and Summer 2020 were used to create change categories based on compliance with MVPA guidelines and relative sedentary time. Participants completed the Patient Health Questionnaire-4 (PHQ-4) in Summer 2020. Associations among changes in MVPA and sedentary time (separately and jointly) with psychological distress (total PHQ-4 score) were examined with ordinal logistic regression and associations with depressive or anxiety symptoms were examined with logistic regression., Results: Among 2,240 participants (65% women, mean age 57.5 years), 67% increased sedentary time and 21% became inactive between the two time points. After multivariate adjustment, participants who became (OR = 1.71, 95% CI: 1.05-2.78) or remained inactive (OR = 2.07, 1.34-3.22) were more likely to experience depressive symptoms compared to those who remained active. Participants who increased sedentary time were also more likely to experience depressive symptoms compared to those who maintained sedentary time (OR = 1.78, 1.13-2.81). Jointly, those who increased sedentary time while remaining (OR = 3.67, 1.83-7.38) or becoming inactive (OR = 3.02, 1.44-6.34) were much more likely to have depressive symptoms compared to the joint referent (remained active/maintained sedentary time). Associations with anxiety symptoms were not statistically significant., Conclusions: These findings support the value of promoting MVPA and limiting sedentary time during stressful events associated with psychological distress, like the COVID-19 pandemic., Competing Interests: None, (© 2021 Elsevier Ltd. All rights reserved.)

Background: Aspirin use reduces colorectal cancer (CRC) incidence, but there is limited evidence regarding associations of aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) with CRC-specific survival., Methods: This prospective analysis includes women and men from the Cancer Prevention Study-II Nutrition Cohort who were cancer free at baseline (1992 or 1993) and diagnosed with CRC during incidence follow-up through 2015. Detailed information on aspirin and non-aspirin NSAID use was self-reported on questionnaires at baseline, in 1997, and every 2 years thereafter. Pre- and postdiagnosis data were available for 2686 and 1931 participants without distant metastases, respectively, among whom 512 and 251 died from CRC during mortality follow-up through 2016. Secondary analyses examined associations between prediagnosis aspirin use and stage at diagnosis (distant metastatic vs localized or regional). All statistical tests were 2-sided., Results: Long-term regular use of aspirin (>15 times per month) before diagnosis was associated with lower CRC-specific mortality (multivariable-adjusted hazard ratio [HR] = 0.69, 95% confidence interval [CI] = 0.52 to 0.92). Postdiagnosis regular aspirin use was not statistically significantly associated with risk of CRC-specific mortality overall (HR = 0.82, 95% CI = 0.62 to 1.09), although participants who began regular aspirin use only after their diagnosis were at lower risk than participants who did not use aspirin at both the pre- and postdiagnosis periods (HR = 0.60, 95% CI = 0.36 to 0.98). Long-term aspirin use before diagnosis was also associated with lower odds of diagnosis with distant metastases (multivariable-adjusted odds ratio = 0.73, 95% CI = 0.53 to 0.99)., Conclusions: Our results suggest that long-term aspirin use before a diagnosis of nonmetastatic colorectal cancer may be associated with lower CRC-specific mortality after diagnosis, consistent with possible inhibition of micrometastases before diagnosis., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Some evidence suggests the association between body mass index (BMI) and pancreatic cancer risk is weaker among current smokers than among never smokers., Methods: We examined the association between BMI and pancreatic cancer mortality among adults who reported smoking status at enrollment into Cancer Prevention Study-II in 1982, including 420,543 never smokers, 282,244 former cigarette smokers, and 219,885 current cigarette smokers. After excluding the first 3 years of follow-up to reduce reverse causation, we calculated multivariable-adjusted hazard ratios (HR)., Results: During the full follow-up period from 1985 to 2014, 7,904 participants died of pancreatic cancer. The HR per 5 BMI units was lower among current smokers [HR = 1.14; 95% confidence interval (CI), 1.07-1.20] than never smokers (HR = 1.22; 95% CI, 1.17-1.27), although this difference was not statistically significant ( P = 0.06). BMI was significantly less strongly associated with pancreatic cancer mortality among current smokers reporting ≥20 cigarettes/day (HR = 1.10; 95% CI, 1.03-1.18) than among never smokers. During follow-up within 10 years of enrollment, when current smokers at enrollment were the most likely to have still been smoking, BMI was not associated with pancreatic cancer mortality among current smokers (HR = 1.02; 95% CI, 0.90-1.16, P = 0.03 for difference between current and never smokers). BMI HRs were similar among former and never smokers., Conclusions: These results support a weaker association between BMI and pancreatic cancer among current smokers than among never smokers., Impact: In populations with low smoking prevalence, the pancreatic cancer burden due to BMI is likely to be higher than that predicted by risk estimates from studies including substantial numbers of smokers., (©2020 American Association for Cancer Research.)

Obesity is known to be associated with primary liver cancer (PLC), but the separate effects of excess abdominal and gluteofemoral size are unclear. Thus, we examined the association between waist and hip circumference with risk of PLC overall and by histologic type-hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). The Liver Cancer Pooling Project is a consortium of prospective cohort studies that include data from 1,167,244 individuals (PLC n = 2,208, HCC n = 1,154, ICC n = 335). Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Waist circumference, per 5 cm increase, was associated with an 11% increased PLC risk (HR = 1.11, 95%CI: 1.09-1.14), including when adjusted for hip circumference (HR = 1.12, 95%CI: 1.08-1.17) and also when restricted to individuals in a normal body mass index (BMI) range (18.5 to <25 kg/m 2 ; HR = 1.14, 95%CI: 1.07-1.21). Hip circumference, per 5 cm increase, was associated with a 9% increased PLC risk (HR = 1.09, 95%CI: 1.06-1.12), but no association remained after adjustment for waist circumference (HR = 0.99, 95%CI: 0.94-1.03). HCC and ICC results were similar. These findings suggest that excess abdominal size is associated with an increased risk of liver cancer, even among individuals considered to have a normal BMI. However, excess gluteofemoral size alone confers no increased risk. Our findings extend prior analyses, which found an association between excess adiposity and risk of liver cancer, by disentangling the separate effects of excess abdominal and gluteofemoral size through utilization of both waist and hip circumference measurements., (© 2019 UICC.)

Higher body mass index (BMI; weight (kg)/height (m)2) is associated with increased risk of pancreatic cancer in epidemiologic studies. However, BMI has usually been assessed at older ages, potentially underestimating the full impact of excess weight. We examined the association between BMI and pancreatic cancer mortality among 963,317 adults who were aged 30-89 years at their enrollment in Cancer Prevention Study II in 1982. During follow-up through 2014, a total of 8,354 participants died of pancreatic cancer. Hazard ratios per 5 BMI units, calculated using proportional hazards regression, declined steadily with age at BMI assessment, from 1.25 (95% confidence interval: 1.18, 1.33) in persons aged 30-49 years at enrollment to 1.13 (95% confidence interval: 1.02, 1.26) in those aged 70-89 years at enrollment (P for trend = 0.005). On the basis of a hazard ratio of 1.25 per 5 BMI units at age 45 years, we estimated that 28% of US pancreatic cancer deaths among persons born in 1970-1974 will be attributable to BMI ≥25.0-nearly twice the equivalent proportion of those born in the 1930s, a birth cohort with much lower BMI in middle age. These results suggest that BMI before age 50 years is more strongly associated with pancreatic cancer risk than BMI at older ages, and they underscore the importance of avoiding excess weight gain before middle age for preventing this highly fatal cancer., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol-CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from 5 case-control and 11 nested case-control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study-specific results were pooled using fixed-effects meta-analysis. Compared to non-/occasional drinking (≤1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (odds ratio [OR]: 0.92, 95% confidence interval [CI]: 0.88-0.98, p = 0.005), heavy drinking (2-3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99-1.24, p = 0.08) and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11-1.40, p < 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J-shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA.)

Objective: Cross-sectional data indicate that systemic inflammation is important in oesophageal adenocarcinoma. We conducted a prospective study to assess whether prediagnostic circulating markers of inflammation were associated with oesophageal adenocarcinoma and to what extent they mediated associations of obesity and cigarette smoking with cancer risk., Design: This nested case-control study included 296 oesophageal adenocarcinoma cases and 296 incidence density matched controls from seven prospective cohort studies. We quantitated 69 circulating inflammation markers using Luminex-based multiplex assays. Conditional logistic regression models estimated associations between inflammation markers and oesophageal adenocarcinoma, as well as direct and indirect effects of obesity and smoking on risk of malignancy., Results: Soluble tumour necrosis factor receptor 2 (sTNFR2) (ORs quartile 4 vs 1 =2.67, 95% CI 1.52 to 4.68) was significantly associated with oesophageal adenocarcinoma. Additional markers close to the adjusted significance threshold included C reactive protein, serum amyloid A, lipocalin-2, resistin, interleukin (IL) 3, IL17A, soluble IL-6 receptor and soluble vascular endothelial growth factor receptor 3. Adjustment for body mass index, waist circumference or smoking status slightly attenuated biomarker-cancer associations. Mediation analysis indicated that sTNFR2 may account for 33% (p=0.005) of the effect of waist circumference on oesophageal adenocarcinoma risk. Resistin, plasminogen activator inhibitor 1, C reactive protein and serum amyloid A were also identified as potential mediators of obesity-oesophageal adenocarcinoma associations. For smoking status, only plasminogen activator inhibitor 1 was a nominally statistically significant (p<0.05) mediator of cancer risk., Conclusion: This prospective study provides evidence of a link between systemic inflammation and oesophageal adenocarcinoma risk. In addition, this study provides the first evidence that indirect effects of excess adiposity and cigarette smoking, via systemic inflammation, increase the risk of oesophageal adenocarcinoma., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Obesity and diabetes are associated with an increased liver cancer risk. However, most studies have examined all primary liver cancers or hepatocellular carcinoma, with few studies evaluating intrahepatic cholangiocarcinoma (ICC), the second most common type of liver cancer. Thus, we examined the association between obesity and diabetes and ICC risk in a pooled analysis and conducted a systematic review/meta-analysis of the literature., Design: For the pooled analysis, we utilized the Liver Cancer Pooling Project, a consortium of 13 US-based, prospective cohort studies with data from 1,541,143 individuals (ICC cases n = 414). In our systematic review, we identified 14 additional studies. We then conducted a meta-analysis, combining the results from LCPP with results from the 5 prospective studies identified through September 2017., Results: In the LCPP, obesity and diabetes were associated with a 62% [Hazard Ratio (HR) = 1.62, 95% Confidence Interval (CI): 1.24-2.12] and an 81% (HR = 1.81, 95% CI: 1.33-2.46) increased ICC risk, respectively. In the meta-analysis of prospectively ascertained cohorts and nested case-control studies, obesity was associated with a 49% increased ICC risk [Relative Risk (RR) = 1.49, 95% CI: 1.32-1.70; n = 4 studies; I 2  = 0%]. Diabetes was associated with a 53% increased ICC risk (RR = 1.53, 95% CI: 1.31-1.78; n = 6 studies). While we noted heterogeneity between studies (I 2  = 67%) for diabetes, results were consistent in subgroup analyses. Results from hospital-based case-control studies (n = 9) were mostly consistent, but these studies are potentially subject to reverse causation., Conclusions: These findings suggest that obesity and diabetes are associated with increased ICC risk, highlighting similar etiologies of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. However, additional prospective studies are needed to verify these associations.

Purpose: Many cohort studies in the United States link with the National Death Index to detect deaths. Although linkage with National Death Index is relatively sensitive, some participant deaths will be missed. These participants continue to contribute person-time to the data set after their death, resulting in bias, which we refer to as ghost-time bias. We sought to evaluate the influence of ghost-time bias on mortality relative risk (RR) estimates., Methods: Simulations were performed to determine the magnitude of ghost-time bias under a variety of plausible conditions., Results: Our simulations demonstrate that ghost-time bias can be substantial, particularly among the elderly, where it can reverse the direction of the RR. For example, we conducted a simulation of a cohort of men beginning follow-up at age of 70 years, assuming 5% missed deaths and a true RR of 2.0. In this simulation, observed RRs were 1.89 during the year the cohort was aged 85 years, 1.60 during the year the cohort was aged 90 years, and 0.61 during the year the cohort was aged 95 years. We also provide results from actual cohort data that are consistent with ghost-time bias., Conclusions: Ghost-time bias may meaningfully affect mortality RR estimates under conditions that can plausibly occur in aging cohorts., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Prior studies of prostate cancer survivors suggest that smoking might be associated with higher prostate cancer-specific mortality (PCSM) after diagnosis with prostate cancer. However, most of these studies were small, and questions remain regarding this association's strength and whether it persists after adjustment for stage and Gleason score. Methods: This analysis included men diagnosed with nonmetastatic prostate cancer between enrollment in the Cancer Prevention Study II Nutrition Cohort in 1992-1993 and June 2013. Cigarette smoking was self-reported at enrollment and updated in 1997 and every 2 years thereafter. Analyses of pre-diagnosis and post-diagnosis smoking included 9,781 and 9,111 prostate cancer cases, respectively, with vital status follow-up through 2014. Results: There were 672 deaths from prostate cancer in analyses of pre-diagnosis smoking and 554 in analyses of post-diagnosis smoking. In multivariable-adjusted Cox proportional hazards regression models including stage and Gleason score, both current smoking before diagnosis [HR = 1.50; 95% confidence interval (CI), 1.06-2.13] and current smoking after diagnosis (HR = 1.71; 95% CI, 1.09-2.67) were associated with higher PCSM compared to never smoking. Prostate cancer survivors who quit smoking <20 years before diagnosis were also at significantly higher risk of PCSM (HR = 1.29; 95% CI, 1.04-1.61). Conclusions: This large prospective study suggests that current smoking both before and after diagnosis of prostate cancer is associated with higher PCSM, even after accounting for stage and Gleason score. Impact: Our results provide evidence that smoking is a relevant prognostic factor for prostate cancer patients and that prostate cancer may be among the causes of death attributable to smoking. Cancer Epidemiol Biomarkers Prev; 27(6); 665-72. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Purpose: Use of glucosamine supplements has been associated with reduced risk of colorectal cancer (CRC) in previous studies; however, information on this association remains limited., Methods: We examined the association between glucosamine use and CRC risk among 113,067 men and women in the Cancer Prevention Study II Nutrition Cohort. Glucosamine use was first reported in 2001 and updated every 2 years thereafter. Participants were followed from 2001 through June of 2011, during which time 1440 cases of CRC occurred., Results: As has been observed in prior studies, current use of glucosamine, modeled using a time-varying exposure, was associated with lower risk of CRC (HR 0.83; 95% CI 0.71-0.97) compared to never use. However, for reasons that are unclear, this reduction in risk was observed for shorter-duration use (HR 0.68; 95% CI 0.52-0.87 for current users with ≤ 2 years use) rather than longer-duration use (HR 0.90; 95% CI 0.72-1.13 for current users with 3 to < 6 years of use; HR 0.99; 95% CI 0.76-1.29 for current users with ≥ 6 years of use)., Conclusions: Further research is needed to better understand the association between glucosamine use and risk of CRC, and how this association may vary by duration of use.

All states in the United States now have a well-established cancer registry. Linkage with these registries may be a cost-effective method of follow-up for cancer incidence in multistate cohort studies. However, the sensitivity of linkage with the current network of state registries for detecting incident cancer diagnoses within cohort studies is not well-documented. We examined the sensitivity of registry linkage among 39,368 men and women from 23 states who enrolled in the Cancer Prevention Study-3 cohort during 2006-2009 and had the opportunity to self-report cancer diagnoses on a questionnaire in 2011. All participants provided name and birthdate, and 94% provided a complete social security number. Of 378 cancer diagnoses between enrollment and 2010 identified through self-report and verified with medical records, 338 were also detected by linkage with the 23 state cancer registries (sensitivity of 89%, 95% confidence interval (CI): 86, 92). Sensitivity was lower for hematologic cancers (69%, 95% CI: 41, 89) and melanoma (70%, 95% CI: 57, 81). After excluding hematologic cancers and melanoma, sensitivity was 94% (95% CI: 91, 97). Our results indicate that linkage with multiple cancer registries can be a sensitive method for ascertaining incident cancers, other than hematologic cancers and melanoma, in multistate cohort studies., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)