Incident Colorectal Cancer Cases Research Articles

Smoking and colorectal cancer survival in relation to tumor LINE-1 methylation levels: a prospective cohort study

BackgroundCarcinogens in cigarette smoke may cause aberrant epigenomic changes. The hypomethylation of long interspersed nucleotide element-1 (LINE-1) in colorectal carcinoma has been associated with genomic instability and worse clinical outcome. We hypothesized that the association between smoking behavior and colorectal cancer mortality might be stronger in tumors with lower LINE-1 methylation levels.FindingsTo test our hypothesis, we examined the interaction of tumor LINE-1 methylation levels and smoking status at diagnosis using data of 1208 cases among 4420 incident colorectal cancer cases that were ascertained in two prospective cohort studies. We conducted multivariable Cox proportional hazards regression analyses, using inverse probability weighting with covariate data of the 4420 cases to control for potential confounders and selection bias due to data availability. The prognostic association of smoking status at diagnosis differed by tumor LINE-1 methylation levels (Pinteraction = 0.050 for overall mortality and 0.017 for colorectal cancer-specific mortality; with an alpha level of 0.005). In cases with <60% LINE-1 methylation, current smoking (vs. never smoking) was associated with worse overall mortality (multivariable hazard ratio, 1.80; 95% confidence interval, 1.19–2.73). In contrast, smoking status was not associated with mortality in cases with ≥60% LINE-1 methylation.ConclusionsOur findings suggest that the association between smoking status and mortality is stronger in colorectal cancer patients with lower tumor LINE-1 methylation levels. These results warrant further investigation into an interactive role of smoking and aberrant DNA methylation in colorectal cancer progression.

Abstract 725: Biomarkers of circulating vitamin D status and expression of tumor molecular markers Ki67, p53, and COX2 among colorectal cancer cases in the Southern Community Cohort Study

Abstract Introduction: Epidemiologic studies and controlled trials provide evidence that higher 25-hydroxyvitaminD is associated with improved survival in colorectal cancer (CRC), although there are limited data in African Americans (AAs), who are at greater risk for CRC mortality and vitamin D deficiency. Herein, we report associations between vitamin D serum biomarkers collected at cohort entry up to 15 years prior to CRC onset and CRC tumor subtypes defined by high expression of tumor markers (Ki67, p53, and COX2) that represent cellular processes (proliferation, apoptosis, and inflammation) affected by vitamin D. Importantly, higher expression of these markers reflects greater risk for metastasis and CRC-specific mortality. Methods: Data arise from the Southern Community Cohort Study, a cohort from the southeastern United States where the majority of participants are AA. Incident CRC cases with tumor sample were analyzed (n=104). Expression of cellular Ki67, p53, and COX2 (% positivity) were measured and categorized by literature-defined high vs. low cut-points (20%, 10%, and 20%, respectively). Logistic models adjusted for age, race, and sex were used to measure associations between vitamin D biomarkers: 25-hydroxyvitaminD, vitamin D binding protein (VDBP), and calculated free 25-hydroxyvitaminD (vitamin D not bound by VDBP) and the odds of a more aggressive tumor subtype, defined by higher cellular expression. Associations were assessed in the full sample and the subsample of AAs (n=70). Results: There were 52 tumors with high Ki67 expression, 37 with high p53, and 50 with high COX2. Fifteen tumors had high expression of all three markers. Cases were 55.8±0.4 (mean±SE) years at enrollment (range 40-79). The median 25-hydroxyvitaminD was lower in cases with high p53 expressing tumors compared to low expression (13.5 vs. 18.0 ng/mL, respectively, p = .03). Median values for other biomarkers were similar by tumor subtype (p &amp;gt .05). 25-hydroxyvitaminD was not associated with having a tumor with high Ki67 expression (odds ratio (OR) per 1 SD increase [95% CI] = 1.29 [0.85-1.95], p-trend = .23), high p53 expression (0.80 [0.52-1.23], p-trend = .30), or high COX2 expression (1.29 [0.83-2.00], p = .25). We observed null associations for VDBP, and free 25-hydroxyvitaminD with all tumor subtypes. Results were similar in AAs, although higher VDBP was associated with lower odds of high Ki67 tumors (0.45 [0.21-0.97], p-trend = .04 per 1 SD increase). Conclusion: In this sample of predominantly AA CRC cases, we observed no association between vitamin D biomarkers in stored serum and subsequent more aggressive CRC molecular subtypes. More work is needed to characterize the relationship between vitamin D and expression of CRC tumor markers, which may help clarify the protective role of maintaining adequate vitamin D levels in association with CRC. Citation Format: Thomas Lawler, Timothy Su, Qiuyin Cai, Mark Steinwandel, Wei Zheng, William J. Blot, Shaneda Warren Andersen. Biomarkers of circulating vitamin D status and expression of tumor molecular markers Ki67, p53, and COX2 among colorectal cancer cases in the Southern Community Cohort Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 725.

Abstract 28: New onset of type 2 diabetes after colorectal cancer diagnosis: Results from three prospective US cohort studies, systematic review, and meta-analysis

Abstract Background: Limited data indicate that patients with colorectal cancer (CRC) are at higher risk of developing type 2 diabetes (T2D). We prospectively examined the risk of T2D between individuals with and without CRC in three large cohorts and conducted a meta-analysis. Methods: We assessed the diagnosis of CRC and T2D among 111 485 women from the Nurses' Health Study, 112 958 women from the Nurses' Health Study II, and 46 581 men from the Health Professionals Follow-up Study. We used multivariable Cox regression with time-varying covariates to calculate the hazard ratio (HR) of T2D in relation to CRC diagnosis. We further performed a systematic review and meta-analysis of cohort studies. Findings: Up to 36 years of follow-up (6.9 million person-years), we documented 3402 incident CRC cases and 26 469 T2D cases. Compared to non-CRC individuals, those with CRC were more likely to develop T2D (multivariable-adjusted HR 1.20, 95% CI 1.05-1.38). The association was most evident for individuals with fewer risk factors for T2D. In the meta-analysis of seven cohort studies (1 061 744 participants), CRC was associated with higher T2D risk (meta-analysis HR 1.21, 95% CI 1.11-1.31, I2=57.9%). By CRC duration, a statistically significant association was observed in the first 10 years but not after 10 years of CRC diagnosis (≤5 years, meta-analysis HR 1.32, 95% CI 1.27-1.36; 5.1-10 years, 1.14 [1.04-1.25]; &amp;gt;10 years, 1.14 [0.91-1.37]). Interpretations: CRC was associated with increased T2D risk, especially in the first ten years after CRC diagnosis. Our findings highlight the importance of T2D prevention for CRC survivorship care. Citation Format: Hongmei Zeng, Chen Yuan, Jakub Morze, Ruiying Fu, Kai Wang, Liang Wang, Feng Sun, John S. Ji, Edward L. Giovannucci, Mingyang Song. New onset of type 2 diabetes after colorectal cancer diagnosis: Results from three prospective US cohort studies, systematic review, and meta-analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 28.

Abstract 684: Body mass index throughout adulthood and incidence of colorectal cancer subclassified by T cell, macrophage, and myeloid cell infiltrates in cancer tissue

Abstract Abstract Background: Biological evidence indicates that obesity influences immune responses, interacting with various immune cell populations via obesity-related systemic inflammation. We hypothesized that the association of obesity with colorectal cancer (CRC) incidence differed by T-cell, macrophage, and other myeloid cell infiltrates in tumor tissue. Methods: We developed multiplexed immunofluorescence assays to identify immune cells, including T-cell (CD3, CD4, CD8, CD45RO, and FOXP3), macrophage [CD68, CD86, IRF5, MAF, and MRC1 (CD206)], and myeloid cell (CD14, CD15, HLA-DR, ARG) subsets in tumor. Utilizing the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS), we examined the association of body mass index (BMI) with incidence of CRC subtypes classified by each immune cell subset. We applied inverse probability-weighted Cox proportional hazards models to control for selection bias and potential confounders. We used the stringent α level of 0.005 due to multiple comparisons. Results: During follow-up of 131,144 participants (3,648,371 person-years), we documented 3,203 incident CRC cases including 886 CRC cases with available data on immune cell densities in tumor tissue. The association of cumulative average BMI (from baseline to the most recent questionnaire cycle) with CRC incidence differed by CD15+CD33- cell (mature granulocyte) densities in tumor intraepithelial regions (Phet=0.004). Cumulative average BMI was associated with incidence of tumors with low CD15+CD33- cell densities [18.5-22.5 kg/m2: reference; 22.5-24.9 kg/m2: HR (95% CI), 1.67 (1.12-2.48); 25.0-27.5 kg/m2: 1.73 (1.14-2.61); 27.5-29.9 kg/m2: 2.06 (1.32-3.21); ≥30 kg/m2: HR, 2.26 (1.45-3.52), Ptrend&amp;lt;0.001], but not with incidence of tumors with intermediate or high CD15+CD33- cell densities (Ptrend&amp;gt;0.049, with the α level of 0.005). The association of young adult BMI (at age 18 for NHS and at age 21 for HPFS) with CRC incidence differed by CD15+CD33+ cell [granulocytic myeloid-derived suppressor cell (MDSC)-like phenotype] densities in tumor intraepithelial regions (Phet&amp;lt;0.001). Young adult BMI was associated with incidence of tumors with low CD15+CD33+ cell densities [18.5-22.5 kg/m2: reference; 22.5-24.9 kg/m2: HR (95% CI), 1.18 (0.96-1.44); 25.0-27.5 kg/m2: 1.44 (1.11-1.87); ≥27.5 kg/m2: 1.88 (1.35-2.62), Ptrend&amp;lt;0.001], but the association was attenuated for tumors with intermediate and high CD15+CD33+ cell densities (Ptrend&amp;gt;0.087). Similar differential associations were not observed in analyses of CRC subclassified by T cell or macrophage densities. Conclusions: The association of BMI with CRC incidence differed by intraepithelial myeloid cell densities. Our findings suggest an interplay of obesity from early life and granulocytic MDSCs/other granulocytes in colorectal carcinogenesis. Citation Format: Tomotaka Ugai, Juha P. Väyrynen, Yasutoshi Takashima, Seyed Mostafa Mousavi Kahaki, Benjamin Langworthy, Koichiro Haruki, Naohiko Akimoto, Mai Chan Lau, Rong Zhong, Sara A. Väyrynen, Melissa Zhao, Andressa Dias Costa, Jennifer Borowsky, Jennifer L. Guerriero, Xuehong Zhang, Andrew T. Chan, Molin Wang, Marios Giannakis, Jeffrey A. Meyerhardt, Edward L. Giovannucci, Jonathan A. Nowak, Shuji Ogino. Body mass index throughout adulthood and incidence of colorectal cancer subclassified by T cell, macrophage, and myeloid cell infiltrates in cancer tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 684.

Energy balance-related factors and risk of colorectal cancer based on KRAS, PIK3CA, and BRAF mutations and MMR status

IntroductionKRAS mutations (KRASmut), PIK3CAmut, BRAFmut, and mismatch repair deficiency (dMMR) have been associated with the Warburg-effect. We previously observed differential associations between energy balance-related factors (BMI, clothing-size, physical activity) and colorectal cancer (CRC) subtypes based on the Warburg-effect. We now investigated whether associations between energy balance-related factors and risk of CRC differ between subgroups based on mutation and MMR status.MethodsInformation on molecular features was available for 2349 incident CRC cases within the Netherlands Cohort Study (NLCS), with complete covariate data available for 1934 cases and 3911 subcohort members. Multivariable-adjusted Cox-regression was used to estimate associations of energy balance-related factors with risk of CRC based on individual molecular features (KRASmut; PIK3CAmut; BRAFmut; dMMR) and combinations thereof (all-wild-type + MMR-proficient (pMMR); any-mutation/dMMR).ResultsIn men, BMI and clothing-size were positively associated with risk of colon, but not rectal cancer, regardless of molecular features subgroups; the strongest associations were observed for PIK3CAmut colon cancer. In women, however, BMI and clothing-size were only associated with risk of KRASmut colon cancer (p-heterogeneityKRASmut versus all-wild-type+pMMR = 0.008). Inverse associations of non-occupational physical activity with risk of colon cancer were strongest for any-mutation/dMMR tumors in men and women, and specifically for PIK3CAmut tumors in women. Occupational physical activity was inversely associated with both combination subgroups of colon cancer in men.ConclusionIn men, associations did not vary according to molecular features. In women, a role of KRAS mutations in the etiological pathway between adiposity and colon cancer is suggested, and of PIK3CA mutations between physical activity and colon cancer.

Closing the gap for post-colonoscopy colorectal cancer

Colonoscopy is key in the diagnosis, prevention, and treatment of colorectal cancer. This technique allows the full examination of the colonic mucosa and resection of most pre-neoplastic lesions. However, as with any observer-dependent procedure, colonoscopy has limitations. In this sense, post-colonoscopy colorectal cancer is a well-described entity, and accounts for up to 8·2% of incident colorectal cancer cases.1 Post-colonoscopy colorectal cancer is associated with endoscopists' ability to evaluate the colonic mucosa and resect colonic lesions.

Age at Initiation of Lower Gastrointestinal Endoscopy and Colorectal Cancer Risk Among US Women

In the past 4 years, the American Cancer Society and the US Preventive Services Task Force updated recommendations to initiate colorectal cancer (CRC) screening at 45 years of age to address the increasing incidence of CRC among adults younger than 50 years. However, empirical evidence evaluating the potential benefits of screening in younger populations is scant. To examine the association between endoscopy initiation at different ages and risk of CRC among US women. This prospective cohort study used data from the Nurses' Health Study II, which included US female health professionals followed up from 1991 through 2017. Data analysis was performed from August 2020 to June 2021. Age at initiation of sigmoidoscopy or colonoscopy for screening (routine screening or because of family history) or symptoms. Incident CRC, confirmed by medical records, pathology reports, and the National Death Index. Cumulative incidence of CRC in each group was estimated with age as the time scale, and the absolute risk reduction associated with endoscopy initiation at different ages through 60 years was calculated. Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% CIs, stratified by age and calendar year of questionnaire cycle and adjusted for CRC risk factors in the multivariable models. Among 111 801 women aged 26 to 46 years (median, 36 years) at enrollment, 519 incident CRC cases were documented over 26 years, encompassing 2 509 358 person-years of follow-up. In the multivariable analysis, compared with no endoscopy, undergoing endoscopy was associated with a significantly lower risk of incident CRC for age at initiation before 45 years (HR, 0.37; 95% CI, 0.26-0.53), 45 to 49 years (HR, 0.43; 95% CI, 0.29-0.62), 50 to 54 years (HR, 0.47; 95% CI, 0.35-0.62), and 55 years or older (HR, 0.46; 95% CI, 0.30-0.69). The absolute reduction in the estimated cumulative incidence of CRC through 60 years of age was 72 per 100 000 persons for initiation of endoscopy at 45 to 49 years of age vs 50 to 54 years of age. Compared with no endoscopy, initiation of endoscopy before 50 years of age was also associated with a reduced risk of CRC diagnosed before 55 years of age (<45 years: HR, 0.45 [95% CI, 0.29-0.70]; 45-49 years: HR, 0.43 [95% CI, 0.24-0.76]). In this cohort study, compared with no endoscopy, initiation of endoscopy before 50 years of age was associated with a reduced risk of CRC, including CRC diagnosed before 55 years of age. Screening before 50 years of age was associated with greater absolute reduction in CRC risk compared with initiation of CRC screening at 50 years of age or later.

Global, regional, and national burden of colorectal cancer and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

SummaryBackgroundColorectal cancer is the third leading cause of cancer deaths worldwide. Given the recent increasing trends in colorectal cancer incidence globally, up-to-date information on the colorectal cancer burden could guide screening, early detection, and treatment strategies, and help effectively allocate resources. We examined the temporal patterns of the global, regional, and national burden of colorectal cancer and its risk factors in 204 countries and territories across the past three decades.MethodsEstimates of incidence, mortality, and disability-adjusted life years (DALYs) for colorectal cancer were generated as a part of the Global Burden of Diseases, Injuries and Risk Factors Study (GBD) 2019 by age, sex, and geographical location for the period 1990–2019. Mortality estimates were produced using the cause of death ensemble model. We also calculated DALYs attributable to risk factors that had evidence of causation with colorectal cancer.FindingsGlobally, between 1990 and 2019, colorectal cancer incident cases more than doubled, from 842 098 (95% uncertainty interval [UI] 810 408–868 574) to 2·17 million (2·00–2·34), and deaths increased from 518 126 (493 682–537 877) to 1·09 million (1·02–1·15). The global age-standardised incidence rate increased from 22·2 (95% UI 21·3–23·0) per 100 000 to 26·7 (24·6–28·9) per 100 000, whereas the age-standardised mortality rate decreased from 14·3 (13·5–14·9) per 100 000 to 13·7 (12·6–14·5) per 100 000 and the age-standardised DALY rate decreased from 308·5 (294·7–320·7) per 100 000 to 295·5 (275·2–313·0) per 100 000 from 1990 through 2019. Taiwan (province of China; 62·0 [48·9–80·0] per 100 000), Monaco (60·7 [48·5–73·6] per 100 000), and Andorra (56·6 [42·8–71·9] per 100 000) had the highest age-standardised incidence rates, while Greenland (31·4 [26·0–37·1] per 100 000), Brunei (30·3 [26·6–34·1] per 100 000), and Hungary (28·6 [23·6–34·0] per 100 000) had the highest age-standardised mortality rates. From 1990 through 2019, a substantial rise in incidence rates was observed in younger adults (age <50 years), particularly in high Socio-demographic Index (SDI) countries. Globally, a diet low in milk (15·6%), smoking (13·3%), a diet low in calcium (12·9%), and alcohol use (9·9%) were the main contributors to colorectal cancer DALYs in 2019.InterpretationThe increase in incidence rates in people younger than 50 years requires vigilance from researchers, clinicians, and policy makers and a possible reconsideration of screening guidelines. The fast-rising burden in low SDI and middle SDI countries in Asia and Africa calls for colorectal cancer prevention approaches, greater awareness, and cost-effective screening and therapeutic options in these regions.FundingBill & Melinda Gates Foundation.

Calcium intake may explain the reduction of colorectal cancer odds by dietary selenium - a case-control study in Poland

BackgroundColorectal cancer (CRC) has been placed among top three cancer sites in high income countries. Although there are several inconsistencies across studies it is widely accepted that diet contributes to approximately 70% of CRC. Several dietary factors have been investigated; however, the knowledge about the role of trace elements and their interplay with other dietary factors in CRC odds is limited. The aim of the study was to estimate the odds ratio of colorectal cancer associated with the content of selenium in diet, and to check whether dietary calcium is a modifier of selenium effect in the population characterized by low selenium intake.MethodsFace-to-face interviews were used to gather data on dietary habits (by 148-item semi-quantitative food frequency questionnaire) and covariates among 683 histologically confirmed incident colorectal cancer cases and 759 hospital-based controls in a case-control study. Data was collected in a period between 2000 and 2012. Setting: Lesser Poland, Central Europe. Logistic regression models were used to assess the role of dietary selenium intake and calcium-selenium interaction in colorectal cancer odds.ResultsAfter the adjustment for several covariates dietary selenium was associated with the decrease of colorectal cancer odds by 8% (OR = 0.92, 95%CI: 0.84–0.99 for every 10μg Se/day increase). In individuals with lower (< 1000 mg/day) calcium content the odds of colorectal cancer was decreased by 13%(for every 10μg Se/day) and by 44% and 66% depending on the categories of selenium intake (60 to < 80 μg/day and ≥ 80 μg/day, respectively). The effect of dietary selenium was modified by dietary calcium (p for interaction < .005).ConclusionsThe study has shown a beneficial effect of dietary selenium for colorectal cancer and a modification effect of dietary calcium in a population characterized by lower levels of selenium intake. The results provide the basis for well-planned controlled trials to confirm the findings.

Statins and Colorectal Cancer Risk: A Population-Based Case-Control Study and Synthesis of the Epidemiological Evidence.

(1) Background: The pleiotropic effects of statins may explain a chemoprotective action against colorectal cancer (CRC). Many studies have tested this hypothesis, but results have been inconsistent so far. Moreover, few have examined statins individually which is important for determining whether there is a class effect and if lipophilicity and intensity may play a role. (2) Methods: From 2001–2014, we carried out a study comprised of 15,491 incident CRC cases and 60,000 matched controls extracted from the primary healthcare database BIFAP. We fit a logistic regression model to compute the adjusted-odds ratios (AOR) with their 95% confidence intervals (CIs). Additionally, we carried out a systematic review and meta-analysis. (3) Results: Current use of statins showed a reduced risk of CRC (AOR = 0.87; 95% CI: 0.83–0.91) not sustained after discontinuation. The association was time-dependent, starting early (AOR6months–1year = 0.85; 95% CI: 0.76–0.96) but weakened beyond 3-years. A class effect was suggested, although only significant for simvastatin and rosuvastatin. The risk reduction was more marked among individuals aged 70 or younger, and among moderate-high intensity users. Forty-eight studies were included in the meta-analysis (pooled-effect-size = 0.90; 95% CI: 0.86–0.93). (4) Conclusions: Results from the case-control study and the pooled evidence support a moderate chemoprotective effect of statins on CRC risk, modified by duration, intensity, and age.

Energy Balance-Related Factors and Risk of Colorectal Cancer Expressing Different Levels of Proteins Involved in the Warburg Effect.

Energy balance-related factors [body mass index (BMI), waist circumference, physical activity] have been associated with colorectal cancer risk. Warburg effect activation via PI3K/Akt signaling is one of the proposed mechanisms. We investigated whether energy balance-related factors were associated with risk of Warburg subtypes in colorectal cancer. We investigated this using immunohistochemistry for six proteins involved in the Warburg effect (LDHA, GLUT1, MCT4, PKM2, P53, PTEN) on tissue microarrays of 2,399 incident colorectal cancer cases from the prospective Netherlands Cohort Study (ntotal = 120,852; nsubcohort = 5,000; aged 55-69 in 1986; 20.3 years follow-up). Data analyses included 3,911 subcohort members and 1,972 colorectal cancer cases with complete covariate data. Expression levels of all proteins were combined into a pathway-based sum score and categorized into three "Warburg subtypes" (Warburg-low/moderate/high). Multivariable Cox regression analyses were used to estimate associations of BMI, clothing size (waist circumference proxy), and physical activity with Warburg subtypes in colorectal cancer. BMI and clothing size were positively associated with Warburg-moderate and Warburg-high colon cancer risk in men (Pheterogeneity = 0.192). In women, clothing size was positively associated with Warburg-low and Warburg-high colon cancer (Pheterogeneity = 0.005). Nonoccupational physical activity was inversely associated with Warburg-low and Warburg-moderate colon cancer in women (Pheterogeneity = 0.045), but positively associated with Warburg-high rectal cancer in men (Pheterogeneity = 0.089). The Warburg effect might be involved in associations between adiposity and colon cancer risk, though additional mechanisms could be at play in women as well. The inverse association between physical activity and colon cancer might be explained by mechanisms other than the Warburg effect. Further research is needed to reproduce these results and investigate possible additional mechanisms.

Energy balance-related factors in childhood and adolescence and risk of colorectal cancer expressing different levels of proteins involved in the Warburg-effect.

Early‐life (childhood to adolescence) energy balance‐related factors (height, energy restriction, BMI) have been associated with adult colorectal cancer (CRC) risk. Warburg‐effect activation via PI3K/Akt‐signaling might explain this link. We investigated whether early‐life energy balance‐related factors were associated with risk of Warburg‐subtypes in CRC. We used immunohistochemistry for six proteins involved in the Warburg‐effect (LDHA, GLUT1, MCT4, PKM2, P53, and PTEN) on tissue microarrays of 2399 incident CRC cases from the prospective Netherlands Cohort Study (NLCS). Expression levels of all proteins were combined into a pathway‐based sum score and categorized into three Warburg‐subtypes (Warburg‐low/‐moderate/‐high). Multivariable Cox‐regression analyses were used to estimate associations of height, energy restriction proxies (exposure to Dutch Hunger Winter; Second World War [WWII]; Economic Depression) and adolescent BMI with Warburg‐subtypes in CRC. Height was positively associated with colon cancer in men, regardless of Warburg‐subtypes, and with Warburg‐low colon and Warburg‐moderate rectal cancer in women. Energy restriction during the Dutch Hunger Winter was inversely associated with colon cancer in men, regardless of Warburg‐subtypes. In women, energy restriction during the Hunger Winter and WWII was inversely associated with Warburg‐low colon cancer, whereas energy restriction during the Economic Depression was positively associated with Warburg‐high colon cancer. Adolescent BMI was positively associated with Warburg‐high colon cancer in men, and Warburg‐moderate rectal cancer in women. In conclusion, the Warburg‐effect seems to be involved in associations of adolescent BMI with colon cancer in men, and of energy restriction during the Economic Depression with colon cancer in women. Further research is needed to validate these results.

Dietary fat and fatty acids in relation to risk of colorectal cancer.

Epidemiologic evidence for specific types and sources of dietary fat and individual fatty acid with colorectal cancer (CRC) risk remains inconclusive. We aimed to comprehensively examine the associations of intakes of specific types (saturated, monounsaturated, polyunsaturated, and trans) and sources (animal, dairy, and vegetable) of dietary fat and individual fatty acid with CRC risk. We prospectively followed 65,550 women from the Nurses' Health Study (1986-2014) and 45,684 men from the Health Professionals Follow-up Study (1986-2014). Dietary intake was assessed every 4years using food frequency questionnaires. Self-reported CRC cases were confirmed through medical record review. Time-dependent Cox proportional hazards regression was used to estimate the hazard ratios (HRs) for intakes of dietary fats and fatty acids and CRC risk. During 2,705,560 person-years of follow-up, 2726 incident CRC cases were confirmed. Intake of monounsaturated fat tended to be positively associated with the risk of CRC (HR comparing extreme quintiles 1.22; 95% CI 1.01, 1.47; p = 0.06 for trend). This positive association was mainly driven by monounsaturated fatty acids from animal sources (MUFA-As) (HR comparing extreme quintiles 1.23; 95% CI 1.02, 1.49; p = 0.02 for trend). The positive association between MUFA-As and CRC was attenuated after adjusting for red and processed meat consumption (HR comparing extreme quintiles 1.17; 95% CI 0.95, 1.44; p = 0.13 for trend). We did not find clear associations between other types and sources of dietary fat or individual fatty acid and CRC risk. Higher intake of MUFA-As was associated with higher CRC risk. This could be partly explained by confounding due to other components of red and processed meat.

Pre-diagnostic telomere length and colorectal cancer risk

BackgroundProgressive telomere shortening may be related to genomic instability and carcinogenesis. Prospective evidence relating telomere length (TL) with colorectal cancer (CRC) risk has been limited and inconsistent. MethodsWe examined the association between pre-diagnostic peripheral blood leukocyte TL and CRC risk in two matched case-control studies nested within the Nurses’ Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS). Relative leukocyte TL was measured using qPCR among 356 incident CRC cases and 801 controls (NHS: 186/465, HPFS: 170/336). ResultsWe did not find a significant association between pre-diagnostic TL and CRC risk [in all participants, multivariable-adjusted odds ratio (OR) (95% CI) for TL Quartile 1 (shortest) vs. Quartile 4 (longest) = 1.36 (0.85, 2.17), P-trend = 0.27; OR (95% CI) per 1 SD decrease in TL = 1.12 (0.92, 1.36)]. ConclusionsOur prospective analysis did not support a significant association between pre-diagnostic leukocyte TL and CRC risk.

Coffee Intake of Colorectal Cancer Patients and Prognosis According to Histopathologic Lymphocytic Reaction and T-Cell Infiltrates

Given previous biologic evidence of immunomodulatory effects of coffee, we hypothesized that the association between coffee intake of colorectal cancer patients and survival differs by immune responses. Using a molecular pathologic epidemiology database of 4465 incident colorectal cancer cases, including 1262 cases with molecular data, in the Nurses’ Health Study and the Health Professionals Follow-up Study, we examined the association between coffee intake of colorectal cancer patients and survival in strata of levels of histopathologic lymphocytic reaction and T-cell infiltrates in tumor tissue. We did not observe a significant association of coffee intake with colorectal cancer–specific mortality (multivariable-adjusted hazard ratio [HR] for 1-cup increase of coffee intake per day, 0.93; 95% CI, 0.84 to 1.03). Although statistical significance was not reached at the stringent level (α=.005), the association of coffee intake with colorectal cancer–specific mortality differed by Crohn disease–like lymphoid reaction (Pinteraction=.007). Coffee intake was associated with lower colorectal cancer–specific mortality in patients with high Crohn disease–like reaction (multivariable HR for 1-cup increase of coffee intake per day, 0.55; 95% CI, 0.37 to 0.81; Ptrend=.002) but not in patients with intermediate Crohn disease–like reaction (the corresponding HR, 1.02; 95% CI, 0.72 to 1.44) or negative/low Crohn disease–like reaction (the corresponding HR, 0.95; 95% CI, 0.83 to 1.07). The associations of coffee intake with colorectal cancer–specific mortality did not significantly differ by levels of other lymphocytic reaction or any T-cell subset (Pinteraction>.18). There is suggestive evidence for differential prognostic effects of coffee intake by Crohn disease–like lymphoid reaction in colorectal cancer.

Association between metabolic syndrome and its components and incident colorectal cancer in a prospective cohort study.

Metabolic syndrome (MetS) has been identified as a contributor to cancer development. However, reports concerning the association between MetS and colorectal cancer (CRC) have been inconsistent. This study investigated whether MetS, its components, and the number of components increase the risk of CRC. This was a prospective cohort study of 41,837 participants recruited from August 2002 to December 2014 from the National Cancer Center in South Korea. The participants were followed until December 2017 to identify incident CRC cases. The participants underwent laboratory tests at the baseline. Additionally, a self-administered questionnaire collected information concerning lifestyle and general characteristics at the baseline. A Cox proportional hazards model was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) to explore the association between MetS and its components and CRC risk after adjustments for confounding variables. In total, 128 incident CRC cases were identified during the follow-up period. An increased CRC risk was found among participants with MetS (HR, 1.63; 95% CI, 1.08-2.44). Additionally, elevated blood pressure (HR, 1.50; 95% CI, 1.05-2.15) and a high fasting glucose level (HR, 1.80; 95% CI, 1.23-2.63) were associated with an elevated risk of CRC. Notably, an increased risk was identified among participants with abdominal obesity coexisting with another component of MetS. These results suggest that MetS is a risk factor for CRC. Greater emphasis should be placed on the importance of CRC screening among individuals with abdominal obesity coexisting with another component of MetS. Colorectal cancer (CRC) ranks as the third most common cancer type in terms of incidence. Metabolic syndrome (MetS) has been identified as a contributor to cancer development. However, the association between MetS and CRC remains controversial because of a lack of consistent findings in previous studies. In this study, the National Cholesterol Education Program's Adult Treatment Panel III guidelines are used for the diagnosis of MetS. MetS is found to be a predictor of CRC. Additionally, the importance of CRC screening among individuals with 2 components of MetS should be emphasized.

Long-Term Statin Use, Total Cholesterol Level, and Risk of Colorectal Cancer: A Prospective Cohort Study.

Statin use has been examined as a potential chemopreventive strategy against colorectal cancer (CRC). Previous studies have not been able to investigate this topic with adequate follow-up time or disentangle the effects of statin use and total cholesterol level. We investigated prospectively this topic. Eligible participants (100,300 women and 47,991 men) in the Nurses' Health Study and Health Professionals Follow-Up Study were followed for up to 24 years. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals. We documented 2,924 incident CRC cases during follow-up. In fully adjusted analyses, longer duration of statin use was associated with higher risk of colon cancer (hazard ratios, the 95% confidence interval was 1.09, 0.95-1.25 for 1-5 years; 1.16, 0.99-1.36 for 6-10 years; 1.08, 0.81-1.44 for 11-15 years; 1.85, 1.30-2.61 for >15 years; vs never users, P = 0.004 for trend) rather than rectal cancer. The risk elevation was driven by proximal colon cancer (1.16, 0.98-1.38 for 1-5 years; 1.19, 0.98-1.45 for 6-10 years; 1.25, 0.89-1.74 for 11-15 years; 2.17, 1.46-3.24 for >15 years; vs never users, P = 0.001 for trend) rather than distal colon cancer. The results remained robust in analyses among participants with hypercholesterolemia or who never received screening. Total cholesterol level was not associated with CRC risk. This study does not support benefit of statin use in CRC chemoprevention or any association between total cholesterol level and CRC risk. On the contrary, long-term statin use may be associated with increased colon cancer risk (driven by proximal colon cancer).

Associations between hepatitis B virus infection and risk of colorectal Cancer: a population-based prospective study

BackgroundPrevious studies have observed a close association between hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC) as well as extrahepatic cancers. However, research concerning the effect of HBV infection on the risk of colorectal cancer (CRC) is rare and inconsistent. This study aims to determine the relationship between HBV infection and new-onset CRC.MethodsWe prospectively examined the relationship between HBV infection and new-onset CRC among 93,390 participants from Kailuan Cohort study. Cox proportional hazards regression models, subgroup analyses and competing risk analyses were used to evaluate the association between HBV infection and the risk of new-onset CRC.ResultsDuring a median follow-up of 11.28 years, 448 incident CRC cases were identified. The adjusted HR (95%confidence interval (CI)) for the association of HBsAg Seropositive with CRC was 1.85(1.15 ~ 2.96) in the Cox regression. Subgroup analyses showed that the HBsAg seropositive group was associated with increased risk of new-onset CRC among male, middle-aged, normal weight, smokers and non-drinker participants, respectively. A positive association of HBV infection with the risk of CRC was observed in the adjusted sub-distribution proportional hazards (SD) models (HRSD = 1.77, 95% CI:1.11–2.84) and cause-specific hazards (CS) models (HRCS = 1.79, 95% CI: 1.13–2.91).ConclusionsOur results have found a significant association between HBV infection and the risk of incident CRC among Chinese participants.Trial registrationKailuan study, ChiCTR–TNRC–11001489. Registered 24 August 2011 - Retrospectively registered, http:// http://www.chictr.org.cn/showprojen.aspx?proj=8050

Immune cell profiles in the tumor microenvironment of early-onset, intermediate-onset, and later-onset colorectal cancer.

Despite heightened interest in early-onset colorectal cancer (CRC) diagnosed before age 50, little is known on immune cell profiles of early-onset CRC. It also remains to be studied whether CRCs diagnosed at or shortly after age 50 are similar to early-onset CRC. We therefore hypothesized that immune cell infiltrates in CRC tissue might show differential heterogeneity patterns between three age groups (< 50 "early onset," 50-54 "intermediate onset," ≥ 55 "later onset"). We examined 1,518 incident CRC cases with available tissue data, including 35 early-onset and 73 intermediate-onset cases. To identify immune cells in tumor intraepithelial and stromal areas, we developed three multiplexed immunofluorescence assays combined with digital image analyses and machine learning algorithms, with the following markers: (1) CD3, CD4, CD8, CD45RO (PTPRC), and FOXP3 for T cells; (2) CD68, CD86, IRF5, MAF, and MRC1 (CD206) for macrophages; and (3) ARG1, CD14, CD15, CD33, and HLA-DR for myeloid cells. Although no comparisons between age groups showed statistically significant differences at the stringent two-sided α level of 0.005, compared to later-onset CRC, early-onset CRC tended to show lower levels of tumor-infiltrating lymphocytes (P = 0.013), intratumoral periglandular reaction (P = 0.025), and peritumoral lymphocytic reaction (P = 0.044). Compared to later-onset CRC, intermediate-onset CRC tended to show lower densities of overall macrophages (P = 0.050), M1-like macrophages (P = 0.062), CD14+HLA-DR+ cells (P = 0.015), and CD3+CD4+FOXP3+ cells (P = 0.039). This hypothesis-generating study suggests possible differences in histopathologic lymphocytic reaction patterns, macrophages, and regulatory T cells in the tumor microenvironment by age at diagnosis.

Potential Impact of Time Trend of Lifestyle Risk Factors on Burden of Major Gastrointestinal Cancers in China

China has the largest number of incident liver, esophageal, gastric, and colorectal cancer cases in 2020. Examining the time trend of relevant lifestyle risk factors would help project the trend of these gastrointestinal (GI) cancer incidence in China. We estimated the time trend of the lifestyle factors based on the China Health and Nutrition Survey 1991 to 2011. We applied the comparative risk assessment method to estimate the population attributable fraction of GI cancers attributable to each risk factor. We also projected the prevalence of lifestyle factors and the associated burden of GI cancer from 2011 to2031. In 2011, 56.5% of colorectal, 59.8% of gastric, 48.5% of esophageal, and 35.2% of liver cancer in China were attributable to the lifestyle risk factors under study. Smoking, sodium intake, low vegetable intake, and low fruit intake have improved over time but remained far from optimal and are expected to be responsible for 170,000, 35,000, 22,000, and 50,000 GI cancer cases in 2031, respectively. High body mass index, red and processed meat consumption, and low physical activity are expected to contribute increasingly more GI cancer, accounting for 142,000, 185,000, 60,000, and 53,000 cases in 2031, respectively. The estimated population attributable fraction for all risk factors in 2031 is 52.1%. Lifestyle risk factors have had an impact on the risk of GI cancer in China, and the impact is projected to increase. If everyone could adhere to the optimal lifestyle, half of all GI cancer events would be prevented by year2031.