Andrew T. Chan’s research while affiliated with Massachusetts General Hospital and other places

Introduction: Colorectal cancer (CRC) is a prevalent cancer and a leading cause of cancer deaths in the US. CRC survivors have a high risk of developing cardiovascular disease (CVD), which accounts for nearly 20% of their total mortality, likely due to shared risk factors including lifestyle. Hypothesis: We hypothesized that maintaining a healthy lifestyle after a CRC diagnosis is associated with a lower risk of CVD incidence and mortality. Methods: We analyzed data from 2,737 survivors with stages I-III CRC in the Nurses’ Health Study and Health Professional Follow-up Study. A lifestyle score, ranging from 0 to 5, was calculated for participants based on diet quality, smoking status, alcohol intake, physical activity, and body mass index. We calculated cumulative averaged scores before and after CRC diagnosis and used Cox proportional hazards regression to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for CVD incidence and mortality. We further examined changes in pre- and post-diagnostic lifestyle in relation to CVD outcomes and assessed potential effect modification by age, tumor characteristics, and medical history. Results: Over a median follow-up of 13.3 years after CRC diagnosis, we documented 449 incident CVD cases, including 201 coronary heart disease and 104 stroke cases, and 307 CVD-specific deaths. After adjustment for demographics, medical history, tumor characteristics, and pre-diagnostic lifestyle score, one unit increase in post-diagnostic score was associated with a 13% lower CVD incidence (HR [95% CI]: 0.87 [0.77-0.98]; p-trend: 0.03) and 29% lower CVD mortality (0.71 [0.61-0.83]; <0.0001). When stratified by tumor stage, the inverse association with CVD incidence was observed for stage I (0.74 [0.60-0.92]) but not stages II-III CRC (1.12 [0.93-1.35]; p-interaction: 0.005); whereas no differential associations were found for CVD mortality. Survivors who maintained a healthy lifestyle (score ≥4) pre- and post-diagnosis had a 28% lower risk of CVD incidence (0.72 [0.57-0.92]) and a 48% lower risk of CVD mortality (0.52 [0.39-0.70]) compared to those with a constantly poor lifestyle (score <4). Conclusions: In conclusion, a healthy lifestyle after CRC diagnosis was associated with a substantially lower risk of CVD incidence and mortality, highlighting the role of a healthy lifestyle in improving survivorship. These findings offer valuable insights for integrating lifestyle interventions into CRC oncology care.

Background The tumor immunosurveillance theory supports that allergic conditions could decrease cancer risk. However, observational evidence yielded inconsistent results for the association between allergic diseases and colorectal cancer risk. We used Mendelian randomization (MR) to examine potential causal associations of allergies with the risk of overall and early-onset colorectal cancer. Methods Genome-wide association study summary statistical data were used to identify genetic variants associated with allergic diseases (Nvariants = 65) and individual allergic conditions (asthma, hay fever/allergic rhinitis, and eczema). Using two-sample MR, we examined these variants in relation to incident overall (Ncases = 52,775 cases) and early-onset colorectal cancer (Ncases = 6,176). The mediating role of white blood cells was examined using multivariable MR. Results In inverse-variance–weighted models, genetic liability to allergic diseases was inversely associated with overall {OR per log (odds) = 0.90 [95% confidence interval (CI), 0.85–0.96]; P < 0.01} and early-onset colorectal cancer [OR = 0.83 (95% CI, 0.73–0.95); P = 0.01]. Similar inverse associations were found for hay fever/allergic rhinitis or eczema, whereas no evidence of association was found between liability to asthma-related phenotypes and colorectal cancer risk. Multivariable MR adjustment for eosinophils weakened the inverse associations for liability to allergic diseases for overall [OR = 0.96 (95% CI, 0.89–1.03); P = 0.26] and early-onset colorectal cancer [OR = 0.86 (95% CI, 0.73–1.01); P = 0.06]. Conclusions Our study supports a potential causal association between liability to allergic diseases, specifically hay fever/allergic rhinitis or eczema, and colorectal cancer, possibly at least in part mediated via eosinophil counts. Impact Our results provide evidence that allergic responses may also have a role in immunosurveillance against colorectal cancer.

Introduction We aimed to analyze gastrointestinal guidelines to assess quality of evidence and strength of recommendation. Methods We abstracted clinical practice guidelines and guidance statements from 4 American GI societies (ACG, AGA, ASGE and AASLD) and the United States Multi-Society Task Forc. Results Of the 3,609 statements analyzed, only 13% were supported by high level of evidence. The number of statements published annually is increasing, but the level of evidence supporting recommendations is declining over time. Conclusions This analysis highlights the need for high quality research in GI to support the development of stronger evidence-based guideline statements.

Background and Objectives Migraine is strongly comorbid with irritable bowel syndrome (IBS), one of several gastrointestinal (GI) conditions that are distinguished by symptomatic profiles that are partly overlapping. Potential shared mechanisms of migraine and the GI conditions were investigated by assessing shared genetics on a genome-wide basis. Methods Analyses leveraged genome-wide summary statistics from large-scale genetic studies for migraine, including by aura status, IBS, peptic ulcer disease (PUD), gastrointestinal reflux (GERD), functional dyspepsia (FD), diverticular disease (DD), and the immune-related inflammatory bowel disease (IBD) or its constituents, ulcerative colitis (UC) and Crohn disease (CD). Genetic correlation was evaluated on a genome-wide basis and at independent local regions, including those related to therapeutic targeting of serotonin and the calcitonin gene-related peptide. Genetic correlation was assessed for enrichment at genes according to tissue specificity of gene expression. Potential causality between migraine and the GI conditions was assessed by Mendelian randomization. Results Genetic correlation with migraine was strongly significant among the nonimmune GI disorders, maximally for IBS (rg [SE] = 0.37[0.04], p = 10⁻²¹) and minimally for DD (0.18 (0.04), 7.5 × 10⁻⁷), but null for IBD. There were distinct patterns of local genetic sharing with migraine across the GI conditions at 22 significant segments of the genome, 7 of which were novel for either migraine or GI or both. Enrichment analysis suggested involvement of the CNS in genetic overlap of GERD, IBS, and PUD with migraine. There was local genetic sharing with migraine at CALCA/CALCB (encoding calcitonin gene-related peptide [CGRP]) in an inverse sense for GERD and PUD, but with concordance and greater significance for DD, IBD, and UC. Mendelian randomization supported causal effects of PUD, GERD and particularly DD (OR[SE] = 1.90 (1.35–2.68, p = 2.2 × 10⁻⁴) on migraine, but not of migraine on any GI condition. Discussion Genetic sharing of migraine and non–immune-related GI disorders was extensive yet distinct across GI disorders that have overlapping symptoms, with enrichment signals that imply neurologic mechanisms. Causal effects of some GI conditions on migraine were supported. A concordant local correlation at CALCA/CALCB of migraine with both DD and the immune-related disorders suggests potential benefit to these conditions from repurposed migraine therapeutics targeting CGRP.

The impact of metabolic dysfunction-associated steatotic liver disease (MASLD), the preferred nomenclature for NAFLD, on cardiovascular health and mortality among older adults is uncertain. As such, we aimed to identify whether MASLD increases the risk of Major Adverse Cardiovascular Events (MACE) (a composite of fatal coronary heart disease [excluding heart failure], nonfatal myocardial infarction, or fatal or nonfatal ischemic stroke), Atrial Fibrillation (AF), or all-cause mortality in older adults, and whether aspirin attenuates these risks in individuals with MASLD. This is a non-prespecified post-hoc analysis of the ASPREE (ASPirin in Reducing Events in the Elderly) randomized trial. Participants were community dwelling well adults aged ≥ 70 years without a history of atherosclerotic cardiovascular disease or AF. Fatty Liver Index (FLI) was used to identify MASLD at baseline. FLI is a composite of anthropometric and biochemical markers used in epidemiologic studies to rule in and rule out hepatic steatosis. MACE and cause of death were adjudicated by clinical experts; AF was assessed by previously defined algorithm in ASPREE. 9,097 participants were stratified into groups according to FLI. In univariate analysis, prevalent MASLD (FLI ≥ 60 with evidence of metabolic dysfunction; n = 2,998 [33.0%]) was associated with an increased risk of MACE (HR 1.47 [95% CI 1.22–1.78]) and AF (HR 1.50 [95% CI 1.19–1.88] but not all-cause mortality (HR 1.04 [95% CI 0.91–1.19]). After adjusting for cardiovascular disease risk factors, only the association between MASLD and AF remained significant (HR 1.46 [95% CI 1.11–1.93]). Aspirin did not reduce the risk of MACE, death, or AF in the MASLD group. MASLD was associated with an increased hazard of incident AF, but not of MACE or all-cause mortality, in community dwelling older adults. Primary prevention with aspirin does not ameliorate these risks in older adults with MASLD.

Importance The current recommendation for a 10-year rescreening interval after a negative colonoscopy screening (NCS) result has been questioned, with some studies showing a persistently lower risk of colorectal cancer (CRC) after NCS results. Objective To examine long-term CRC incidence and mortality after NCS results (ie, no presence of CRC or polyps) and according to a risk score based on major demographic and lifestyle risk factors. Design, Setting, and Participants In this cohort study, 3 prospective US population–based cohorts from the Nurses’ Health Study, Nurses’ Health Study II, and Health Professionals Follow-up Study were followed up from 1988 and 1991 to 2020. Data from the National Health and Nutrition Examination Survey (NHANES) from the January 1, 2017, to December 31, 2018, cycle were used to compare the risk profile distribution with that of the general US population. Data analysis was performed from October 2023 to August 2024. Exposures Time-varying status of NCS results and risk score. Main Outcomes and Measures Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% CIs for incidence and mortality of CRC. Results A total of 195 453 participants (median [IQR] age, 44 [37-56] years at baseline; 81% female) were followed up for a median (IQR) of 12 (6-20) years. Among 81 151 individuals with NCS results and 114 302 without endoscopy, 394 and 2229 CRC cases and 167 and 637 CRC deaths, respectively, were documented. Negative colonoscopy screening results were consistently associated with lower CRC incidence (HR, 0.51; 95% CI, 0.44-0.58) and mortality (HR, 0.56; 95% CI, 0.46-0.70) for 20 years. Among individuals with NCS results, those with an intermediate risk (scores, 6-7) and low risk (scores, 0-5) did not reach the 10-year cumulative incidence of CRC (0.78%) of the high-risk individuals (scores, 8-12) until 16 and 25 years after initial screening, respectively. Conclusion and Relevance These findings provide evidence for shared decision-making between patients and physicians to consider extending the rescreening intervals after an NCS result beyond the currently recommended 10 years, particularly for individuals with a low-risk profile. These results showed, as a proof of concepts, the importance of considering known CRC risk factors when making decisions for colonoscopy rescreening.

Background Whether blood lipids are causally associated with colorectal cancer (CRC) risk remains unclear. Methods Using two-sample Mendelian randomisation (MR), our study examined the associations of genetically-predicted blood concentrations of lipids and lipoproteins (primary: LDL-C, HDL-C, triglycerides, and total cholesterol), and genetically-proxied inhibition of HMGCR, NPC1L1, and PCSK9 (which mimic therapeutic effects of LDL-lowering drugs), with risks of CRC and its subsites. Genetic associations with lipids were obtained from the Global Lipids Genetics Consortium ( n = 1,320,016), while genetic associations with CRC were obtained from the largest existing CRC consortium ( n = 58,221 cases and 67,694 controls). Our main analysis was a multivariable MR (MVMR) with mutual adjustments for LDL-C, HDL-C, and triglycerides. Secondary analyses, including MVMR additionally-adjusting for BMI or diabetes, were also performed. Results Genetically-predicted LDL-C was positively associated with CRC risk in the MVMR adjusted for HDL-C and triglycerides (OR = 1.09; 95%CI 1.02–1.16 per SD increase) and additionally-adjusted for BMI (OR = 1.12; 95%CI 1.05–1.21) or diabetes (OR = 1.09; 95%CI 1.02–1.17). Associations were generally consistent across anatomical subsites. No clear evidence of association was found for other lipids, lipoproteins, or LDL-lowering drug-targets. Conclusions We found evidence of a weak positive association between LDL-C and CRC that did not appear to be explained by potential pleiotropic pathways such as via HDL-C, triglycerides, BMI, or diabetes.