Associations Between Glycemic Traits and Colorectal Cancer: A Mendelian Randomization Analysis

Murphy, Neil; Song, Mingyang; Papadimitriou, Nikos; Carreras‐Torres, Robert; Langenberg, Claudia; Martin, Richard M.; Tsilidis, Konstantinos K.; Barroso, Inês; Chen, Ji; Frayling, Tim; Bull, Caroline J.; Vincent, Emma E.; Cotterchio, Michelle; Gruber, Stephen B.; Pai, Rish K.; Newcomb, Polly A.; Pérez-Cornago, Aurora; Duijnhoven, Fränzel J.B. van; Guelpen, Bethany Van; Vodička, Pavel; Wolk, Alicja; Wu, Anna H.; Peters, Ulrike; Chan, Andrew T.; Gunter, Marc J.

doi:10.1093/jnci/djac011

Cited by 59 publications

(57 citation statements)

References 44 publications

(46 reference statements)

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“…Third, evening chronotype has been associated with DNA methylation of certain gene sites, like BACH2 , JRK and RPS6KA2 , which are related to the cancer development 39 . Fourth, evening chronotype may be associated with impaired metabolic homeostasis, like insulin resistance and increased levels of low‐density lipoprotein, 40 which have been associated with an increased risk of colorectal cancer 41,42 . In addition, increased levels of BMI have been proposed to be a possible mediator in the association between chronotype and digestive tract cancer since people with morning preference have a decreased frequency of obesity 43 that is a causal risk factor for digestive tract cancers 5 .…”

Section: Discussionmentioning

confidence: 99%

Morning chronotype and digestive tract cancers: Mendelian randomization study

Yuan

Mason

Titova

et al. 2022

Intl Journal of Cancer

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Morning chronotype has been associated with a reduced risk of prostate and breast cancer. However, few studies have examined whether chronotype is associated with digestive tract cancer risk. We conducted a Mendelian randomization (MR) study to assess the associations of chronotype with major digestive tract cancers. A total of 317 independent genetic variants associated with chronotype at the genome-wide significance level (P < 5 Â 10 À8 ) were used as instrumental variables from a genomewide meta-analysis of 449 734 individuals. Summary-level data on overall and six digestive tract cancers, including esophageal, stomach, liver, biliary tract, pancreatic and colorectal cancers, were obtained from the UK Biobank (11 952 cases) and FinnGen (7638 cases) study. Genetic liability to morning chronotype was associated with reduced risk of overall digestive tract cancer and cancers of stomach, biliary tract and colorectum in UK Biobank. The associations for the overall digestive tract, stomach and colorectal cancers were directionally replicated in FinnGen. In the meta-analysis of the two sources, genetic liability to morning chronotype was associated with a decreased risk of overall digestive tract cancer (odds ratio[OR] 0.94, 95% confidence interval [CI]: 0.90-0.98), stomach cancer (OR 0.84, 95%

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Section: Discussionmentioning

confidence: 99%

Morning chronotype and digestive tract cancers: Mendelian randomization study

Yuan

Mason

Titova

et al. 2022

Intl Journal of Cancer

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“…A meta-analysis of 35 studies involving 25,566 cases showed that higher FI levels were significantly associated with an increased risk of colorectal cancer ( 37 ). A recent MR study also validated the association between FI and colorectal cancer risk ( 38 ). In contrast, a longitudinal study with a median follow-up period of 11.9 years demonstrated that serum insulin was not related to the risk of colorectal cancer in postmenopausal women ( 39 ).…”

Section: Discussionmentioning

confidence: 83%

Fasting Insulin and Risk of Overall and 14 Site-Specific Cancers: Evidence From Genetic Data

Zhang

Liu

et al. 2022

Front. Oncol.

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ObjectiveWhether fasting insulin (FI) plays a role in cancer risk remains unclear. This study aimed to investigate the association between FI and cancer risk and to explore its potential mediator role in the association between type 2 diabetes mellitus (T2DM) and cancer.MethodsTwo-sample Mendelian randomization (TSMR) analysis was performed to evaluate the effect of FI on overall and 14 site-specific cancers using genome-wide association study (GWAS) summary-level data from Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) and consortia of 14 site-specific cancers. The primary MR approach was conducted by using the random-effect inverse-variance weighted (IVW) method, and sensitivity analyses were implemented by adopting weighted-median, weighted-mode, MR-Egger, and MR-PRESSO tests. Polygenic risk score analysis was executed by using individual-level data from UK Biobank to validate the findings from TSMR analyses. Multivariable Mendelian randomization (MVMR) was carried out to estimate the mediation effect of FI on the association between T2DM and cancer.ResultsTSMR study suggested that genetically determined high FI levels were associated with increased risk of colorectal cancer (odds ratio (OR) = 1.87, 95% CI: 1.23–2.84, p = 0.003) and endometrial cancer (OR = 1.89, 95% CI: 1.08–3.01, p = 0.008), but not associated with overall cancer risk or the other 12 studied cancer sites. Polygenic risk score analysis successfully replicated the association between genetic liability to high FI levels and the increased risk of colorectal and endometrial cancers. MVMR and MR mediation analyses detected an intermediary effect of FI and quantified that FI mediated 21.3% of the association between T2DM and endometrial cancer.ConclusionsThis study demonstrated that FI levels are associated with the risk of colorectal and endometrial cancers, and FI was found to play an intermediary role in the association between T2DM and endometrial cancer. The associations between FI and other cancers need to be further studied.

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“…The results of this previous study are comparable to those of the present study. Further, a mendelian randomization analysis by Murphy et al showed that fasting glucose exerted no effect on the risk of developing CRC ( 27 ). To date, this is the largest and most comprehensive study examining the effects of multiple glycemic profiles on CRC risk ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

The prognostic role of fasting plasma glucose levels on survival in advanced colorectal cancer patients with type II diabetes mellitus: a retrospective cohort study

Meng¹,

Yu²,

Wang³

et al. 2022

J Gastrointest Oncol

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Background: Previous studies have shown that type II diabetes mellitus (T2DM) has a significant effect on the occurrence and development of colorectal cancer (CRC). The associations between fasting plasma glucose (FPG) and overall survival (OS) of CRC patients with T2DM are still controversial. The present study sought to examine the association between FPG control and OS in advanced CRC patients with T2DM. Methods:The data of advanced CRC patients with T2DM who were admitted to Harbin Medical University Cancer Hospital from May 2010 to May 2019 were retrospectively collected and examined.Record patient clinical data including age, sex, blood pressure, body mass index (BMI), primary tumor site, T stage, N stage, histological grade, number of metastatic sites, primary tumor surgery, etc. The baseline FPG which was measured before the first-line treatment and the FPG measured before each admission treatment during advanced chemotherapy were collected. OS was determined as the end point of the study. All the patients were followed-up for at least 3 years. The Kaplan-Meier log-rank method and the Cox proportional hazards regression analyses were used for the analysis of OS and hazard factors.Results: A total of 210 patients met the inclusion criteria for the study, who had a median age of 66.5 years; 94 patients had baseline FPG levels ≤7 mmol/L, and 116 patients had baseline FPG levels >7 mmol/L. Compared to the baseline FPG >7 mmol/L group, the OS of patients in the baseline FPG ≤7 mmol/L group was not significantly prolonged (P=0.88). There were 52 patients in the FPG-A group and 61 in the FPG-B group. Similarly, there was no significant difference in OS between the FPG-A and FPG-B groups (P=0.96).The N0 stage subgroup analysis showed that glycemic control ≤7 mmol/L resulted in longer OS. Conclusions:The results of the present study showed that FPG levels may not affect the survival of advanced CRC patients with T2DM. However, this needs multicenter prospective studies to confirm.

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Associations Between Glycemic Traits and Colorectal Cancer: A Mendelian Randomization Analysis

Cited by 59 publications

References 44 publications

Morning chronotype and digestive tract cancers: Mendelian randomization study

Morning chronotype and digestive tract cancers: Mendelian randomization study

Fasting Insulin and Risk of Overall and 14 Site-Specific Cancers: Evidence From Genetic Data

The prognostic role of fasting plasma glucose levels on survival in advanced colorectal cancer patients with type II diabetes mellitus: a retrospective cohort study

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