Genetic variation in prostaglandin synthesis and related pathways, NSAID use and colorectal cancer risk in the Colon Cancer Family Registry

Resler, Alexa J.; Makar, Karen W.; Heath, Laura; Whitton, John; Potter, John D.; Poole, Elizabeth M.; Habermann, Nina; Scherer, Dominique; Duggan, David; Wang, Hansong; Lindor, Noralane M.; Passarelli, Michael N.; Baron, John A.; Newcomb, Polly A.; Marchand, Loı̈c Le; Ulrich, Cornelia M.

doi:10.1093/carcin/bgu119

Cited by 20 publications

(7 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, several gene-by-environment (GxE) interaction analyses have been pursued that focus on genetic variants associated with PG or aspirin function 54,89–93 ; however, few of these studies have demonstrated a significant interaction between aspirin use and genetic variants in the context of CRC or adenoma risk. One cohort study did observe that the GA genotype of the single nucleotide polymorphism (SNP) rs2920421, which lies in an intronic region of ALOX12 (which encodes arachidonate 12-lipoxygenase), was associated with a lower risk of CRC only among current NSAID users and not among never users or former users 94 . This finding requires corroboration in other populations as candidate-gene-based approaches to GxE interaction studies have a high potential for false-positive results.…”

Section: Molecular Risk Stratificationmentioning

confidence: 99%

Aspirin and colorectal cancer: the promise of precision chemoprevention

2016

View full text Add to dashboard Cite

Aspirin (acetylsalicylic acid) has become one of the most commonly used drugs, given its role as an analgesic, antipyretic and agent for cardiovascular prophylaxis. Several decades of research have provided considerable evidence demonstrating its potential for the prevention of cancer, particularly colorectal cancer. Broader clinical recommendations for aspirin-based chemoprevention strategies have recently been established; however, given the known hazards of long-term aspirin use, larger-scale adoption of an aspirin chemoprevention strategy is likely to require improved identification of individuals for whom the protective benefits outweigh the harms. Such a precision medicine approach may emerge through further clarification of aspirin's mechanism of action.

show abstract

Section: Molecular Risk Stratificationmentioning

confidence: 99%

Aspirin and colorectal cancer: the promise of precision chemoprevention

2016

View full text Add to dashboard Cite

show abstract

“…Leukotrienes are important for immune cell signaling and differentiation, while prostaglandins have various homeostatic, developmental, and immune related functions [69,70]. Although both COX-1 and COX-2 produce the shortlived intermediate PGH 2 , COX-1 is generally coupled with homeostatic prostaglandin (PG) levels, while COX-2 and mPGES-1 are associated with inducible levels of PGE 2 production [55,71]. Therefore, in the context of disease, COX-2 and mPGES-1 are generally accepted as the cyclooxygenase and synthase associated with pathogenic PG production.…”

Section: Mir-708 Suppresses Pge 2 Production By Targeting the Cox-2 And Mpges-1 3′ Utrsmentioning

confidence: 99%

miR-708-5p targets oncogenic prostaglandin E2 production to suppress a pro-tumorigenic phenotype in lung cancer cells

Monteleone

Lutz

2020

Oncotarget

View full text Add to dashboard Cite

Many cancers maintain an inflammatory microenvironment to promote their growth. Lung cancer is of particular importance, as it is the deadliest cancer worldwide. One inflammatory pathway commonly dysregulated in cancer is the metabolism of arachidonic acid (AA) by Cyclooxygenase-2 (COX-2) and microsomal Prostaglandin E Synthase 1 (mPGES-1) into Prostaglandin E2 (PGE 2 ). While researchers have identified PGE 2 's pro-tumorigenic functions, the mechanisms governing overexpression of COX-2 and mPGES-1 are incompletely understood. MicroRNAs (miRNAs) are important posttranscriptional regulators commonly dysregulated in cancer. Interestingly, miR-708-5p (miR-708) is predicted to target both COX-2 and mPGES-1. In this study, we show that high miR-708 expression is associated with survival rates in lung squamous cell carcinoma patients. miR-708 also represses PGE 2 production by suppressing both COX-2 and mPGES-1 expression in lung cancer cells. miR-708 regulation of COX-2 and mPGES-1 is mediated through targeting of their 3′ untranslated regions (UTRs). Moreover, miR-708 decreases proliferation, survival, and migration of lung cancer cells, which can be partially attributed to miR-708's inhibition of PGE 2 signaling. Lastly, we identify novel miR-708 predicted targets and possible regulators of miR-708 expression in lung cancer. Collectively, these data demonstrate that dysregulated miR-708 expression contributes to exacerbated PGE 2 production, leading to an enhanced pro-tumorigenic phenotype in lung cancer cells.

show abstract

“…One of the ALOX12 SNPs that was associated with differential colorectal polyp prevention activity of aspirin in our study (the intronic SNP rs2920421) has been reported to interact with NSAID use in a case–control study of colorectal cancer risk ( 26 ). In that study, NSAID use was associated with decreased colorectal cancer risk in heterozygous rs2920421 genotypes, but not major or minor homozygotes ( 26 ).…”

Section: Discussionmentioning

confidence: 64%

Polymorphisms in Cyclooxygenase, Lipoxygenase, and TP53 Genes Predict Colorectal Polyp Risk Reduction by Aspirin in the seAFOod Polyp Prevention Trial

Davies,

Mell,

Fuller

et al. 2023

Cancer Prevention Research

View full text Add to dashboard Cite

Aspirin and eicosapentaenoic acid (EPA) reduce colorectal adenomatous polyp risk and affect synthesis of oxylipins including prostaglandin E2. We investigated whether 35 single nucleotide polymorphisms (SNPs) in oxylipin metabolism genes such as cyclooxygenase [PTGS] and lipoxygenase [ALOX], as well as 7 SNPs already associated with colorectal cancer (CRC) risk reduction by aspirin (eg. TP53; rs104522), modified the effects of aspirin and EPA on colorectal polyp recurrence in the randomised 2x2 factorial seAFOod trial. Treatment effects were reported as the incidence rate ratio (IRR) and 95% confidence interval (CI) by stratifying negative binomial and Poisson regression analyses of colorectal polyp risk on SNP genotype. Statistical significance was reported with adjustment for the false discovery rate as the P and q value. Five hundred and forty-two (of 707) trial participants had both genotype and colonoscopy outcome data. Reduction in colorectal polyp risk in aspirin users compared with non-aspirin users was restricted to rs4837960 (PTGS1) common homozygotes (IRR 0.69 [95%CI 0.53,0.90]; q=0.06), rs2745557 (PTGS2) compound heterozygote-rare homozygotes (IRR 0.60 [0.41,0.88]; q=0.06), rs7090328 (ALOX5) rare homozygotes (IRR 0.27 [0.11,0.64]; q=0.05), rs2073438 (ALOX12) common homozygotes (IRR 0.57 [0.41,0.80]; q=0.05), and rs104522 (TP53) rare homozygotes (IRR 0.37 [0.17,0.79]; q=0.06). No modification of colorectal polyp risk in EPA users was observed. In conclusion, genetic variants relevant to the proposed mechanism of action on oxylipins are associated with differential colorectal polyp risk reduction by aspirin in individuals who develop multiple colorectal polyps. SNP genotypes should be considered during development of personalised, predictive models of CRC chemoprevention by aspirin.

show abstract

Genetic variation in prostaglandin synthesis and related pathways, NSAID use and colorectal cancer risk in the Colon Cancer Family Registry

Cited by 20 publications

References 59 publications

Aspirin and colorectal cancer: the promise of precision chemoprevention

Aspirin and colorectal cancer: the promise of precision chemoprevention

miR-708-5p targets oncogenic prostaglandin E2 production to suppress a pro-tumorigenic phenotype in lung cancer cells

Polymorphisms in Cyclooxygenase, Lipoxygenase, and TP53 Genes Predict Colorectal Polyp Risk Reduction by Aspirin in the seAFOod Polyp Prevention Trial

Contact Info

Product

Resources

About