Μελέτη Μεντελιανής τυχαιοποίησης για τη συσχέτιση του χρονότυπου με τον καρκίνο παχέος εντέρου

Εισαγωγή: Τις τελευταίες δεκαετίες, τα παγκόσμια πρότυπα επίπτωσης και θνησιμότητας των διαφόρων καρκινικών τύπων έχουν σημειώσει ραγδαίες αλλαγές, οι οποίες οφείλονται σε σημαντικό βαθμό στις μεταβολές της κατανομής των συνυφασμένων με τον σύγχρονο τρόπο ζωής παραγόντων κινδύνου του καρκίνου. Η μετάβαση από τις μεταδοτικές στις εκφυλιστικές ανθρωπογενείς ασθένειες τοποθετούν τον καρκίνο του παχέος εντέρου τρίτο σε επίπτωση και δεύτερο σε θνησιμότητα. Μεταξύ των αλλαγών που συντελούνται στις αναπτυσσόμενες κοινωνίες συγκαταλέγεται και η εργασία σε βάρδιες που προκαλεί διαταραχή του φυσιολογικού ενδογενούς κιρκάδιου ρυθμού και έχει αναδειχθεί ως πιθανός παράγοντας κινδύνου της καρκινογένεσης. Τα αποτελέσματα, ωστόσο, των δημοσιευμένων επιδημιολογικών μελετών για την σχέση της εργασίας σε βάρδιες και του καρκίνου του παχέος εντέρου είναι περιορισμένα και συχνά αντικρουόμενα. Σκοπός της παρούσας μελέτης ήταν να ξεπεραστούν οι περιορισμοί που θέτουν οι μελέτες παρατήρησης και να εξεταστεί εάν τα γενετικά καθορισμένα χαρακτηριστικά του ύπνου έχουν αιτιακή επίδραση στον κίνδυνο ανάπτυξης καρκίνου του παχέος εντέρου συνολικά, καθώς και ανά φύλο του ασθενούς και ανατομική εντόπιση του καρκίνου (κόλον, ανιόν κόλον, κατιόν κόλον, ορθό). Μεθοδολογία: Εφαρμόστηκε η μέθοδος της Μεντελιανής τυχαιοποίησης δύο δειγμάτων και οι μέθοδοι ανάλυσης ευαισθησίας για την αξιολόγηση των παραδοχών των βοηθητικών μεταβλητών σε περιληπτικά δεδομένα σε 341 SNPs για τον χρονότυπο, 56 SNPs για την αϋπνία και 90 SNPs για τη διάρκεια ύπνου. Τα περιληπτικά δεδομένα για τη συσχέτιση των επιλεγμένων SNPs με τον κίνδυνο ανάπτυξης καρκίνου του παχέος εντέρου σε 125,478 συμμετέχοντες (58,131 ασθενείς και 67,347 μάρτυρες) αντλήθηκαν από τον συνασπισμό της GECCO, ενώ τα περιληπτικά δεδομένα για τη συσχέτιση των SNPs με τα χαρακτηριστικά του ύπνου αντλήθηκαν από δημοσιευμένες GWAS σε 651,295 συμμετέχοντες για τον χρονότυπο (UK Biobank και 23andMe), 254,767 για τα συχνά συμπτώματα αϋπνίας, 470,528 για οποιαδήποτε συμπτώματα αϋπνίας (UK Biobank, HUNT και Partners Biobank) και 493,298 για τη διάρκεια ύπνου (CHARGE και UK Biobank). Αποτελέσματα: Ο κίνδυνος ανάπτυξης καρκίνου του παχέος εντέρου στους άντρες βρέθηκε μειωμένος κατά 13.6% στους ‘πρωινούς’ σε σχέση με τους ‘βραδινούς’ τύπους (IVW random effects OR: 1.005, 95% CI: 0.956, 1.057). Το αποτέλεσμα αυτό παρέμεινε στατιστικά σημαντικό μετά από αφαίρεση των έκτοπων πλειοτροπικών SNPs και επιβεβαιώθηκε από τις υπόλοιπες μεθόδους ευαισθησίας. Αντίστοιχα, η επίδραση του χρονότυπου στον κίνδυνο ανάπτυξης καρκίνου του παχέος εντέρου στις γυναίκες δε βρέθηκε στατιστικά σημαντική (IVW random effects OR: 1.005, 95% CI: 0.956, 1.057). Από τις αναλύσεις των δεδομένων για τον ολικό καρκίνο του παχέος εντέρου και των στρωματοποιημένων δεδομένων, δεν υπήρξαν επαρκείς ενδείξεις για την αιτιακή επίδραση της αϋπνίας και της διάρκειας ύπνου στον κίνδυνο ανάπτυξης καρκίνου του παχέος εντέρου. Από την αναζήτηση στη Phenoscanner αναδείχθηκε ένας ικανός αριθμός συσχετίσεων με δευτερογενή φαινοτυπικά χαρακτηριστικά που μπορεί να σχετίζονται με τον κίνδυνο ανάπτυξης καρκίνου του παχέος εντέρου και να ευθύνονται για την εισαγωγή οριζόντιας πλειοτροπίας, μεταξύ αυτών το κάπνισμα, η κατανάλωση αλκοόλ, ο ΔΜΣ, ο διαβήτης, η σωματική αδράνεια, οι φλεγμονώδεις νόσοι του εντέρου και η αντίσταση στην ινσουλίνη. Συμπεράσματα: Η προτίμηση του να είναι κάποιος ‘πρωινός’ έναντι του να είναι ‘βραδινός’ τύπος επιδρά προστατευτικά στον κίνδυνο ανάπτυξης καρκίνου του παχέος εντέρου. Ωστόσο, απαιτείται η πραγματοποίηση περαιτέρω μελετών σε ανεξάρτητα δείγματα για την επαλήθευση των αποτελεσμάτων αυτών και η διασταύρωσή τους με τα ευρήματα μελετών προερχόμενων από άλλα πεδία (επιδημιολογικές μελετες παρατήρησης, κλινικές δοκιμές, προκλινικές μελέτες, γενετική μηχανική, μελέτες υποψήφιων γονιδίων), ούτως ώστε να διερευνηθούν οι υποκείμενοι βιολογικοί μηχανισμοί του αιτιακού μονοπατιού της καρκινογένεσης του παχέος εντέρου.Introduction: Over the past decades, the global patterns of incidence and mortality of the various tumour types have undergone some rapid changes, largely due to the variation in the distribution of inherent to modern lifestyle cancer risk factors. The transition from transmitted to human degenerative diseases, places cancers of the colorectum third in incidence and second in mortality. Amongst the changes taking place in developing societies, shift work that causes the disruption of the natural endogenous circadian rhythm has been nominated as a potential carcinogenic. Nevertheless, the published epidemiological evidence for the association between shift work and colorectal cancer is limited and often contradictory. The purpose of the current study was to overcome the limitations of observational studies and to investigate whether the genetically determined sleep characteristics have a causal effect on the risk of overall colon cancer, as well as by patient sex and according to cancer anatomical distribution (colon, distant colon, proximal colon, rectal cancer). Methods: A two-sample MR study was conducted on summary data and the subsequent sensitivity analysis were implemented to assess potential violation of the instrumental variable assumptions using 341 single nucleotide polymorphisms (SNPs) associated with chronotype, 56 SNPs associated with insomnia symptoms and 90 SNPs associated with sleep duration. Summary data for the association between the selected SNPs and the risk of colorectal cancer in 125,478 participants (58,131 cases και 67,347 controls) were retrieved from GECCO, while summary data for the association between the SNPs and the sleep characteristics were retrieved from published GWAS in 651,295 participants for chronotype (UK Biobank and 23andMe), 254,767 for frequent insomnia symptoms, 470,528 for any insomnia symptoms (UK Biobank, HUNT and Partners Biobank) and 493,298 for sleep duration (CHARGE and UK Biobank). Results: Morning preference in men was associated with a 13.6% lower risk of overall colorectal cancer (IVW random effects OR: 1.005, 95% CI: 0.956, 1.057). This finding remained robust after the exclusion of the outlying pleiotropic variants from the analysis and was confirmed by the rest of the sensitivity analysis methods. Respectively, the effect of chronotype on colorectal cancer in women was not statistically significant (IVW random effects OR: 1.005, 95% CI: 0.956, 1.057). From both the analysis of the overall colorectal cancer and the stratified data analysis, there was little evidence for the causal effect of insomnia and sleep duration on the risk of colorectal cancer. Several statistically significant associations emerged between the genetic instruments and a number of secondary traits via Phenoscanner search, including smoking, alcohol consumption, BMI, diabetes, physical inactivity, inflammatory bowel disease and insulin resistance, which may be associated with the risk of colorectal cancer and be responsible for the induction of horizontal pleiotropy. Conclusions: There was consistent evidence for a protective effect of morning preference on the risk of colorectal cancer. However, further studies on independent samples are required to validate this finding, as well as the triangulation of evidence stemming from other fields of study (epidemiological observational studies, clinical trials, preclinical studies, genetic engineering studies, candidate gene studies) in order to further investigate the underlying biological mechanisms of the colorectal carcinogenesis causal pathway

Could Reducing Body Fatness Reduce the Risk of Aggressive Prostate Cancer via the Insulin Signalling Pathway? A Systematic Review of the Mechanistic Pathway

Excess body weight is thought to increase the risk of aggressive prostate cancer (PCa), although the biological mechanism is currently unclear. Body fatness is positively associated with a diminished cellular response to insulin and biomarkers of insulin signalling have been positively associated with PCa risk. We carried out a two-pronged systematic review of (a) the effect of reducing body fatness on insulin biomarker levels and (b) the effect of insulin biomarkers on PCa risk, to determine whether a reduction in body fatness could reduce PCa risk via effects on the insulin signalling pathway. We identified seven eligible randomised controlled trials of interventions designed to reduce body fatness which measured insulin biomarkers as an outcome, and six eligible prospective observational studies of insulin biomarkers and PCa risk. We found some evidence that a reduction in body fatness improved insulin sensitivity although our confidence in this evidence was low based on GRADE (Grading of Recommendations, Assessment, Development and Evaluations). We were unable to reach any conclusions on the effect of insulin sensitivity on PCa risk from the few studies included in our systematic review. A reduction in body fatness may reduce PCa risk via insulin signalling, but more high-quality evidence is needed before any conclusions can be reached regarding PCa

Systematic review of Mendelian randomization studies on risk of cancer

Abstract Background We aimed to map and describe the current state of Mendelian randomization (MR) literature on cancer risk and to identify associations supported by robust evidence. Methods We searched PubMed and Scopus up to 06/10/2020 for MR studies investigating the association of any genetically predicted risk factor with cancer risk. We categorized the reported associations based on a priori designed levels of evidence supporting a causal association into four categories, namely robust, probable, suggestive, and insufficient, based on the significance and concordance of the main MR analysis results and at least one of the MR-Egger, weighed median, MRPRESSO, and multivariable MR analyses. Associations not presenting any of the aforementioned sensitivity analyses were not graded. Results We included 190 publications reporting on 4667 MR analyses. Most analyses (3200; 68.6%) were not accompanied by any of the assessed sensitivity analyses. Of the 1467 evaluable analyses, 87 (5.9%) were supported by robust, 275 (18.7%) by probable, and 89 (6.1%) by suggestive evidence. The most prominent robust associations were observed for anthropometric indices with risk of breast, kidney, and endometrial cancers; circulating telomere length with risk of kidney, lung, osteosarcoma, skin, thyroid, and hematological cancers; sex steroid hormones and risk of breast and endometrial cancer; and lipids with risk of breast, endometrial, and ovarian cancer. Conclusions Despite the large amount of research on genetically predicted risk factors for cancer risk, limited associations are supported by robust evidence for causality. Most associations did not present a MR sensitivity analysis and were thus non-evaluable. Future research should focus on more thorough assessment of sensitivity MR analyses and on more transparent reporting. </jats:sec

Systematic review of Mendelian randomization studies on risk of cancer

Background We aimed to map and describe the current state of Mendelian randomization (MR) literature on cancer risk and to identify associations supported by robust evidence. Methods We searched PubMed and Scopus up to 06/10/2020 for MR studies investigating the association of any genetically predicted risk factor with cancer risk. We categorized the reported associations based on a priori designed levels of evidence supporting a causal association into four categories, namely robust, probable, suggestive, and insufficient, based on the significance and concordance of the main MR analysis results and at least one of the MR-Egger, weighed median, MRPRESSO, and multivariable MR analyses. Associations not presenting any of the aforementioned sensitivity analyses were not graded. Results We included 190 publications reporting on 4667 MR analyses. Most analyses (3200; 68.6%) were not accompanied by any of the assessed sensitivity analyses. Of the 1467 evaluable analyses, 87 (5.9%) were supported by robust, 275 (18.7%) by probable, and 89 (6.1%) by suggestive evidence. The most prominent robust associations were observed for anthropometric indices with risk of breast, kidney, and endometrial cancers; circulating telomere length with risk of kidney, lung, osteosarcoma, skin, thyroid, and hematological cancers; sex steroid hormones and risk of breast and endometrial cancer; and lipids with risk of breast, endometrial, and ovarian cancer. Conclusions Despite the large amount of research on genetically predicted risk factors for cancer risk, limited associations are supported by robust evidence for causality. Most associations did not present a MR sensitivity analysis and were thus non-evaluable. Future research should focus on more thorough assessment of sensitivity MR analyses and on more transparent reporting

Genetically proxied glucose-lowering drug target perturbation and risk of cancer: a Mendelian randomisation analysis.

AIMS/HYPOTHESIS: Epidemiological studies have generated conflicting findings on the relationship between glucose-lowering medication use and cancer risk. Naturally occurring variation in genes encoding glucose-lowering drug targets can be used to investigate the effect of their pharmacological perturbation on cancer risk. METHODS: We developed genetic instruments for three glucose-lowering drug targets (peroxisome proliferator activated receptor γ [PPARG]; sulfonylurea receptor 1 [ATP binding cassette subfamily C member 8 (ABCC8)]; glucagon-like peptide 1 receptor [GLP1R]) using summary genetic association data from a genome-wide association study of type 2 diabetes in 148,726 cases and 965,732 controls in the Million Veteran Program. Genetic instruments were constructed using cis-acting genome-wide significant (p<5×10-8) SNPs permitted to be in weak linkage disequilibrium (r2<0.20). Summary genetic association estimates for these SNPs were obtained from genome-wide association study (GWAS) consortia for the following cancers: breast (122,977 cases, 105,974 controls); colorectal (58,221 cases, 67,694 controls); prostate (79,148 cases, 61,106 controls); and overall (i.e. site-combined) cancer (27,483 cases, 372,016 controls). Inverse-variance weighted random-effects models adjusting for linkage disequilibrium were employed to estimate causal associations between genetically proxied drug target perturbation and cancer risk. Co-localisation analysis was employed to examine robustness of findings to violations of Mendelian randomisation (MR) assumptions. A Bonferroni correction was employed as a heuristic to define associations from MR analyses as 'strong' and 'weak' evidence. RESULTS: In MR analysis, genetically proxied PPARG perturbation was weakly associated with higher risk of prostate cancer (for PPARG perturbation equivalent to a 1 unit decrease in inverse rank normal transformed HbA1c: OR 1.75 [95% CI 1.07, 2.85], p=0.02). In histological subtype-stratified analyses, genetically proxied PPARG perturbation was weakly associated with lower risk of oestrogen receptor-positive breast cancer (OR 0.57 [95% CI 0.38, 0.85], p=6.45×10-3). In co-localisation analysis, however, there was little evidence of shared causal variants for type 2 diabetes liability and cancer endpoints in the PPARG locus, although these analyses were likely underpowered. There was little evidence to support associations between genetically proxied PPARG perturbation and colorectal or overall cancer risk or between genetically proxied ABCC8 or GLP1R perturbation with risk across cancer endpoints. CONCLUSIONS/INTERPRETATION: Our drug target MR analyses did not find consistent evidence to support an association of genetically proxied PPARG, ABCC8 or GLP1R perturbation with breast, colorectal, prostate or overall cancer risk. Further evaluation of these drug targets using alternative molecular epidemiological approaches may help to further corroborate the findings presented in this analysis. DATA AVAILABILITY: Summary genetic association data for select cancer endpoints were obtained from the public domain: breast cancer ( https://bcac.ccge.medschl.cam.ac.uk/bcacdata/ ); and overall prostate cancer ( http://practical.icr.ac.uk/blog/ ). Summary genetic association data for colorectal cancer can be accessed by contacting GECCO (kafdem at fredhutch.org). Summary genetic association data on advanced prostate cancer can be accessed by contacting PRACTICAL (practical at icr.ac.uk). Summary genetic association data on type 2 diabetes from Vujkovic et al (Nat Genet, 2020) can be accessed through dbGAP under accession number phs001672.v3.p1 (pha004945.1 refers to the European-specific summary statistics). UK Biobank data can be accessed by registering with UK Biobank and completing the registration form in the Access Management System (AMS) ( https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access )

Genetically proxied glucose-lowering drug target perturbation and risk of cancer: a Mendelian randomisation analysis

Aims/hypothesis: Epidemiological studies have generated conflicting findings on the relationship between glucose-lowering medication use and cancer risk. Naturally occurring variation in genes encoding glucose-lowering drug targets can be used to investigate the effect of their pharmacological perturbation on cancer risk. Methods: We developed genetic instruments for three glucose-lowering drug targets (peroxisome proliferator activated receptor γ [PPARG]; sulfonylurea receptor 1 [ATP binding cassette subfamily C member 8 (ABCC8)]; glucagon-like peptide 1 receptor [GLP1R]) using summary genetic association data from a genome-wide association study of type 2 diabetes in 148,726 cases and 965,732 controls in the Million Veteran Program. Genetic instruments were constructed using cis-acting genome-wide significant (p−8) SNPs permitted to be in weak linkage disequilibrium (r 21c: OR 1.75 [95% CI 1.07, 2.85], p=0.02). In histological subtype-stratified analyses, genetically proxied PPARG perturbation was weakly associated with lower risk of oestrogen receptor-positive breast cancer (OR 0.57 [95% CI 0.38, 0.85], p=6.45×10−3). In co-localisation analysis, however, there was little evidence of shared causal variants for type 2 diabetes liability and cancer endpoints in the PPARG locus, although these analyses were likely underpowered. There was little evidence to support associations between genetically proxied PPARG perturbation and colorectal or overall cancer risk or between genetically proxied ABCC8 or GLP1R perturbation with risk across cancer endpoints. Conclusions/interpretation: Our drug target MR analyses did not find consistent evidence to support an association of genetically proxied PPARG, ABCC8 or GLP1R perturbation with breast, colorectal, prostate or overall cancer risk. Further evaluation of these drug targets using alternative molecular epidemiological approaches may help to further corroborate the findings presented in this analysis. Data availability: Summary genetic association data for select cancer endpoints were obtained from the public domain: breast cancer (https://bcac.ccge.medschl.cam.ac.uk/bcacdata/); and overall prostate cancer (http://practical.icr.ac.uk/blog/). Summary genetic association data for colorectal cancer can be accessed by contacting GECCO (kafdem at fredhutch.org). Summary genetic association data on advanced prostate cancer can be accessed by contacting PRACTICAL (practical at icr.ac.uk). Summary genetic association data on type 2 diabetes from Vujkovic et al (Nat Genet, 2020) can be accessed through dbGAP under accession number phs001672.v3.p1 (pha004945.1 refers to the European-specific summary statistics). UK Biobank data can be accessed by registering with UK Biobank and completing the registration form in the Access Management System (AMS) (https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access).</p