Kopp, Tine Iskov

Cancer incidensen i Vesten er steget stødt de sidste 50 år. For tre af de mest prævalente cancer typer i Danmark, prostata-, bryst- og kolorektal cancer, er kun en lille del (1-15%) af incidensen forårsaget af højpenetrans enkelt-genmutationer pga. deres lave frekvens i populationen. Generelt set bidrager nedarvede faktorer til årsagsforhold for bryst cancer kun med 27%, hvorimod genetik bidrager med 35% og 42% for henholdsvis kolorektal- og prostata cancer. Derudover indikerer immigrationsstudier at miljø-faktorer har en stærk indflydelse på karcinogenesen. Derfor kan hyppige, lav-effekt polymorfier have et større bidrag på populationsniveau i kombination med miljøfaktorer. Flere kost- og livstilsfaktorer er nu veletablerede risikofaktorer for forskellige cancer typer, såsom indtag af alkohol, rygning, fedme, inflammation og højt indtag af kød; hvorimod andre faktorer beskytter mod cancer, såsom et højt indtag af kostfibre, frugt og grønt, og fysisk aktivitet. Ved at undersøge samspillet mellem genetiske variationer og miljøfaktorer, som kost- og livsstilsfaktorer, kan der opnås viden om de bagvedliggende mekanismer og afdækkes nye biologiske veje.Formålet med denne ph.d. afhandling var at undersøge relevante risikofaktorer i forhold til de tre store cancer typer i Danmark: prostata-, bryst- og kolorektal cancer. De to primære risikofaktorer som blev undersøgt i denne afhandling var inflammation og alkohol indtag. I forhold til inflammation, blev biologiske veje der er involveret i inflammation og disses samspil med forskellige kost- og livsstilsfaktorer som ændrer på risikoen for henholdsvis kolorektal- (Paper II-IV) og prostata (Paper I) cancer undersøgt. Ydermere blev en mulig mekanisme i alkoholrelateret bryst cancer hos postmenopausale kvinder undersøgt (Paper V-VI). Denne mekanisme involverer en specifik polymorfi i PPARG (som koder for peroxisome proliferator-activated receptor (PPARγ)) og interaktion med aromatasen (som er kodet af CYP19A1).Det danske prospektive “Kost, Kræft og Helbred” kohorte studie blev brugt til at undersøge gen-gen og genmiljø interaktioner i forhold til risikoen for cancer (Paper I-V). Et humant interventions studie (Paper V) blev udført for direkte at undersøge effekten af samtidig indtag af non-steroide anti-inflammatoriske lægemidler (NSAID) og alkohol på cirkulerende kvindelige kønshormoner. Slutteligt blev der udført nogle in vitro forsøg for at undersøge effekten på PPARγ trans-aktivering og kønshormon niveau efter eksponering af andre almindeligt brugte organiske opløsningsmidler end alkohol (Paper VI).På baggrund af resultaterne fra Paper I, syntes inflammation ikke at være en betydelig risikofaktor for aggressiv prostata cancer, hvorimod resultaterne fra non-aggressiv prostata cancer var mere tvetydige. Derimod indikerede Paper II og III at immunforsvaret er involveret i kolorektal karcinogenesen. At være bærer af det pro-inflammatoriske allel fra NFKB1 genet var ikke associeret med aggressiv prostata cancer risiko, men var derimod associeret med nedsat risiko for non-aggressiv prostata cancer, og med øget risiko for kolorektal cancer. Selvom ingen af resultaterne var statistisk stærke, viste de at cancer er en meget heterogen sygdom; og indikerede at inflammation højst sandsynlig ikke er en risikofaktor for (aggressiv) prostata cancer, men tyder på at være vigtig i forhold til kolorektal cancer. I Paper III blev en ny mekanisme der involverer de ATP-bindende cassette (ABC) transportere, cytokinet interleukin (IL) 10 og kostfibre i forhold til beskyttelse mod inflammations-induceret kolorektal cancer fundet. Ydermere tydede resultaterne på at brug af NSAID interagerer med ABC transporterne og IL-10 i forhold til kolorektal cancer.Paper V illustrerede at genetiske variationer i CYP19A1 prædikterer cirkulerende kønshormon niveauer hos postmenopausale kvinder, og at indtag af alkohol påvirker koncentrationen af kvindelige kønshormoner i blodet. Dog var det ikke muligt at anbringe PPARγ og aromatasen i den samme biologiske vej som antaget a priori i forhold til alkoholrelateret bryst cancer; og den formodede effekt modifikation af samtidigt brug af NSAID og alkohol blev ikke bekræftet. Ikke desto mindre indikerede resultaterne fra Paper VI at eksponering til almindeligt brugte organiske opløsningsmidler muligvis ændrer på kønshormonniveauer via PPARγ. Men om der er en fælles mekanisme som linker aromatasen og PPARγ; og ligeledes om ændringerne i hormonniveau øger risikoen for bryst cancer, er stadig uopklaret. Disse studier viste desuden at akut og kronisk alkoholindtag muligvis har forskellig effekt på kønshormon syntese og metabolisme, og at det ikke er ligetil at sammenligne observationelle studier med eksperimentelle studier.Overordnet har denne ph.d. afhandling vist at genetisk epidemiologi kan bruges til at studere biologiske mekanismer i kombination med andre mekanistiske studier på trods af flere begrænsninger såsom manglende viden om confounding og begrænset statistisk power til at undersøge gen-miljø interaktioner.Fremtidige studier vil kunne påvise om og hvordan kostfibre, IL-10 og ABC transportere er forbundet i forhold til at nedsætte risikoen for kolorektal cancer; og afklare hvorvidt rødt kød per se, tilberedelses metoden eller livsstilen, som er associeret med højt kød indtag, er karcinogent. Denne viden vil kunne forbedre de nuværende kostanbefalinger.Der synes også at være adskillige hidtil ukendte effekter af NSAID forbrug som er nødvendige at klarlægge. Viden om disse mulige (bi-)virkninger ville kunne medføre bedre og mere sikker medicinering og derfor også forbedret folkesundhed. Yderligere viden om de sundhedsskadelige effekter som er relateret til indtag af alkohol, inklusiv den mulige effekt modificering af samtidig brug af NSAID, ville også føre til forbedrede forebyggende folkesundhedsstrategier.The incidence of cancer in the western world has increased steeply during the last 50 years. For three of the most prevalent cancer types in Denmark, prostate, breast and colorectal cancer (PC, BC and CRC, respectively), only a small fraction (1-15%) of the incidences are caused by highly penetrant single-gene mutations due to their low frequency in the general population. Overall, the contribution from hereditary factors to the causation of BC is only 27%, whereas genetics contributes to 35% and 42% for CRC and PC, respectively. Additionally, immigrations studies point to environmental factors as having strong influence on carcinogenesis. Therefore, very frequent, low effect polymorphisms may have a greater contribution on a population level in combination with environmental factors. Indeed, several dietary and life style factors are now well-established risk factors for different cancer types, such as alcohol consumption, smoking, obesity, inflammation and high meat intake; whereas other factors protect against cancer, such as high intake of dietary fibre, fruits and vegetables, and physical activity. Investigating the interactions between genetic variations and environmental factors, such as dietary and lifestyle factors may provide information about the underlying mechanisms and reveal new biological pathways.The aim of this PhD thesis was to investigate relevant risk factors in relation to the three major cancer types in Denmark: PC, BC and CRC, respectively. The two major risk factors examined in this thesis are inflammation and alcohol consumption. With regard to inflammation, biological pathways involved in inflammation and the interaction with different dietary and lifestyle factors modulating the risk of CRC (PaperII-IV) and PC (Paper I), respectively, was examined. Moreover, a possible mechanism in alcohol-related BC in postmenopausal women involving a specific polymorphism in PPARG (coding the peroxisome proliferatoractivated receptor (PPARγ)) and its interaction with the aromatase (encoded by CYP19A1) was investigated (Paper V-VI).The Danish prospective “Diet, Cancer and Health” cohort study was used to examine gene-gene and geneenvironment interactions in relation to risk of cancer (Paper I-V). A human intervention trial (Paper V) was conducted in order to directly examine the effect on concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs) and alcohol consumption on circulating female sex-hormones. Finally, in vitro assays were performed to study the effect on PPARγ transactivation and sex-hormone concentrations following exposure to other commonly used organic solvents than alcohol (Paper VI).Based on the results from Paper I, inflammation did not seem to be a major risk factor for aggressive PC, whereas the results on non-aggressive PC were equivocal. In contrast, Paper II and III indicated that the immune system is indeed involved in the carcinogenesis of CRC. Carriage of a pro-inflammatory allele of the NFKB1 gene, was not associated with aggressive PC risk, but was associated to lowered risk of nonaggressive PC, and to increased risk of CRC. Even though none of the results were strong statistically, they demonstrated that cancer is a very heterogeneous disease; and indicated that inflammation may not be a risk factor for (aggressive) PC, but in relation to CRC, inflammation seems important. In Paper III, a new possible mechanism involving the ATP-binding cassette (ABC) transporters, the cytokine interleukin (IL) 10 and dietary fibre in relation to protection against inflammation-induced CRC was found. Furthermore, use of NSAIDs seemed to interact with the ABC transporters and IL-10 in relation to CRC.Paper V illustrated that genetic variations in CYP19A1 predicts circulating sex-hormone levels in postmenopausal women, and that alcohol intake affects female sex-hormone concentrations in the blood. However, it was not possible to put PPARγ and the aromatase in the same pathway as hypothesized a priori in alcohol-related BC; and the possible effect modification of concurrent use of NSAIDs and alcohol consumption was not confirmed. Nevertheless, results from Paper VI, indicated that exposure to commonly used organic solvents may act via PPARγ modulating sex-hormone levels. However, whether there is a common mechanism linking the aromatase and PPARγ, and also whether the differences in hormone levels increases risk of BC, still needs to be elucidated. Furthermore, these studies illustrated that acute and chronic alcohol consumption may have different effects on sex-hormone biosynthesis and metabolism, and that it is not straightforward to compare observational studies with experimental studies.Overall, this PhD thesis has shown that genetic epidemiology can be used to study biological mechanisms in combination with other mechanistic studies, although there are several limitations involved such as missing knowledge of confounders and limited statistical power to study gene-environment interactions.Future research could establish whether and how dietary fibre, IL-10 and ABC transporters are connected in reducing the risk of CRC; and whether red meat per se, specific preparation methods or the life style associated with high red meat intake is carcinogenic. The acquired knowledge would improve the current dietary recommendations.There also seem to be several yet unknown effects of NSAID usage that need to be clarified. Information of these potential (side) effects would lead to better and safer medication regimens and, hence, improved public health. Also, further knowledge of the harmful health effects related to alcohol consumption, including the potential effect modification with concurrent use of NSAIDs, would lead to improved public preventive strategies

Online Research Database In Technology

Gene-gene and gene-environment interactions in prostate, breast and colorectal cancer

http://orbit.dtu.dk/ws/files/119983239/PhD_Kopp_TI_final_combined_print1.pdf

Gene-gene and gene-environment interactions in prostate, breast and colorectal cancer

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