You will be presented with a collection of medical randomized controlled trial (RCT) reports addressing a shared clinical question -- for instance, the efficacy of a medical intervention on a disease or condition. Given the titles and abstracts of these reports, your task is to generate the conclusion of the systematic review article synthesizing the key findings. Your conclusion should be a few sentences long. In your response, include only the conclusion and no other text. The RCT reports are below.



Title 1:
Polymorphisms in the xenobiotic transporter Multidrug Resistance 1 (MDR1) and interaction with meat intake in relation to risk of colorectal cancer in a Danish prospective case-cohort study
Abstract 1:
Background The xenobiotic transporters , Multidrug Resistance 1 ( MDR1/ABCB1 ) and Breast Cancer Resistance Protein ( BCRP/ABCG2 ) may restrict intestinal absorption of various carcinogens , including heterocyclic amines ( HCA ) and polycyclic aromatic hydrocarbons ( PAH ) . Cyclooxygenase-2 ( COX-2 ) derived prostagl and ins promote gastrointestinal carcinogenesis , affecting angiogenesis , apoptosis , and invasiveness . The aim of this study was to investigate if polymorphisms in these genes were associated with risk of colorectal cancer ( CRC ) , and to investigate possible interactions with lifestyle factors such as smoking , meat consumption , and NSAID use . Methods The following polymorphisms were analyzed ; a synonymous MDR1 C3435 T ( rs1045642 ) in exon26 , G-rs3789243-A in intron3 , the functional BCRP C421A ( rs2231142 ) , the two COX-2 A-1195 G ( rs689466 ) and G-765C ( rs20417 ) in the promoter region , and the COX-2 T8473C ( rs5275 ) polymorphisms in the 3'-untranslated region . The polymorphisms were assessed together with lifestyle factors in a nested case-cohort study of 359 cases and a r and om cohort sample of 765 participants from the Danish prospect i ve Diet , Cancer and Health study . Results Carriers of the variant allele of MDR1 intron 3 polymorphism were at 1.52-fold higher risk of CRC than homozygous wild type allele carriers ( Incidence rate ratio ( IRR ) = 1.52 , 95 % Confidence Interval ( CI ) : 1.12 - 2.06 ) . Carriers of the variant allele of MDR1 C3435 T exon 26 had a lower risk of CRC than homozygous C-allele carriers ( IRR = 0.71 ( CI:0.50 - 1.00 ) ) . There was interaction between these MDR1 polymorphisms and intake of red and processed meat in relation to CRC risk . Homozygous MDR1 C3435 T C-allele carriers were at 8 % increased risk pr 25 gram meat per day ( CI : 1.00 - 1.16 ) whereas variant allele carriers were not at increased risk ( p for interaction = 0.02 ) . COX-2 and BCRP polymorphisms were not associated with CRC risk . There was interaction between NSAID use and MDR1 C3435 T and COX-2 T8473C ( p-values for interaction 0.001 and 0.04 , respectively ) . Conclusion Two polymorphisms in MDR1 were associated with CRC risk and there was interaction between these polymorphisms and meat intake in relation to CRC risk . Our results suggest that MDR1 polymorphisms affect the relationship between meat and CRC risk


Title 2:
Analysis of VEGF polymorphisms, tumor expression of VEGF mRNA and colorectal cancer susceptibility in a Swedish population.
Abstract 2:
Vascular endothelial growth factor ( VEGF ) plays a significant role in tumor angiogenesis and is found to be overexpressed and involved in the development and progression of colorectal cancer ( CRC ) . The VEGF gene contains several polymorphic sites known to influence VEGF expression . We examined the possible association between five polymorphisms , located in the promoter/5'-untranslated region [ -2578 ( C/A ) , -2549 ( del/ins 18 bp ) , -1154 ( G/A ) , -634 ( G/C ) ] or 3'-untranslated region [ + 936 ( C/T ) ] of the VEGF gene , and CRC  susceptibility  and clinicopathological characteristics  in 302 Swedish CRC patients and 336 healthy r and omly selected controls . Both genotypes and combined haplotypes were analyzed . No significant differences were observed when VEGF genotype/haplotype frequencies in the CRC cases and controls were compared , nor were any associations found between the genotypes/haplotypes and clinicopathological characteristics . However , when the -2578 C and + 936 T alleles were combined , a small but significant association with CRC susceptibility was detected ( OR=1.6 , 95 % CI 1.3 - 1.9 , p=0.01 ) . In addition , VEGF mRNA expression was determined in a subset of patients , revealing a 2-fold VEGF upregulation in CRC tissue compared to normal colonic mucosa , but no association between the genotypes or haplotypes and VEGF mRNA levels . Linkage analysis was performed , revealing that the polymorphisms in the promoter and 5'-untranslated region were in tight linkage disequilibrium ( LD ) ( _ _ AMB__verbar;D'__AMB__verbar;=0.91 - 1.00 ) , while the + 936 C/T polymorphism was only weakly associated with the others ( _ _ AMB__verbar;D'__AMB__verbar;=0.05 - 0.19 ) . In conclusion , VEGF is generally upregulated in colorectal tumors . However , the single nucleotide polymorphisms examined do not appear to influence the mRNA expression of VEGF in colorectal tumors , and most likely play a limited role in CRC development and progression


Title 3:
Vitamin D Receptor Gene Polymorphism and the Risk of Colorectal Cancer: A Nested Case-Control Study
Abstract 3:
Epidemiological and experimental evidence suggest that vitamin D is protective against the risk of  colorectal cancer  . Polymorphisms in the gene encoding vitamin D receptor ( VDR ) , which mediates most of the known cellular effects of vitamin D , have been suggested to alter this association . Here , using a tag SNP approach , we comprehensively evaluated the role of common genetic variants in VDR and their interaction with plasma vitamin D levels in relation to colorectal cancer risk in Japanese population s. A total of 356 colorectal cancer cases and 709 matched control subjects were selected from the participants of the Japan Public Health Center-based Prospect i ve Cohort Study . Among these subjects , 29 VDR single nucleotide polymorphisms  ( SNPs ) were selected and genotyped , and  plasma vitamin D concentrations  were measured . Conditional logistic regression models were used to estimate odds ratios ( ORs ) and 95 % confidence intervals ( CIs ) of colorectal cancer , with adjustment for potential confounding factors . Among the results , eight VDR SNPs , namely rs2254210 , rs1540339 , rs2107301 , rs11168267 , rs11574113 , rs731236 , rs3847987 and rs11574143 , the latter 5 of which were located in the 3′ region , were nominally associated with the risk of colorectal cancer ( P = 0.01–0.048 ) . Furthermore , of the above 5 3′ region SNPs , the inverse associations for 3 SNPs ( rs11574113 , rs3847987 and rs11574143 ) appeared to be evident only in those with high plasma vitamin D concentration . However , neither of these direct and suggestive interaction analysis associations was significant after multiple testing adjustment . Overall , the findings of this study provide only limited support for an association between common genetic variations in VDR and colorectal cancer risk in the Japanese population


Title 4:
The prevalence of somatic RAS mutations in medullary thyroid cancer - a Polish population study.
Abstract 4:
INTRODUCTION Somatic RET mutations are detectable in two-thirds of sporadic cases of medullary thyroid cancer ( MTC ) . Recent studies reported a high proportion of RAS somatic mutations in RET negative tumours , which may indicate RAS mutation as a possible alternative genetic event in sporadic MTC tumorigenesis . Thus , the aim of the study was to evaluate the frequency of somatic RAS mutations in sporadic medullary thyroid cancer in the Polish population and to relate the obtained data to the presence of somatic RET mutations . MATERIAL AND METHODS  Somatic mutations ( RET , RAS genes ) were evaluated in 78 snap-frozen MTC sample s ( 57 sporadic and 21 hereditary ) by direct sequencing .  Next , three r and omly selected RET-negative MTC sample s were analysed by the next generation sequencing . RESULTS RAS mutation was detected in 26.5 % of 49 sporadic MTC tumours . None of all the analysed sample s showed N-RAS mutation . When only RET-negative sample s were considered , the prevalence of RAS mutation was 68.7 % , compared to 6 % observed in RET-positive sample s. Most of these mutations were located in H-RAS codon 61 ( 72 % ) . None of 21 hereditary MTC sample s showed any RAS mutations . CONCLUSIONS RAS mutations constitute a frequent molecular event in RET-negative sporadic medullary thyroid carcinoma in Polish patients . However , their role in MTC tumorigenesis remains unclear


Title 5:
Interactions between Diet, Lifestyle and IL10, IL1B, and PTGS2/COX-2 Gene Polymorphisms in Relation to Risk of Colorectal Cancer in a Prospective Danish Case-Cohort Study
Abstract 5:
Background & Aims Diet contributes to colorectal cancer development and may be potentially modified . We wanted to identify the biological mechanisms underlying colorectal carcinogenesis by assessment of diet-gene interactions . Methods The polymorphisms IL10 C-592A ( rs1800872 ) , C-rs3024505-T , IL1b C-3737 T ( rs4848306 ) , G-1464C ( rs1143623 ) , T-31C ( rs1143627 ) and PTGS2 ( encoding COX-2 ) A-1195 G ( rs689466 ) , G-765C ( rs20417 ) , and T8473C ( rs5275 ) were assessed in relation to risk of colorectal cancer ( CRC ) and interaction with diet ( red meat , fish , fibre , cereals , fruit and vegetables ) and lifestyle ( non-steroid-anti-inflammatory drug use and smoking status ) was assessed in a nested case-cohort study of nine hundred and seventy CRC cases and 1789 r and omly selected participants from a prospect i ve study of 57,053 persons . Results IL1b C-3737 T , G-1464C and PTGS2 T8473C variant genotypes were associated with risk of CRC compared to the homozygous wildtype genotype ( IRR=0.81 , 95%CI : 0.68 - 0.97 , p=0.02 , and IRR=1.22 , 95%CI : 1.04 - 1.44 , p=0.02 , IRR=0.75 , 95%CI : 0.57 - 0.99 , p=0.04 , respectively ) . Interactions were found between  diet and IL10 rs3024505 ( P-value for interaction ( Pint ) ; meat=0.04 , fish=0.007 , fibre=0.0008 , vegetables=0.0005 ) , C-592A ( Pint ; fibre=0.025 ) , IL1b C-3737 T ( Pint ; vegetables=0.030 , NSAID use=0.040 ) and PTGS2 genotypes G-765C ( Pint ; meat=0.006 , fibre=0.0003 , fruit 0.004 ) , and T8473C ( Pint ; meat 0.049 , fruit=0.03 ) and A-1195 G ( Pint ; meat 0.038 , fibre 0.040 , fruit=0.059 , vegetables=0.025 , and current smoking=0.046 ) . Conclusions Genetically determined low COX-2 and high IL-1β activity were associated with increased risk of CRC in this northern Caucasian cohort . Furthermore , interactions were found between IL10 , IL1b , and PTGS2 and diet and lifestyle factors in relation to CRC . The present study demonstrates that gene-environment interactions may identify genes and environmental factors involved in colorectal carcinogenesis


Title 6:
Polymorphisms in the genes involved in the arachidonic acid‐pathway, fish consumption and the risk of colorectal cancer
Abstract 6:
The objective of this study on colorectal cancer was to investigate the associations between SNPs in the genes involved in the arachidonic acid (AA)‐pathway , their haplotypes and colorectal cancer . Moreover , interactions between SNPs and fish consumption were considered . In this study , a total of 508 cases and 772 controls were included , originating from 2 prospect i ve cohorts , the Monitoring Project on Cardiovascular Disease Risk Factors ( PPHV ) and Diagnostisch Onderzoek Mammacarcinoom ( DOM ) . Genotypes of 23 SNPs in 7 c and i date genes were determined and the modifying effect of fish consumption was considered . A protective effect of the minor allele of SNP V102V in PTGS2 was observed ( odds ratio ( OR ) , 0.37 ; 95 % confidence intervals ( CI ) , 0.16–0.87 ) . The haplotype representing this allele showed a weaker inverse association , indicating that 2 alleles are necessary to obtain this protective effect .  Fish consumption  data was available for 209 cases and 418 controls .  Increased fish consumption was inversely associated with cancer , although not significant ( OR , 0.83 ; 95 % CI , 0.57–1.20 ) . Despite the substantial reductions in cancer risk for some genotypes in combination with high fish intake , no significant interactions between any SNP studied and fish consumption were observed . We have previously described an association between colorectal adenomas and SNP V102V in PTGS2 and have now confirmed this association for colorectal adenocarcinomas . Fish consumption of once a week or more might protect against colorectal cancer , but no significant interactions with SNPs in the genes involved in the AA‐pathway could be detected within the study . © 2006 Wiley‐Liss ,
In conclusion , minor allele of rs3025039 , rs3212986 , and rs712 polymorphisms increases the risk of CRC in the East Asian population , and heterozygote model of rs731236 polymorphism shows protective effect in the Middle East population .
In Europeans , the minor allele of rs17281995 may increase the risk of CRC , while rs712 may have a protective effect .