BACKGROUND: Tobacco smoking is an established risk factor for colorectal cancer. However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer. METHODS: A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia. RESULTS: Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs9880919, P = 4.58 × 10-8), with higher associated risk in subjects carrying the GG genotype [OR, 1.25; 95% confidence interval (CI), 1.20-1.30] compared with the other genotypes (OR <1.17 for GA and AA). Among ever smokers, we observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p21.33 (rs4151657, P = 1.72 × 10-8) and 8q24.23 (rs7005722, P = 2.88 × 10-8). Subjects carrying the rs4151657 TT genotype showed higher risk (OR, 1.12; 95% CI, 1.09-1.16) compared with the other genotypes (OR <1.06 for TC and CC). Similarly, higher risk was observed among subjects carrying the rs7005722 AA genotype (OR, 1.17; 95% CI, 1.07-1.28) compared with the other genotypes (OR <1.13 for AC and CC). Functional annotation revealed that SNPs in 3p12.1 and 6p21.33 loci were located in regulatory regions, and were associated with expression levels of nearby genes. Genetic models predicting gene expression revealed that smoking parameters were associated with lower colorectal cancer risk with higher expression levels of CADM2 (3p12.1) and ATF6B (6p21.33). CONCLUSIONS: Our study identified novel genetic loci that may modulate the risk for colorectal cancer of smoking status and intensity, linked to tumor suppression and immune response. IMPACT: These findings can guide potential prevention treatments.

• MeSH
• genetická predispozice k nemoci * MeSH
• genetické lokusy MeSH
• genotyp MeSH
• jednonukleotidový polymorfismus MeSH
• kolorektální nádory * epidemiologie   MeSH
• kouření tabáku MeSH
• kouření genetika   MeSH
• lidé MeSH
• rizikové faktory MeSH
• studie případů a kontrol MeSH
• zánět MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: Evidence for aspirin's chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk. METHODS: Human colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labeling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL (N = 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N = 31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls). RESULTS: Altered expression was detected for 125/5886 proteins. Of these, aspirin decreased MCM6, RRM2, and ARFIP2 expression, and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR: 1.08, 95% CI, 1.03-1.13; OR: 3.33, 95% CI, 2.46-4.50; and OR: 1.15, 95% CI, 1.02-1.29, respectively). CONCLUSIONS: MCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation, indicating a possible role in aspirin's reduction of metastasis. IMPACT: Our approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk.

• MeSH
• Aspirin farmakologie   terapeutické užití   MeSH
• kolorektální nádory farmakoterapie   MeSH
• lidé MeSH
• mendelovská randomizace metody   MeSH
• proteomika metody   MeSH
• rizikové faktory MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH

BACKGROUND AND AIMS: Susceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes. METHODS: Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (n = 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dual-luciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted. RESULTS: We identified 25 genes associated with CRC risk at a Bonferroni-corrected threshold of P < 9.1 × 10-6, including genes in 4 novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In 9 known GWAS-identified loci, we uncovered 9 genes that have not been reported previously, whereas 4 genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P < .01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis. CONCLUSIONS: Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.

• MeSH
• alely MeSH
• celogenomová asociační studie MeSH
• genetická predispozice k nemoci * MeSH
• genový knockdown MeSH
• jednonukleotidový polymorfismus MeSH
• karcinogeneze genetika   MeSH
• kohortové studie MeSH
• kolorektální nádory epidemiologie   genetika   MeSH
• lidé MeSH
• modely genetické * MeSH
• nádorové biomarkery genetika   MeSH
• promotorové oblasti (genetika) genetika   MeSH
• rizikové faktory MeSH
• sekvenování transkriptomu MeSH
• studie případů a kontrol MeSH
• xenogenní modely - testy antitumorózní aktivity MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH

BACKGROUND & AIMS: Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development. METHODS: Serum levels of IGF1 were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow-up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls]) RESULTS: After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [CI] 1.05-1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03-1.12; P = 3.3 × 10-4). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06-1.18; P = 4.2 × 10-5). Colorectal cancer risk was associated with only 1 variant in the IGFBP3 gene region (rs11977526), which also associated with anthropometric traits and circulating level of IGF2. CONCLUSIONS: In an analysis of blood samples from almost 400,000 participants in the UK Biobank, we found an association between circulating level of IGF1 and colorectal cancer. Using genetic data from 52,865 cases with colorectal cancer and 46,287 controls, a higher level of IGF1, determined by genetic factors, was associated with colorectal cancer. Further studies are needed to determine how this signaling pathway might contribute to colorectal carcinogenesis.

• MeSH
• hodnocení rizik metody   MeSH
• IGFBP-3 krev   genetika   MeSH
• incidence MeSH
• insulinu podobný růstový faktor I analýza   genetika   MeSH
• insulinu podobný růstový faktor II analýza   MeSH
• jednonukleotidový polymorfismus MeSH
• kolorektální nádory krev   epidemiologie   genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mendelovská randomizace MeSH
• nádorové biomarkery krev   genetika   MeSH
• následné studie MeSH
• registrace statistika a číselné údaje   MeSH
• rizikové faktory MeSH
• senioři MeSH
• sexuální faktory MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH
• Geografické názvy
• Spojené království MeSH

BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC. METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants. RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10-5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings. CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.

• MeSH
• anamnéza MeSH
• celogenomová asociační studie MeSH
• datové soubory jako téma MeSH
• genetická predispozice k nemoci * MeSH
• genotypizační techniky MeSH
• jednonukleotidový polymorfismus MeSH
• kohortové studie MeSH
• kolorektální nádory genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutační analýza DNA MeSH
• mutační rychlost MeSH
• rizikové faktory MeSH
• sekvenování celého genomu MeSH
• studie případů a kontrol MeSH
• věk při počátku nemoci MeSH
• životní styl MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH

BACKGROUND: Risk variants identified so far for colorectal cancer explain only a small proportion of familial risk of this cancer, particularly in Asians. METHODS: We performed a genome-wide association study (GWAS) of colorectal cancer in East Asians, including 23,572 colorectal cancer cases and 48,700 controls. To identify novel risk loci, we selected 60 promising risk variants for replication using data from 58,131 colorectal cancer cases and 67,347 controls of European descent. To identify additional risk variants in known colorectal cancer loci, we performed conditional analyses in East Asians. RESULTS: An indel variant, rs67052019 at 1p13.3, was found to be associated with colorectal cancer risk at P = 3.9 × 10-8 in Asians (OR per allele deletion = 1.13, 95% confidence interval = 1.08-1.18). This association was replicated in European descendants using a variant (rs2938616) in complete linkage disequilibrium with rs67052019 (P = 7.7 × 10-3). Of the remaining 59 variants, 12 showed an association at P < 0.05 in the European-ancestry study, including rs11108175 and rs9634162 at P < 5 × 10-8 and two variants with an association near the genome-wide significance level (rs60911071, P = 5.8 × 10-8; rs62558833, P = 7.5 × 10-8) in the combined analyses of Asian- and European-ancestry data. In addition, using data from East Asians, we identified 13 new risk variants at 11 loci reported from previous GWAS. CONCLUSIONS: In this large GWAS, we identified three novel risk loci and two highly suggestive loci for colorectal cancer risk and provided evidence for potential roles of multiple genes and pathways in the etiology of colorectal cancer. In addition, we showed that additional risk variants exist in many colorectal cancer risk loci identified previously. IMPACT: Our study provides novel data to improve the understanding of the genetic basis for colorectal cancer risk.

• MeSH
• Asijci genetika   MeSH
• celogenomová asociační studie MeSH
• dospělí MeSH
• genetická predispozice k nemoci * MeSH
• genetické lokusy * MeSH
• jednonukleotidový polymorfismus MeSH
• kolorektální nádory epidemiologie   genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lidské chromozomy, pár 1 genetika   MeSH
• mutace INDEL MeSH
• rizikové faktory MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• vazebná nerovnováha MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH
• Geografické názvy
• Čína MeSH
• Japonsko MeSH
• Korejská republika MeSH