Abstract
Background and purpose: Colorectal cancer (CRC) is the third leading cause of cancer deaths in the U.S. Establishing new genetic variants associated with CRC risk may lead to early CRC ...detection and novel treatment options. Recently, mouse genetic studies identified the cystic fibrosis transmembrane conductance regulator (CFTR) gene as a tumor suppressor in CRC. In line with this, a human study using MarketScan claims data showed that cystic fibrosis (CF) carriers – individuals with one copy of mutant CFTR – are at increased CRC risk. Although there are more than 10 million CF carriers in the U.S., to our knowledge, no studies comprehensively examined CFTR mutations in relation to CRC risk. Our hypothesis is that CFTR mutations are associated with an increased risk of CRC. Methods: We used whole exome sequencing (WES) data in 454,333 individuals (age 44-82 years), including 4,975 cases of CRC, in the UK Biobank study. We utilized risk set sampling to select up to four controls per CRC case based on age of diagnosis, gender, race, and year of joining the study. To examine associations between CFTR mutations and CRC risk, logistic regression (odds ratio and p-value) was used after adjusting for age, gender and 10 principal components capturing global ancestry. An aggregate burden score was constructed that included all variants listed as CF-causing in the CFTR2 online database. Results: Of the 465 CFTR variants in the CFTR2 database, 378 are classified as CF-causing, and of those 153 were observed in the UK Biobank WES data set. Individuals with two CF-causing alleles were excluded from further analysis (8 cases and 35 controls), since the association between CF and CRC is already well established. The frequency of the F508del variant, the most common CF-causing mutation, was 3.77% in cases versus 3.11% in controls, while the frequency of any other CF-causing mutation was 1.07% in cases versus 0.80% in controls. Having any CF-causing mutation was associated with a significant 24% increased CRC risk (one-sided p=0.002). Having one copy of the F508del mutation, was associated with a significant 21% increased risk of CRC (one-sided p=0.012), while having one copy of any other CF-causing mutation was associated with a slightly larger 34% increased risk of CRC (one-sided p=0.036). Conclusions: CF-causing mutations in the heterozygous state lead to a significantly increased risk of CRC. Individuals with multiple genetic risk factors, such as in CFTR, may require earlier screening for CRC.
Citation Format: Anna E. Prizment, Abigail Standafer, Shuo Wang, Conghui Qu, Ulrike Peters, Patricia Scott, Timothy Starr, Nathan Pankratz. Heterozygote carriers of cystic fibrosis mutations have increased risk of colorectal cancer abstract. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A031.
High red meat and/or processed meat consumption are established colorectal cancer risk factors. We conducted a genome-wide gene-environment (GxE) interaction analysis to identify genetic variants ...that may modify these associations.
A pooled sample of 29,842 colorectal cancer cases and 39,635 controls of European ancestry from 27 studies were included. Quantiles for red meat and processed meat intake were constructed from harmonized questionnaire data. Genotyping arrays were imputed to the Haplotype Reference Consortium. Two-step EDGE and joint tests of GxE interaction were utilized in our genome-wide scan.
Meta-analyses confirmed positive associations between increased consumption of red meat and processed meat with colorectal cancer risk per quartile red meat OR = 1.30; 95% confidence interval (CI) = 1.21-1.41; processed meat OR = 1.40; 95% CI = 1.20-1.63. Two significant genome-wide GxE interactions for red meat consumption were found. Joint GxE tests revealed the rs4871179 SNP in chromosome 8 (downstream of HAS2); greater than median of consumption ORs = 1.38 (95% CI = 1.29-1.46), 1.20 (95% CI = 1.12-1.27), and 1.07 (95% CI = 0.95-1.19) for CC, CG, and GG, respectively. The two-step EDGE method identified the rs35352860 SNP in chromosome 18 (SMAD7 intron); greater than median of consumption ORs = 1.18 (95% CI = 1.11-1.24), 1.35 (95% CI = 1.26-1.44), and 1.46 (95% CI = 1.26-1.69) for CC, CT, and TT, respectively.
We propose two novel biomarkers that support the role of meat consumption with an increased risk of colorectal cancer.
The reported GxE interactions may explain the increased risk of colorectal cancer in certain population subgroups.
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.
A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia.
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).
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.
These findings can guide potential prevention treatments.
Background
The pathogenic effect of colorectal tumor molecular features may be influenced by several factors, including those related to microbiota, inflammation, metabolism, and epigenetics, which ...may change along colorectal segments. We hypothesized that the prognostic association of colon cancer location might differ by tumor molecular characteristics.
Methods
Utilizing a consortium dataset of 13,101 colorectal cancer cases, including 2994 early-onset cases, we conducted survival analyses of detailed tumor location stratified by statuses of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and
KRAS
and
BRAF
oncogenic mutation.
Results
There was a statistically significant trend for better colon cancer-specific survival in relation to tumor location from the cecum to sigmoid colon (
P
trend
= 0.002), excluding the rectum. The prognostic association of colon location differed by MSI status (
P
interaction
= 0.001). Non-MSI-high tumors exhibited the cecum-to-sigmoid trend for better colon cancer-specific survival
P
trend
< 0.001; multivariable hazard ratio (HR) for the sigmoid colon (vs. cecum), 0.80; 95% confidence interval (CI) 0.70–0.92, whereas MSI-high tumors demonstrated a suggestive cecum-to-sigmoid trend for worse survival (
P
trend
= 0.020; the corresponding HR, 2.13; 95% CI 1.15–3.92). The prognostic association of colon tumor location also differed by CIMP status (
P
interaction
= 0.003) but not significantly by age, stage, or other features. Furthermore, MSI-high status was a favorable prognostic indicator in all stages.
Conclusions
Both detailed colonic location and tumor molecular features need to be accounted for colon cancer prognostication to advance precision medicine. Our study indicates the important role of large-scale studies to robustly examine detailed colonic subsites in molecular oncology research.
Polygenic risk scores (PRS) which summarize individuals' genetic risk profile may enhance targeted colorectal cancer screening. A critical step towards clinical implementation is rigorous external ...validations in large community-based cohorts. This study externally validated a PRS-enhanced colorectal cancer risk model comprising 140 known colorectal cancer loci to provide a comprehensive assessment on prediction performance.
The model was developed using 20,338 individuals and externally validated in a community-based cohort (n = 85,221). We validated predicted 5-year absolute colorectal cancer risk, including calibration using expected-to-observed case ratios (E/O) and calibration plots, and discriminatory accuracy using time-dependent AUC. The PRS-related improvement in AUC, sensitivity and specificity were assessed in individuals of age 45 to 74 years (screening-eligible age group) and 40 to 49 years with no endoscopy history (younger-age group).
In European-ancestral individuals, the predicted 5-year risk calibrated well E/O = 1.01; 95% confidence interval (CI), 0.91-1.13 and had high discriminatory accuracy (AUC = 0.73; 95% CI, 0.71-0.76). Adding the PRS to a model with age, sex, family and endoscopy history improved the 5-year AUC by 0.06 (P < 0.001) and 0.14 (P = 0.05) in the screening-eligible age and younger-age groups, respectively. Using a risk-threshold of 5-year SEER colorectal cancer incidence rate at age 50 years, adding the PRS had a similar sensitivity but improved the specificity by 11% (P < 0.001) in the screening-eligible age group. In the younger-age group it improved the sensitivity by 27% (P = 0.04) with similar specificity.
The proposed PRS-enhanced model provides a well-calibrated 5-year colorectal cancer risk prediction and improves discriminatory accuracy in the external cohort.
The proposed model has potential utility in risk-stratified colorectal cancer prevention.
Dietary factors, including meat, fruits, vegetables and fiber, are associated with colorectal cancer; however, there is limited information as to whether these dietary factors interact with genetic ...variants to modify risk of colorectal cancer. We tested interactions between these dietary factors and approximately 2.7 million genetic variants for colorectal cancer risk among 9,287 cases and 9,117 controls from ten studies. We used logistic regression to investigate multiplicative gene-diet interactions, as well as our recently developed Cocktail method that involves a screening step based on marginal associations and gene-diet correlations and a testing step for multiplicative interactions, while correcting for multiple testing using weighted hypothesis testing. Per quartile increment in the intake of red and processed meat were associated with statistically significant increased risks of colorectal cancer and vegetable, fruit and fiber intake with lower risks. From the case-control analysis, we detected a significant interaction between rs4143094 (10p14/near GATA3) and processed meat consumption (OR = 1.17; p = 8.7E-09), which was consistently observed across studies (p heterogeneity = 0.78). The risk of colorectal cancer associated with processed meat was increased among individuals with the rs4143094-TG and -TT genotypes (OR = 1.20 and OR = 1.39, respectively) and null among those with the GG genotype (OR = 1.03). Our results identify a novel gene-diet interaction with processed meat for colorectal cancer, highlighting that diet may modify the effect of genetic variants on disease risk, which may have important implications for prevention.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Colorectal cancer has a strong epigenetic component that is accompanied by frequent DNA methylation (DNAm) alterations in addition to heritable genetic risk. It is of interest to understand the ...interrelationship of germline genetics, DNAm, and colorectal cancer risk.
We performed a genome-wide methylation quantitative trait locus (meQTL) analysis in 1,355 people, assessing the pairwise associations between genetic variants and lymphocytes methylation data. In addition, we used penalized regression with cis-genetic variants ± 1 Mb of methylation to identify genome-wide heritable DNAm. We evaluated the association of genetically predicted methylation with colorectal cancer risk based on genome-wide association studies (GWAS) of over 125,000 cases and controls using the multivariate sMiST as well as univariately via examination of marginal association with colorectal cancer risk.
Of the 142 known colorectal cancer GWAS loci, 47 were identified as meQTLs. We identified four novel colorectal cancer-associated loci (NID2, ATXN10, KLHDC10, and CEP41) that reside over 1 Mb outside of known colorectal cancer loci and 10 secondary signals within 1 Mb of known loci.
Leveraging information of DNAm regulation into genetic association of colorectal cancer risk reveals novel pathways in colorectal cancer tumorigenesis. Our summary statistics-based framework sMiST provides a powerful approach by combining information from the effect through methylation and residual direct effects of the meQTLs on disease risk. Further validation and functional follow-up of these novel pathways are needed.
Using genotype, DNAm, and GWAS, we identified four new colorectal cancer risk loci. We studied the landscape of genetic regulation of DNAm via single-SNP and multi-SNP meQTL analyses.
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