| 1. |
- Antoniou, Antonis C., et al.
(författare)
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A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:10, s. 885-892
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Tidskriftsartikel (refereegranskat)abstract
- Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (P-trend = 2.3 x 10(-9) to Ptrend = 3.9 x 10(-7)), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17-1.35; rs2363956 HR = 0.84, 95% CI 0.80-0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor-negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75-0.92, P-trend = 0.0003) and an association with estrogen receptor-positive disease in the opposite direction (OR = 1.07, 95% CI 1.01-1.14, P-trend = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (Ptrend = 1 x 10(-7) to Ptrend = 8 x 10(-5); rs2363956 per-allele OR = 0.80, 95% CI 0.74-0.87, P-trend = 1.1 x 10(-7)).
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| 2. |
- Archambault, Alexi N., et al.
(författare)
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Cumulative Burden of Colorectal Cancer Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer
- 2020
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 158:5, s. 1274-1286.e12
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Tidskriftsartikel (refereegranskat)abstract
- 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 x 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.
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| 3. |
- Bien, Stephanie A., et al.
(författare)
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Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer
- 2019
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Ingår i: Human Genetics. - : Springer. - 0340-6717 .- 1432-1203. ; 138:4, s. 307-326
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n=169) and whole blood (n=922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P=2.2x10(-4), replication P=0.01), and PYGL (discovery P=2.3x10(-4), replication P=6.7x10(-4)). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P<0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight into, risk loci.
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| 4. |
- Dimou, Niki, et al.
(författare)
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Causal effects of lifetime smoking on breast and colorectal cancer risk: Mendelian randomization study
- 2021
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research (AACR). - 1055-9965 .- 1538-7755. ; 30:5, s. 953-964
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Tidskriftsartikel (refereegranskat)abstract
- Background: Observational evidence has shown that smoking is a risk factor for breast and colorectal cancer. We used Mendelian randomization (MR) to examine causal associations between smoking and risks of breast and colorectal cancer.Methods: Genome-Wide Association Study summary data were used to identify genetic variants associated with lifetime amount of smoking (n ¼ 126 variants) and ever having smoked regularly (n ¼ 112 variants). Using two-sample MR, we examined these variants in relation to incident breast (122,977 cases/ 105,974 controls) and colorectal cancer (52,775 cases/45,940 controls).Results: In inverse-variance weighted models, a genetic predisposition to higher lifetime amount of smoking was positively associated with breast cancer risk [OR per 1-SD increment: 1.13; 95% confidence interval (CI): 1.00–1.26; P ¼ 0.04]; although heterogeneity was observed. Similar associations were found for estrogen receptor–positive and estrogen receptor–negative tumors. Higher lifetime amount of smoking was positively associated with colorectal cancer (OR per 1-SD increment, 1.21; 95% CI, 1.04–1.40; P ¼ 0.01), colon cancer (OR, 1.31; 95% CI, 1.11–1.55; P < 0.01), and rectal cancer (OR, 1.36; 95% CI, 1.07–1.73; P ¼ 0.01). Ever having smoked regularly was not associated with risks of breast (OR, 1.01; 95% CI, 0.90–1.14; P ¼ 0.85) or colorectal cancer (OR, 0.97; 95% CI, 0.86–1.10; P ¼ 0.68).Conclusions: These findings are consistent with prior observational evidence and support a causal role of higher lifetime smoking amount in the development of breast and colorectal cancer.Impact: The results from this comprehensive MR analysis indicate that lifetime smoking is a causal risk factor for these common malignancies.
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| 5. |
- Harrison, Tabitha A., et al.
(författare)
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Genome-wide association study by colorectal carcinoma subtype
- 2018
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Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 78:13
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Over 50 genetic variants have been associated with colorectal cancer (CRC) risk through genome-wide association studies (GWAS), yet these variants represent only a fraction of the total estimated heritability. CRC is a heterogenous disease with diverse tumor etiology. Assessing genetic risk in molecular subtypes may help to identify novel loci and characterize genetic risk among tumor subtypes. We used microsatellite instability (MSI), an established CRC classifier with etiological and therapeutic relevance, to define CRC subtypes for GWAS analyses. We conducted a case-case analysis to estimate odds ratios (OR) and 95% confidence intervals (CI) for association of genome-wide variants with microsatellite stable (MSS) versus unstable (MSI) carcinomas. We ran an inverse-variance weighted fixed-effects meta-analysis across GWAS in a discovery set of 4,163 population-based CRC cases with harmonized microsatellite instability (MSI) marker and imputed genotype data. For each analysis, we used log-additive logistic regression, adjusting for age, sex, and principal components to account for population substructure. We then followed up with replication of 102 SNPs that reached p-values less than 5x10-6 in 1,698 cases. A total of 845 (20.3%) cancer cases were microsatellite unstable in the discovery population and 174 (10.2%) were unstable in the replication population. No variants reached the genome-wide significance level of 5x10-8 in the discovery set. However, we identified two variants that reached a Bonferroni corrected p-value of 4.0x10-4 in the replication set. This included one variant in MLH1 (Replication: OR=1.74, 95% CI=1.53-1.98, p=1.63x10-5; Discovery+Replication: OR=1.45, 95% CI=1.37-1.54, p=9.76x10-11) and one variant in LOC105377645 (Replication: OR=1.70, 95% CI=1.49-1.94, p=5.13x10-5; Discovery+Replication: OR=1.45, 95% CI=1.37-1.54, p=9.76 x 10-11). The MLH1 gene is a DNA mismatch repair gene implicated in Lynch Syndrome, the hallmark of which is microsatellite instability. This is the first genome-wide scan to identify a common variant in MLH1 that is associated with CRC. This variant (minor allele frequency, MAF = 23% in this all European ancestry population) is located in the 5'-untranslated region of MLH1 and is thought to act as a long-range regulator of DCLK3, a potential tumor driver gene. The second variant, located in LOC105377645 with an MAF of 22%, is in an uncharacterized region of the genome and has not previously been implicated in cancer development. These findings suggest that accounting for molecular heterogeneity is important for discovery and characterization of genetic variants associated with CRC risk. We plan to run polytomous regression analyses, increase our sample size, and further investigate CRC subtypes by CIMP, BRAF mutation, KRAS mutation status.
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| 6. |
- Huyghe, Jeroen R., et al.
(författare)
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Discovery of common and rare genetic risk variants for colorectal cancer
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:1, s. 76-
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Tidskriftsartikel (refereegranskat)abstract
- To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
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| 7. |
- Huyghe, Jeroen R, et al.
(författare)
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Genetic architectures of proximal and distal colorectal cancer are partly distinct
- 2021
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Ingår i: Gut. - : BMJ Publishing Group Ltd. - 0017-5749 .- 1468-3288. ; 70:7, s. 1325-1334
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Tidskriftsartikel (refereegranskat)abstract
- Objective: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined.Design: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling.Results: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
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| 8. |
- Law, Philip J., et al.
(författare)
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Association analyses identify 31 new risk loci for colorectal cancer susceptibility
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.
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| 9. |
- Maxwell, Christopher A., et al.
(författare)
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Interplay between BRCA1 and RHAMM Regulates Epithelial Apicobasal Polarization and May Influence Risk of Breast Cancer
- 2011
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Ingår i: PLoS Biology. - : Public Library of Science (PLoS). - 1545-7885 .- 1544-9173. ; 9:11
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Tidskriftsartikel (refereegranskat)abstract
- Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.
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| 10. |
- Nounu, Aayah, et al.
(författare)
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A combined proteomics and mendelian randomization approach to investigate the effects of aspirin-targeted proteins on colorectal cancer
- 2021
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : Elsevier. - 1055-9965 .- 1538-7755. ; 30:3, s. 564-575
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Tidskriftsartikel (refereegranskat)abstract
- 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 ¼ 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N ¼ 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.
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