| 1. |
- Schmit, Stephanie L, et al.
(författare)
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Novel Common Genetic Susceptibility Loci for Colorectal Cancer.
- 2019
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 111:2, s. 146-157
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
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| 2. |
- 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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| 3. |
- Thomas, Minta, et al.
(författare)
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Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk.
- 2020
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Ingår i: American Journal of Human Genetics. - Cambridge : Elsevier BV. - 0002-9297 .- 1537-6605. ; 107:3, s. 432-444
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Tidskriftsartikel (refereegranskat)abstract
- Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but might benefit from earlier screening. The developed PRS offers a way for risk-stratified CRC screening and other targeted interventions.
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| 4. |
- Thomas, Minta, et al.
(författare)
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Response to Li and Hopper
- 2021
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 108:3, s. 527-529
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Tidskriftsartikel (refereegranskat)
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| 5. |
- Zaidi, Syed H., et al.
(författare)
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Landscape of somatic single nucleotide variants and indels in colorectal cancer and impact on survival
- 2020
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR=0.42, 95% CI: 0.21-0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR=1.53, 95% CI: 1.21-1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features. Large scale sequencing study is of paramount importance to unravel the heterogeneity of colorectal cancer. Here, the authors sequenced 205 cancer genes in more than 2000 tumours and identified additional mutated driver genes, determined that mutational burden and specific mutations in TP53 are associated with survival odds.
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| 6. |
- Krümmel, Eva M., et al.
(författare)
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Updated review on contaminant communication experiences in the circumpolar Arctic
- 2024
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Ingår i: International Journal of Circumpolar Health. - : Taylor & Francis. - 1239-9736 .- 2242-3982. ; 83:1
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Forskningsöversikt (refereegranskat)abstract
- Arctic populations are amongst the highest exposed populations to long-range transported contaminants globally, with the main exposure pathway being through the diet. Dietary advice is an important immediate means to address potential exposure and help minimize adverse health effects. The objective of this work is to enable easier access to dietary advice and communication guidance on contaminants with a focus on the Arctic. This manuscript is part of a special issue summarizing the Arctic Monitoring and Assessment Programme’s Assessment 2021: Human Health in the Arctic. The information was derived with internet searches, and by contacting relevant experts directly. Results include risk communication efforts in European Arctic countries, effectiveness evaluation studies for several Arctic countries, experience of social media use, and the advantages and challenges of using social media in risk communication. We found that current risk communication activities in most Arctic countries emphasize the importance of a nutritious diet. Contaminant-related restrictions are mostly based on mercury; a limited amount of dietary advice is based on other contaminants. While more information on effectiveness evaluation was available, specific information, particularly from Arctic countries other than Canada, is still very limited.
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| 7. |
- Adlard, Bryan, et al.
(författare)
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MercuNorth–monitoring mercury in pregnant women from the Arctic as a baseline to assess the effectiveness of the Minamata Convention
- 2021
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Ingår i: International Journal of Circumpolar Health. - : Taylor & Francis. - 1239-9736 .- 2242-3982. ; 80:1
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Tidskriftsartikel (refereegranskat)abstract
- Exposure to mercury (Hg) is a global concern, particularly among Arctic populations that rely on the consumption of marine mammals and fish which are the main route of Hg exposure for Arctic populations.The MercuNorth project was created to establish baseline Hg levels across several Arctic regions during the period preceding the Minamata Convention. Blood samples were collected from 669 pregnant women, aged 18–44 years, between 2010 and 2016 from sites across the circumpolar Arctic including Alaska (USA), Nunavik (Canada), Greenland, Iceland, Norway, Sweden, Northern Lapland (Finland) and Murmansk Oblast (Russia). Descriptive statistics were calculated, multiple pairwise comparisons were made between regions, and unadjusted linear trend analyses were performed.Geometric mean concentrations of total Hg were highest in Nunavik (5.20 µg/L) and Greenland (3.79 µg/L), followed by Alaska (2.13 µg/L), with much lower concentrations observed in the other regions (ranged between 0.48 and 1.29 µg/L). In Nunavik, Alaska and Greenland, blood Hg concentrations have decreased significantly since 1992, 2000 and 2010 respectively with % annual decreases of 4.7%, 7.5% and 2.7%, respectively.These circumpolar data combined with fish and marine mammal consumption data can be used for assessing long-term Hg trends and the effectiveness of the Minamata Convention.
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