| 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. |
- Wang, Zhaoming, et al.
(författare)
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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| 3. |
- Machiela, Mitchell J, et al.
(författare)
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Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome
- 2016
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.
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| 4. |
- Jacobs, Kevin B, et al.
(författare)
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Detectable clonal mosaicism and its relationship to aging and cancer.
- 2012
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Ingår i: Nature Genetics. - New York : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 44:6, s. 651-658
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Tidskriftsartikel (refereegranskat)abstract
- In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.
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| 5. |
- Machiela, Mitchell J., et al.
(författare)
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Characterization of Large Structural Genetic Mosaicism in Human Autosomes
- 2015
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 96:3, s. 487-497
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Tidskriftsartikel (refereegranskat)abstract
- Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 x 3 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.
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| 6. |
- Fanidi, Anouar, et al.
(författare)
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Is high vitamin B12 status a cause of lung cancer?
- 2019
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 145:6, s. 1499-1503
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Tidskriftsartikel (refereegranskat)abstract
- Vitamin B supplementation can have side effects for human health, including cancer risk. We aimed to elucidate the role of vitamin B12 in lung cancer etiology via direct measurements of pre‐diagnostic circulating vitamin B12 concentrations in a nested case–control study, complemented with a Mendelian randomization (MR) approach in an independent case–control sample. We used pre‐diagnostic biomarker data from 5183 case–control pairs nested within 20 prospective cohorts, and genetic data from 29,266 cases and 56,450 controls. Exposures included directly measured circulating vitamin B12 in pre‐diagnostic blood samples from the nested case–control study, and 8 single nucleotide polymorphisms associated with vitamin B12 concentrations in the MR study. Our main outcome of interest was increased risk for lung cancer, overall and by histological subtype, per increase in circulating vitamin B12 concentrations. We found circulating vitamin B12 to be positively associated with overall lung cancer risk in a dose response fashion (odds ratio for a doubling in B12 [ORlog2B12] = 1.15, 95% confidence interval (95%CI) = 1.06–1.25). The MR analysis based on 8 genetic variants also indicated that genetically determined higher vitamin B12 concentrations were positively associated with overall lung cancer risk (OR per 150 pmol/L standard deviation increase in B12 [ORSD] = 1.08, 95%CI = 1.00–1.16). Considering the consistency of these two independent and complementary analyses, these findings support the hypothesis that high vitamin B12 status increases the risk of lung cancer.
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| 7. |
- Barrett, Jennifer H., et al.
(författare)
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Genome-wide association study identifies three new melanoma susceptibility loci
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:11, s. 1108-1113
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Tidskriftsartikel (refereegranskat)abstract
- We report a genome-wide association study for melanoma that was conducted by the GenoMEL Consortium. Our discovery phase included 2,981 individuals with melanoma and 1,982 study-specific control individuals of European ancestry, as well as an additional 6,426 control subjects from French or British populations, all of whom were genotyped for 317,000 or 610,000 single-nucleotide polymorphisms (SNPs). Our analysis replicated previously known melanoma susceptibility loci. Seven new regions with at least one SNP with P < 10(-5) and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Texas, USA). Additional replication came from case-control series from the UK and The Netherlands. Variants at three of the seven loci replicated at P < 10(-3): an SNP in ATM (rs1801516, overall P = 3.4 x 10(-9)), an SNP in MX2 (rs45430, P = 2.9 x 10-9) and an SNP adjacent to CASP8 (rs13016963, P = 8.6 x 10(-10)). A fourth locus near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication (rs1485993, overall P = 4.6 x 10(-7) under a fixed-effects model and P = 1.2 x 10(-3) under a random-effects model). These newly associated variants showed no association with nevus or pigmentation phenotypes in a large British case-control series.
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| 8. |
- Battram, Thomas, et al.
(författare)
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Appraising the causal relevance of DNA methylation for risk of lung cancer
- 2019
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Ingår i: International Journal of Epidemiology. - : Oxford University Press. - 0300-5771 .- 1464-3685. ; 48:5, s. 1493-1504
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Tidskriftsartikel (refereegranskat)abstract
- Background: DNA methylation changes in peripheral blood have recently been identified in relation to lung cancer risk. Some of these changes have been suggested to mediate part of the effect of smoking on lung cancer. However, limitations with conventional mediation analyses mean that the causal nature of these methylation changes has yet to be fully elucidated.Methods: We first performed a meta-analysis of four epigenome-wide association studies (EWAS) of lung cancer (918 cases, 918 controls). Next, we conducted a two-sample Mendelian randomization analysis, using genetic instruments for methylation at CpG sites identified in the EWAS meta-analysis, and 29 863 cases and 55 586 controls from the TRICL-ILCCO lung cancer consortium, to appraise the possible causal role of methylation at these sites on lung cancer.Results: Sixteen CpG sites were identified from the EWAS meta-analysis [false discovery rate (FDR) < 0.05], for 14 of which we could identify genetic instruments. Mendelian randomization provided little evidence that DNA methylation in peripheral blood at the 14 CpG sites plays a causal role in lung cancer development (FDR > 0.05), including for cg05575921-AHRR where methylation is strongly associated with both smoke exposure and lung cancer risk.Conclusions: The results contrast with previous observational and mediation analysis, which have made strong claims regarding the causal role of DNA methylation. Thus, previous suggestions of a mediating role of methylation at sites identified in peripheral blood, such as cg05575921-AHRR, could be unfounded. However, this study does not preclude the possibility that differential DNA methylation at other sites is causally involved in lung cancer development, especially within lung tissue.
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| 9. |
- Kachuri, Linda, et al.
(författare)
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Fine mapping of chromosome 5p15.33 based on a targeted deep sequencing and high density genotyping identifies novel lung cancer susceptibility loci
- 2016
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 37:1, s. 96-105
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Tidskriftsartikel (refereegranskat)abstract
- Chromosome 5p15.33 has been identified as a lung cancer susceptibility locus, however the underlying causal mechanisms were not fully elucidated. Previous fine-mapping studies of this locus have relied on imputation or investigated a small number of known, common variants. This study represents a significant advance over previous research by investigating a large number of novel, rare variants, as well as their underlying mechanisms through telomere length. Variants for this fine-mapping study were identified through a targeted deep sequencing (average depth of coverage greater than 4000x) of 576 individuals. Subsequently, 4652 SNPs, including 1108 novel SNPs, were genotyped in 5164 cases and 5716 controls of European ancestry. After adjusting for known risk loci, rs2736100 and rs401681, we identified a new, independent lung cancer susceptibility variant in LPCAT1: rs139852726 (OR = 0.46, P = 4.73x10(-9)), and three new adenocarcinoma risk variants in TERT: rs61748181 (OR = 0.53, P = 2.64x10(-6)), rs112290073 (OR = 1.85, P = 1.27x10(-5)), rs138895564 (OR = 2.16, P = 2.06x10(-5); among young cases, OR = 3.77, P = 8.41x10(-4)). In addition, we found that rs139852726 (P = 1.44x10(-3)) was associated with telomere length in a sample of 922 healthy individuals. The gene-based SKAT-O analysis implicated TERT as the most relevant gene in the 5p15.33 region for adenocarcinoma (P = 7.84x10(-7)) and lung cancer (P = 2.37x10(-5)) risk. In this largest fine-mapping study to investigate a large number of rare and novel variants within 5p15.33, we identified novel lung and adenocarcinoma susceptibility loci with large effects and provided support for the role of telomere length as the potential underlying mechanism.
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| 10. |
- MacGregor, Stuart, et al.
(författare)
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Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:11, s. 1114-1118
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Tidskriftsartikel (refereegranskat)abstract
- We performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm several previously characterized melanoma-associated loci at MC1R, ASIP and MTAP-CDKN2A. We selected variants at nine loci for replication in three independent case-control studies (Europe: 2,804 subjects with melanoma, 7,618 control subjects; United States 1: 1,804 subjects with melanoma, 1,026 control subjects; United States 2: 585 subjects with melanoma, 6,500 control subjects). The combined meta-analysis of all case-control studies identified a new susceptibility locus at 1q21.3 (rs7412746, P = 9.0 x 10(-11), OR in combined replication cohorts of 0.89 (95% CI 0.85-0.95)). We also show evidence suggesting that melanoma associates with 1q42.12 (rs3219090, P = 9.3 x 10(-8)). The associated variants at the 1q21.3 locus span a region with ten genes, and plausible candidate genes for melanoma susceptibility include ARNT and SETDB1. Variants at the 1q21.3 locus do not seem to be associated with human pigmentation or measures of nevus density.
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