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1. Genome-Wide Interaction Analyses between Genetic Variants and Alcohol Consumption and Smoking for Risk of Colorectal Cancer.

Author

Jian Gong, Carolyn M Hutter, Polly A Newcomb, Cornelia M Ulrich, Stephanie A Bien, Peter T Campbell, John A Baron, Sonja I Berndt, Stephane Bezieau, Hermann Brenner, Graham Casey, Andrew T Chan, Jenny Chang-Claude, Mengmeng Du, David Duggan, Jane C Figueiredo, Steven Gallinger, Edward L Giovannucci, Robert W Haile, Tabitha A Harrison, Richard B Hayes, Michael Hoffmeister, John L Hopper, Thomas J Hudson, Jihyoun Jeon, Mark A Jenkins, Jonathan Kocarnik, Sébastien Küry, Loic Le Marchand, Yi Lin, Noralane M Lindor, Reiko Nishihara, Shuji Ogino, John D Potter, Anja Rudolph, Robert E Schoen, Petra Schrotz-King, Daniela Seminara, Martha L Slattery, Stephen N Thibodeau, Mark Thornquist, Reka Toth, Robert Wallace, Emily White, Shuo Jiao, Mathieu Lemire, Li Hsu, Ulrike Peters, and CCFR and GECCO

Subjects
Genetics, QH426-470
Abstract

Genome-wide association studies (GWAS) have identified many genetic susceptibility loci for colorectal cancer (CRC). However, variants in these loci explain only a small proportion of familial aggregation, and there are likely additional variants that are associated with CRC susceptibility. Genome-wide studies of gene-environment interactions may identify variants that are not detected in GWAS of marginal gene effects. To study this, we conducted a genome-wide analysis for interaction between genetic variants and alcohol consumption and cigarette smoking using data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Interactions were tested using logistic regression. We identified interaction between CRC risk and alcohol consumption and variants in the 9q22.32/HIATL1 (Pinteraction = 1.76×10-8; permuted p-value 3.51x10-8) region. Compared to non-/occasional drinking light to moderate alcohol consumption was associated with a lower risk of colorectal cancer among individuals with rs9409565 CT genotype (OR, 0.82 [95% CI, 0.74-0.91]; P = 2.1×10-4) and TT genotypes (OR,0.62 [95% CI, 0.51-0.75]; P = 1.3×10-6) but not associated among those with the CC genotype (p = 0.059). No genome-wide statistically significant interactions were observed for smoking. If replicated our suggestive finding of a genome-wide significant interaction between genetic variants and alcohol consumption might contribute to understanding colorectal cancer etiology and identifying subpopulations with differential susceptibility to the effect of alcohol on CRC risk.

Published
2016
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2. Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants.

Author

Mengmeng Du, Shuo Jiao, Stephanie A Bien, Manish Gala, Goncalo Abecasis, Stephane Bezieau, Hermann Brenner, Katja Butterbach, Bette J Caan, Christopher S Carlson, Graham Casey, Jenny Chang-Claude, David V Conti, Keith R Curtis, David Duggan, Steven Gallinger, Robert W Haile, Tabitha A Harrison, Richard B Hayes, Michael Hoffmeister, John L Hopper, Thomas J Hudson, Mark A Jenkins, Sébastien Küry, Loic Le Marchand, Suzanne M Leal, Polly A Newcomb, Deborah A Nickerson, John D Potter, Robert E Schoen, Fredrick R Schumacher, Daniela Seminara, Martha L Slattery, Li Hsu, Andrew T Chan, Emily White, Sonja I Berndt, and Ulrike Peters

Subjects
Medicine, Science
Abstract

Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s).

Published
2016
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3. Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes

Author

Zhishan Chen, Xingyi Guo, Ran Tao, Jeroen R. Huyghe, Philip J. Law, Ceres Fernandez-Rozadilla, Jie Ping, Guochong Jia, Jirong Long, Chao Li, Quanhu Shen, Yuhan Xie, Maria N. Timofeeva, Minta Thomas, Stephanie L. Schmit, Virginia Díez-Obrero, Matthew Devall, Ferran Moratalla-Navarro, Juan Fernandez-Tajes, Claire Palles, Kitty Sherwood, Sarah E. W. Briggs, Victoria Svinti, Kevin Donnelly, Susan M. Farrington, James Blackmur, Peter G. Vaughan-Shaw, Xiao-Ou Shu, Yingchang Lu, Peter Broderick, James Studd, Tabitha A. Harrison, David V. Conti, Fredrick R. Schumacher, Marilena Melas, Gad Rennert, Mireia Obón-Santacana, Vicente Martín-Sánchez, Jae Hwan Oh, Jeongseon Kim, Sun Ha Jee, Keum Ji Jung, Sun-Seog Kweon, Min-Ho Shin, Aesun Shin, Yoon-Ok Ahn, Dong-Hyun Kim, Isao Oze, Wanqing Wen, Keitaro Matsuo, Koichi Matsuda, Chizu Tanikawa, Zefang Ren, Yu-Tang Gao, Wei-Hua Jia, John L. Hopper, Mark A. Jenkins, Aung Ko Win, Rish K. Pai, Jane C. Figueiredo, Robert W. Haile, Steven Gallinger, Michael O. Woods, Polly A. Newcomb, David Duggan, Jeremy P. Cheadle, Richard Kaplan, Rachel Kerr, David Kerr, Iva Kirac, Jan Böhm, Jukka-Pekka Mecklin, Pekka Jousilahti, Paul Knekt, Lauri A. Aaltonen, Harri Rissanen, Eero Pukkala, Johan G. Eriksson, Tatiana Cajuso, Ulrika Hänninen, Johanna Kondelin, Kimmo Palin, Tomas Tanskanen, Laura Renkonen-Sinisalo, Satu Männistö, Demetrius Albanes, Stephanie J. Weinstein, Edward Ruiz-Narvaez, Julie R. Palmer, Daniel D. Buchanan, Elizabeth A. Platz, Kala Visvanathan, Cornelia M. Ulrich, Erin Siegel, Stefanie Brezina, Andrea Gsur, Peter T. Campbell, Jenny Chang-Claude, Michael Hoffmeister, Hermann Brenner, Martha L. Slattery, John D. Potter, Kostas K. Tsilidis, Matthias B. Schulze, Marc J. Gunter, Neil Murphy, Antoni Castells, Sergi Castellví-Bel, Leticia Moreira, Volker Arndt, Anna Shcherbina, D. Timothy Bishop, Graham G. Giles, Melissa C. Southey, Gregory E. Idos, Kevin J. McDonnell, Zomoroda Abu-Ful, Joel K. Greenson, Katerina Shulman, Flavio Lejbkowicz, Kenneth Offit, Yu-Ru Su, Robert Steinfelder, Temitope O. Keku, Bethany van Guelpen, Thomas J. Hudson, Heather Hampel, Rachel Pearlman, Sonja I. Berndt, Richard B. Hayes, Marie Elena Martinez, Sushma S. Thomas, Paul D. P. Pharoah, Susanna C. Larsson, Yun Yen, Heinz-Josef Lenz, Emily White, Li Li, Kimberly F. Doheny, Elizabeth Pugh, Tameka Shelford, Andrew T. Chan, Marcia Cruz-Correa, Annika Lindblom, David J. Hunter, Amit D. Joshi, Clemens Schafmayer, Peter C. Scacheri, Anshul Kundaje, Robert E. Schoen, Jochen Hampe, Zsofia K. Stadler, Pavel Vodicka, Ludmila Vodickova, Veronika Vymetalkova, Christopher K. Edlund, W. James Gauderman, David Shibata, Amanda Toland, Sanford Markowitz, Andre Kim, Stephen J. Chanock, Franzel van Duijnhoven, Edith J. M. Feskens, Lori C. Sakoda, Manuela Gago-Dominguez, Alicja Wolk, Barbara Pardini, Liesel M. FitzGerald, Soo Chin Lee, Shuji Ogino, Stephanie A. Bien, Charles Kooperberg, Christopher I. Li, Yi Lin, Ross Prentice, Conghui Qu, Stéphane Bézieau, Taiki Yamaji, Norie Sawada, Motoki Iwasaki, Loic Le Marchand, Anna H. Wu, Chenxu Qu, Caroline E. McNeil, Gerhard Coetzee, Caroline Hayward, Ian J. Deary, Sarah E. Harris, Evropi Theodoratou, Stuart Reid, Marion Walker, Li Yin Ooi, Ken S. Lau, Hongyu Zhao, Li Hsu, Qiuyin Cai, Malcolm G. Dunlop, Stephen B. Gruber, Richard S. Houlston, Victor Moreno, Graham Casey, Ulrike Peters, Ian Tomlinson, and Wei Zheng

Subjects
Science
Abstract

Abstract Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.

Published
2024
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4. Genome-wide search for gene-gene interactions in colorectal cancer.

Author

Shuo Jiao, Li Hsu, Sonja Berndt, Stéphane Bézieau, Hermann Brenner, Daniel Buchanan, Bette J Caan, Peter T Campbell, Christopher S Carlson, Graham Casey, Andrew T Chan, Jenny Chang-Claude, Stephen Chanock, David V Conti, Keith R Curtis, David Duggan, Steven Gallinger, Stephen B Gruber, Tabitha A Harrison, Richard B Hayes, Brian E Henderson, Michael Hoffmeister, John L Hopper, Thomas J Hudson, Carolyn M Hutter, Rebecca D Jackson, Mark A Jenkins, Elizabeth D Kantor, Laurence N Kolonel, Sébastien Küry, Loic Le Marchand, Mathieu Lemire, Polly A Newcomb, John D Potter, Conghui Qu, Stephanie A Rosse, Robert E Schoen, Fred R Schumacher, Daniela Seminara, Martha L Slattery, Cornelia M Ulrich, Brent W Zanke, and Ulrike Peters

Subjects
Medicine, Science
Abstract

Genome-wide association studies (GWAS) have successfully identified a number of single-nucleotide polymorphisms (SNPs) associated with colorectal cancer (CRC) risk. However, these susceptibility loci known today explain only a small fraction of the genetic risk. Gene-gene interaction (GxG) is considered to be one source of the missing heritability. To address this, we performed a genome-wide search for pair-wise GxG associated with CRC risk using 8,380 cases and 10,558 controls in the discovery phase and 2,527 cases and 2,658 controls in the replication phase. We developed a simple, but powerful method for testing interaction, which we term the Average Risk Due to Interaction (ARDI). With this method, we conducted a genome-wide search to identify SNPs showing evidence for GxG with previously identified CRC susceptibility loci from 14 independent regions. We also conducted a genome-wide search for GxG using the marginal association screening and examining interaction among SNPs that pass the screening threshold (p

Published
2012
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5. MLH1 region polymorphisms show a significant association with CpG island shore methylation in a large cohort of healthy individuals.

Author

Andrea J Savio, Mathieu Lemire, Miralem Mrkonjic, Steven Gallinger, Brent W Zanke, Thomas J Hudson, and Bharati Bapat

Subjects
Medicine, Science
Abstract

Single nucleotide polymorphisms (SNPs) are the most common form of genetic variation. We previously demonstrated that SNPs (rs1800734, rs749072, and rs13098279) in the MLH1 gene region are associated with MLH1 promoter island methylation, loss of MLH1 protein expression, and microsatellite instability (MSI) in colorectal cancer (CRC) patients. Recent studies have identified less CpG-dense "shore" regions flanking many CpG islands. These shores often exhibit distinct methylation profiles between different tissues and matched normal versus tumor cells of patients. To date, most epigenetic studies have focused on somatic methylation events occurring within solid tumors; less is known of the contributions of peripheral blood cell (PBC) methylation to processes such as aging and tumorigenesis. To address whether MLH1 methylation in PBCs is correlated with tumorigenesis we utilized the Illumina 450 K microarrays to measure methylation in PBC DNA of 846 healthy controls and 252 CRC patients from Ontario, Canada. Analysis of a region of chromosome 3p21 spanning the MLH1 locus in healthy controls revealed that a CpG island shore 1 kb upstream of the MLH1 gene exhibits different methylation profiles when stratified by SNP genotypes (rs1800734, rs749072, and rs13098279). Individuals with wild-type genotypes incur significantly higher PBC shore methylation than heterozygous or homozygous variant carriers (p

Published
2012
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6. Specific variants in the MLH1 gene region may drive DNA methylation, loss of protein expression, and MSI-H colorectal cancer.

Author

Miralem Mrkonjic, Nicole M Roslin, Celia M Greenwood, Stavroula Raptis, Aaron Pollett, Peter W Laird, Vaijayanti V Pethe, Theodore Chiang, Darshana Daftary, Elizabeth Dicks, Stephen N Thibodeau, Steven Gallinger, Patrick S Parfrey, H Banfield Younghusband, John D Potter, Thomas J Hudson, John R McLaughlin, Roger C Green, Brent W Zanke, Polly A Newcomb, Andrew D Paterson, and Bharati Bapat

Subjects
Medicine, Science
Abstract

We previously identified an association between a mismatch repair gene, MLH1, promoter SNP (rs1800734) and microsatellite unstable (MSI-H) colorectal cancers (CRCs) in two samples. The current study expanded on this finding as we explored the genetic basis of DNA methylation in this region of chromosome 3. We hypothesized that specific polymorphisms in the MLH1 gene region predispose it to DNA methylation, resulting in the loss of MLH1 gene expression, mismatch-repair function, and consequently to genome-wide microsatellite instability.We first tested our hypothesis in one sample from Ontario (901 cases, 1,097 controls) and replicated major findings in two additional samples from Newfoundland and Labrador (479 cases, 336 controls) and from Seattle (591 cases, 629 controls). Logistic regression was used to test for association between SNPs in the region of MLH1 and CRC, MSI-H CRC, MLH1 gene expression in CRC, and DNA methylation in CRC. The association between rs1800734 and MSI-H CRCs, previously reported in Ontario and Newfoundland, was replicated in the Seattle sample. Two additional SNPs, in strong linkage disequilibrium with rs1800734, showed strong associations with MLH1 promoter methylation, loss of MLH1 protein, and MSI-H CRC in all three samples. The logistic regression model of MSI-H CRC that included MLH1-promoter-methylation status and MLH1 immunohistochemistry status fit most parsimoniously in all three samples combined. When rs1800734 was added to this model, its effect was not statistically significant (P-value = 0.72 vs. 2.3×10(-4) when the SNP was examined alone).The observed association of rs1800734 with MSI-H CRC occurs through its effect on the MLH1 promoter methylation, MLH1 IHC deficiency, or both.

Published
2010
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7. Genetic variation in the familial Mediterranean fever gene (MEFV) and risk for Crohn's disease and ulcerative colitis.

Author

Alexandra-Chloé Villani, Mathieu Lemire, Edouard Louis, Mark S Silverberg, Catherine Collette, Geneviève Fortin, Elaine R Nimmo, Yannick Renaud, Sébastien Brunet, Cécile Libioulle, Jacques Belaiche, Alain Bitton, Daniel Gaudet, Albert Cohen, Diane Langelier, John D Rioux, Ian D R Arnott, Gary E Wild, Paul Rutgeerts, Jack Satsangi, Séverine Vermeire, Thomas J Hudson, and Denis Franchimont

Subjects
Medicine, Science
Abstract

The familial Mediterranean fever (FMF) gene (MEFV) encodes pyrin, a major regulator of the inflammasome platform controlling caspase-1 activation and IL-1beta processing. Pyrin has been shown to interact with the gene product of NLRP3, NALP3/cryopyrin, also an important active member of the inflammasome. The NLRP3 region was recently reported to be associated with Crohn's disease (CD) susceptibility. We therefore sought to evaluate MEFV as an inflammatory bowel disease (IBD) susceptibility gene.MEFV colonic mucosal gene expression was significantly increased in experimental colitis mice models (TNBS p

Published
2009
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8. Disruption of AP1S1, causing a novel neurocutaneous syndrome, perturbs development of the skin and spinal cord.

Author

Alexandre Montpetit, Stéphanie Côté, Edna Brustein, Christian A Drouin, Line Lapointe, Michèle Boudreau, Caroline Meloche, Régen Drouin, Thomas J Hudson, Pierre Drapeau, and Patrick Cossette

Subjects
Genetics, QH426-470
Abstract

Adaptor protein (AP) complexes regulate clathrin-coated vesicle assembly, protein cargo sorting, and vesicular trafficking between organelles in eukaryotic cells. Because disruption of the various subunits of the AP complexes is embryonic lethal in the majority of cases, characterization of their function in vivo is still lacking. Here, we describe the first mutation in the human AP1S1 gene, encoding the small subunit sigma1A of the AP-1 complex. This founder splice mutation, which leads to a premature stop codon, was found in four families with a unique syndrome characterized by mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratodermia (MEDNIK). To validate the pathogenic effect of the mutation, we knocked down Ap1s1 expression in zebrafish using selective antisens morpholino oligonucleotides (AMO). The knockdown phenotype consisted of perturbation in skin formation, reduced pigmentation, and severe motility deficits due to impaired neural network development. Both neural and skin defects were rescued by co-injection of AMO with wild-type (WT) human AP1S1 mRNA, but not by co-injecting the truncated form of AP1S1, consistent with a loss-of-function effect of this mutation. Together, these results confirm AP1S1 as the gene responsible for MEDNIK syndrome and demonstrate a critical role of AP1S1 in development of the skin and spinal cord.

Published
2008
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9. Germline EPHB2 receptor variants in familial colorectal cancer.

Author

George Zogopoulos, Claus Jorgensen, Julinor Bacani, Alexandre Montpetit, Pierre Lepage, Vincent Ferretti, Lauren Chad, Subani Selvarajah, Brent Zanke, Thomas J Hudson, Tony Pawson, and Steven Gallinger

Subjects
Medicine, Science
Abstract

Familial clustering of colorectal cancer occurs in 15-20% of cases, however recognized cancer syndromes explain only a small fraction of this disease. Thus, the genetic basis for the majority of hereditary colorectal cancer remains unknown. EPHB2 has recently been implicated as a candidate tumor suppressor gene in colorectal cancer. The aim of this study was to evaluate the contribution of EPHB2 to hereditary colorectal cancer. We screened for germline EPHB2 sequence variants in 116 population-based familial colorectal cancer cases by DNA sequencing. We then estimated the population frequencies and characterized the biological activities of the EPHB2 variants identified. Three novel nonsynonymous missense alterations were detected. Two of these variants (A438T and G787R) result in significant residue changes, while the third leads to a conservative substitution in the carboxy-terminal SAM domain (V945I). The former two variants were found once in the 116 cases, while the V945I variant was present in 2 cases. Genotyping of additional patients with colorectal cancer and control subjects revealed that A438T and G787R represent rare EPHB2 alleles. In vitro functional studies show that the G787R substitution, located in the kinase domain, causes impaired receptor kinase activity and is therefore pathogenic, whereas the A438T variant retains its receptor function and likely represents a neutral polymorphism. Tumor tissue from the G787R variant case manifested loss of heterozygosity, with loss of the wild-type allele, supporting a tumor suppressor role for EPHB2 in rare colorectal cancer cases. Rare germline EPHB2 variants may contribute to a small fraction of hereditary colorectal cancer.

Published
2008
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10. Genes to diseases (G2D) computational method to identify asthma candidate genes.

Author

Karine Tremblay, Mathieu Lemire, Camille Potvin, Alexandre Tremblay, Gary M Hunninghake, Benjamin A Raby, Thomas J Hudson, Carolina Perez-Iratxeta, Miguel A Andrade-Navarro, and Catherine Laprise

Subjects
Medicine, Science
Abstract

Asthma is a complex trait for which different strategies have been used to identify its environmental and genetic predisposing factors. Here, we describe a novel methodological approach to select candidate genes for asthma genetic association studies. In this regard, the Genes to Diseases (G2D) computational tool has been used in combination with a genome-wide scan performed in a sub-sample of the Saguenay-Lac-St-Jean (SLSJ) asthmatic familial collection (n = 609) to identify candidate genes located in two suggestive loci shown to be linked with asthma (6q26) and atopy (10q26.3), and presenting differential parent-of-origin effects. This approach combined gene selection based on the G2D data mining analysis of the bibliographic and protein public databases, or according to the genes already known to be associated with the same or a similar phenotype. Ten genes (LPA, NOX3, SNX9, VIL2, VIP, ADAM8, DOCK1, FANK1, GPR123 and PTPRE) were selected for a subsequent association study performed in a large SLSJ sample (n = 1167) of individuals tested for asthma and atopy related phenotypes. Single nucleotide polymorphisms (n = 91) within the candidate genes were genotyped and analysed using a family-based association test. The results suggest a protective association to allergic asthma for PTPRE rs7081735 in the SLSJ sample (p = 0.000463; corrected p = 0.0478). This association has not been replicated in the Childhood Asthma Management Program (CAMP) cohort. Sequencing of the regions around rs7081735 revealed additional polymorphisms, but additional genotyping did not yield new associations. These results demonstrate that the G2D tool can be useful in the selection of candidate genes located in chromosomal regions linked to a complex trait.

Published
2008
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11. Differential allelic expression in the human genome: a robust approach to identify genetic and epigenetic cis-acting mechanisms regulating gene expression.

Author

David Serre, Scott Gurd, Bing Ge, Robert Sladek, Donna Sinnett, Eef Harmsen, Marina Bibikova, Eugene Chudin, David L Barker, Todd Dickinson, Jian-Bing Fan, and Thomas J Hudson

Subjects
Genetics, QH426-470
Abstract

The recent development of whole genome association studies has lead to the robust identification of several loci involved in different common human diseases. Interestingly, some of the strongest signals of association observed in these studies arise from non-coding regions located in very large introns or far away from any annotated genes, raising the possibility that these regions are involved in the etiology of the disease through some unidentified regulatory mechanisms. These findings highlight the importance of better understanding the mechanisms leading to inter-individual differences in gene expression in humans. Most of the existing approaches developed to identify common regulatory polymorphisms are based on linkage/association mapping of gene expression to genotypes. However, these methods have some limitations, notably their cost and the requirement of extensive genotyping information from all the individuals studied which limits their applications to a specific cohort or tissue. Here we describe a robust and high-throughput method to directly measure differences in allelic expression for a large number of genes using the Illumina Allele-Specific Expression BeadArray platform and quantitative sequencing of RT-PCR products. We show that this approach allows reliable identification of differences in the relative expression of the two alleles larger than 1.5-fold (i.e., deviations of the allelic ratio larger than 60:40) and offers several advantages over the mapping of total gene expression, particularly for studying humans or outbred populations. Our analysis of more than 80 individuals for 2,968 SNPs located in 1,380 genes confirms that differential allelic expression is a widespread phenomenon affecting the expression of 20% of human genes and shows that our method successfully captures expression differences resulting from both genetic and epigenetic cis-acting mechanisms.

Published
2008
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12. Correction of population stratification in large multi-ethnic association studies.

Author

David Serre, Alexandre Montpetit, Guillaume Paré, James C Engert, Salim Yusuf, Bernard Keavney, Thomas J Hudson, and Sonia Anand

Subjects
Medicine, Science
Abstract

The vast majority of genetic risk factors for complex diseases have, taken individually, a small effect on the end phenotype. Population-based association studies therefore need very large sample sizes to detect significant differences between affected and non-affected individuals. Including thousands of affected individuals in a study requires recruitment in numerous centers, possibly from different geographic regions. Unfortunately such a recruitment strategy is likely to complicate the study design and to generate concerns regarding population stratification.We analyzed 9,751 individuals representing three main ethnic groups - Europeans, Arabs and South Asians - that had been enrolled from 154 centers involving 52 countries for a global case/control study of acute myocardial infarction. All individuals were genotyped at 103 candidate genes using 1,536 SNPs selected with a tagging strategy that captures most of the genetic diversity in different populations. We show that relying solely on self-reported ethnicity is not sufficient to exclude population stratification and we present additional methods to identify and correct for stratification.Our results highlight the importance of carefully addressing population stratification and of carefully "cleaning" the sample prior to analyses to obtain stronger signals of association and to avoid spurious results.

Published
2008
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13. An evaluation of the performance of tag SNPs derived from HapMap in a Caucasian population.

Author

Alexandre Montpetit, Mari Nelis, Philippe Laflamme, Reedik Magi, Xiayi Ke, Maido Remm, Lon Cardon, Thomas J Hudson, and Andres Metspalu

Subjects
Genetics, QH426-470
Abstract

The Haplotype Map (HapMap) project recently generated genotype data for more than 1 million single-nucleotide polymorphisms (SNPs) in four population samples. The main application of the data is in the selection of tag single-nucleotide polymorphisms (tSNPs) to use in association studies. The usefulness of this selection process needs to be verified in populations outside those used for the HapMap project. In addition, it is not known how well the data represent the general population, as only 90-120 chromosomes were used for each population and since the genotyped SNPs were selected so as to have high frequencies. In this study, we analyzed more than 1,000 individuals from Estonia. The population of this northern European country has been influenced by many different waves of migrations from Europe and Russia. We genotyped 1,536 randomly selected SNPs from two 500-kbp ENCODE regions on Chromosome 2. We observed that the tSNPs selected from the CEPH (Centre d'Etude du Polymorphisme Humain) from Utah (CEU) HapMap samples (derived from US residents with northern and western European ancestry) captured most of the variation in the Estonia sample. (Between 90% and 95% of the SNPs with a minor allele frequency of more than 5% have an r2 of at least 0.8 with one of the CEU tSNPs.) Using the reverse approach, tags selected from the Estonia sample could almost equally well describe the CEU sample. Finally, we observed that the sample size, the allelic frequency, and the SNP density in the dataset used to select the tags each have important effects on the tagging performance. Overall, our study supports the use of HapMap data in other Caucasian populations, but the SNP density and the bias towards high-frequency SNPs have to be taken into account when designing association studies.

Published
2006
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14. PRKCA and multiple sclerosis: association in two independent populations.

Author

Janna Saarela, Suvi P Kallio, Daniel Chen, Alexandre Montpetit, Anne Jokiaho, Eva Choi, Rosanna Asselta, Denis Bronnikov, Matthew R Lincoln, A Dessa Sadovnick, Pentti J Tienari, Keijo Koivisto, Aarno Palotie, George C Ebers, Thomas J Hudson, and Leena Peltonen

Subjects
Genetics, QH426-470
Abstract

Multiple sclerosis (MS) is a chronic disease of the central nervous system responsible for a large portion of neurological disabilities in young adults. Similar to what occurs in numerous complex diseases, both unknown environmental factors and genetic predisposition are required to generate MS. We ascertained a set of 63 Finnish MS families, originating from a high-risk region of the country, to identify a susceptibility gene within the previously established 3.4-Mb region on 17q24. Initial single nucleotide polymorphism (SNP)-based association implicated PRKCA (protein kinase C alpha) gene, and this association was replicated in an independent set of 148 Finnish MS families (p = 0.0004; remaining significant after correction for multiple testing). Further, a dense set of 211 SNPs evenly covering the PRKCA gene and the flanking regions was selected from the dbSNP database and analyzed in two large, independent MS cohorts: in 211 Finnish and 554 Canadian MS families. A multipoint SNP analysis indicated linkage to PRKCA and its telomeric flanking region in both populations, and SNP haplotype and genotype combination analyses revealed an allelic variant of PRKCA, which covers the region between introns 3 and 8, to be over-represented in Finnish MS cases (odds ratio = 1.34, 95% confidence interval 1.07-1.68). A second allelic variant, covering the same region of the PRKCA gene, showed somewhat stronger evidence for association in the Canadian families (odds ratio = 1.64, 95% confidence interval 1.39-1.94). Initial functional relevance for disease predisposition was suggested by the expression analysis: The transcript levels of PRKCA showed correlation with the copy number of the Finnish and Canadian "risk" haplotypes in CD4-negative mononuclear cells of five Finnish multiplex families and in lymphoblast cell lines of 11 Centre d'Etude du Polymorphisme Humain (CEPH) individuals of European origin.

Published
2006
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15. Does the likelihood of malignancy in thyroid nodules with RAS mutations increase in direct proportion with the allele frequency percentage?

Author

Thomas J. Hudson, Marc Philippe Pusztaszeri, Michael P. Hier, Veronique-Isabelle Forest, Ji-Wei Yang, and Richard J. Payne

Subjects
Thyroid cancer, Genetics, Cytology, Allele frequency, Thyroid nodules, Surgery, RD1-811
Abstract

Abstract Background Genomic testing has enhanced pre-surgical decision making for cytologically indeterminate thyroid nodules, but there remains uncertainty regarding RAS mutations. The addition of extra genetic alterations to previous driver mutation panels has been shown to improve predictive value. This study aims to evaluate the relationship between the mutant allele frequency (AF) and likelihood of malignancy in thyroid nodules with RAS mutations. Methods A retrospective cohort review was performed evaluating patients with indeterminate cytology (Bethesda categories III, IV and V) and ThyroSeq® v3 testing demonstrating a RAS mutation, who underwent surgery. Univariate and multivariate regression analyses were used to evaluate relationships between AF, other genetic alterations, and malignancy. Results Thirty-nine patients met criteria, 77% of the thyroid nodules (30/39) were found to be malignant. None demonstrated aggressive pathology. On univariate regression, there was no relationship between AF and likelihood of malignancy. There was, however, a significant correlation between AF and the rate of an additional genetic alteration. Multivariate analysis found a trend between RAS, a second genetic alteration and malignancy, but it did not reach statistical significance. Conclusions There was no direct relationship between the level of allelic frequency in thyroid nodules expressing RAS mutations and the likelihood of malignancy. There was a statistically significant relationship between increasing AF and the presence of a second genetic abnormality, suggesting a possible progression from initial driver mutation and then a second genetic alteration prior to malignant transformation. Graphical abstract

Published
2023
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16. Morphological analysis of sigmoid sinus anatomy: clinical applications to neurotological surgery

Author

Kylen Van Osch, Daniel Allen, Bradley Gare, Thomas J. Hudson, Hanif Ladak, and Sumit K. Agrawal

Subjects
Sigmoid sinus, Transverse sinus, Jugular bulb - facial nerve, Statistical shape model, Anatomy, Neurotology, Surgery, RD1-811
Abstract

Abstract Objectives The primary objective of this study was to use high-resolution micro-CT images to create accurate three-dimensional (3D) models of several intratemporal structures, and to compare several surgically important dimensions within the temporal bone. The secondary objective was to create a statistical shape model (SSM) of a dominant and non-dominant sigmoid sinus (SS) to provide a template for automated segmentation algorithms. Methods A free image processing software, 3D Slicer, was utilized to create three-dimensional reconstructions of the SS, jugular bulb (JB), facial nerve (FN), and external auditory canal (EAC) from micro-CT scans. The models were used to compare several clinically important dimensions between the dominant and non-dominant SS. Anatomic variability of the SS was also analyzed using SSMs generated using the Statismo software framework. Results Three-dimensional models from 38 temporal bones were generated and analyzed. Right dominance was observed in 74% of the paired SSs. All distances were significantly shorter on the dominant side (p < 0.05), including: EAC – SS (dominant: 13.7 ± 3.4 mm; non-dominant: 15.3 ± 2.7 mm), FN – SS (dominant: 7.2 ± 1.8 mm; non-dominant: 8.1 ± 2.3 mm), 2nd genu FN – superior tip of JB (dominant: 8.7 ± 2.2 mm; non-dominant: 11.2 ± 2.6 mm), horizontal distance between the superior tip of JB – descending FN (dominant: 9.5 ± 2.3 mm; non-dominant: 13.2 ± 3.5 mm), and horizontal distance between the FN at the stylomastoid foramen – JB (dominant: 5.4 ± 2.2 mm; non-dominant: 7.7 ± 2.1). Analysis of the SSMs indicated that SS morphology is most variable at its junction with the transverse sinus, and least variable at the JB. Conclusions This is the first known study to investigate the anatomical variation and relationships of the SS using high resolution scans, 3D models and statistical shape analysis. This analysis seeks to guide neurotological surgical approaches and provide a template for automated segmentation and surgical simulation.

Published
2019
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17. The Difference in Clinical Behavior of Gene Fusions Involving RET/PTC Fusions and THADA/IGF2BP3 Fusions in Thyroid Nodules

Author

Forest, George Tali, Alexandra E. Payne, Thomas J. Hudson, Sabrina Daniela da Silva, Marc Pusztaszeri, Michael Tamilia, and Véronique-Isabelle

Subjects
thyroid, endocrine, cancer, RET/PTC, THADA/IGF2BP3, thyroidectomy, molecular panel, genetic translocation, Bethesda score
Abstract

Background: Molecular testing has been used as an adjunct to morphological evaluation in the workup of thyroid nodules. This study investigated the impact of two gene fusions, RET/PTC and THADA/IGF2BP3, that have been described as oncogenic events in thyroid neoplasms. Methods: We performed a retrospective, single-centered study at a McGill University teaching hospital in Montreal, Canada, from January 2016 to August 2021. We included patients who underwent surgery for thyroid nodules that pre-operatively underwent molecular testing showing either RET/PTC or THADA/IGF2BP3 gene fusion. Results: This study included 697 consecutive operated thyroid nodules assessed using molecular testing, of which five had the RET/PTC fusion and seven had the THADA/IGF2BP3 fusion. Of the five nodules in the RET/PTC group, 100% were malignant and presented as Bethesda V/VI. Eighty percent (4/5) were found to have lymph node metastasis. Twenty percent (1/5) had extrathyroidal extensions. Sixty percent (3/5) were a diffuse sclerosing variant of papillary thyroid carcinoma, and the rest were the classical variant. Of the seven THADA/IGF2BP3 nodules, all presented as Bethesda III/IV and 71.4% (5/7) were malignant based on the final pathology analysis, and 28.6% (2/7) were NIFTP. All the THADA/IGF2BP3 fusion malignancies were a follicular variant of papillary thyroid carcinoma. None had lymph node metastasis or displayed extrathyroidal extensions. Conclusions: RET/PTC nodules presented as Bethesda V/VI and potentially had more aggressive features, whereas THADA/IGF2BP3 nodules presented as Bethesda III/IV and had more indolent behavior. This understanding may allow clinicians to develop more targeted treatment plans, such as the extent of surgery and adjuvant radioactive iodine treatment.

Published
2023
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18. Supp. Table S22 from Genetic Mechanisms of Immune Evasion in Colorectal Cancer

Author

Ulrike Peters, Shuji Ogino, Antoni Ribas, Charles S. Fuchs, Thomas J. Hudson, Levi A. Garraway, Eric S. Lander, Stacey B. Gabriel, Jesse M. Zaretsky, Syed H. Zaidi, Ming Yu, Catherine J. Wu, David A. Wheeler, Alexander Upfill-Brown, Jennifer Tsoi, Wei Sun, Janet L. Stanford, Sachet Shukla, Brian Shirts, Eve Shinbrot, Daniel Sanghoon Shin, Stephen J. Salipante, Ben J. Raphael, Elleanor H. Quist, Cristina Puig-Saus, Colin C. Pritchard, Matteo Pellegrini, Brian B. Nadel, Dennis J. Montoya, Mark D.M. Leiserson, Paige Krystofinski, Yeon Joo Kim, Jeroen R. Huyghe, Siwen Hu-Lieskovan, Li Hsu, William M. Grady, Milan S. Geybels, Helena Escuin-Ordinas, Charles Connolly, Gabriel Abril-Rodriguez, Katsuhiko Nosho, Teppei Morikawa, Kentaro Inamura, Zhi Rong Qian, Reiko Nishihara, Jonathan A. Nowak, Michael Quist, Xinmeng Jasmine Mu, Tsuyoshi Hamada, Daniel K. Wells, Marios Giannakis, and Catherine S. Grasso

Abstract

Supplementary Table S22: Segmented b-allele deficits

Published
2023
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19. Supp. Tables S16-S19 from Genetic Mechanisms of Immune Evasion in Colorectal Cancer

Author

Ulrike Peters, Shuji Ogino, Antoni Ribas, Charles S. Fuchs, Thomas J. Hudson, Levi A. Garraway, Eric S. Lander, Stacey B. Gabriel, Jesse M. Zaretsky, Syed H. Zaidi, Ming Yu, Catherine J. Wu, David A. Wheeler, Alexander Upfill-Brown, Jennifer Tsoi, Wei Sun, Janet L. Stanford, Sachet Shukla, Brian Shirts, Eve Shinbrot, Daniel Sanghoon Shin, Stephen J. Salipante, Ben J. Raphael, Elleanor H. Quist, Cristina Puig-Saus, Colin C. Pritchard, Matteo Pellegrini, Brian B. Nadel, Dennis J. Montoya, Mark D.M. Leiserson, Paige Krystofinski, Yeon Joo Kim, Jeroen R. Huyghe, Siwen Hu-Lieskovan, Li Hsu, William M. Grady, Milan S. Geybels, Helena Escuin-Ordinas, Charles Connolly, Gabriel Abril-Rodriguez, Katsuhiko Nosho, Teppei Morikawa, Kentaro Inamura, Zhi Rong Qian, Reiko Nishihara, Jonathan A. Nowak, Michael Quist, Xinmeng Jasmine Mu, Tsuyoshi Hamada, Daniel K. Wells, Marios Giannakis, and Catherine S. Grasso

Abstract

Supplementary Tables S16-S19, describing IHC results on NHS/HPFS data

Published
2023
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20. Supp. Tables S1, S3-S15, S20, and S23 from Genetic Mechanisms of Immune Evasion in Colorectal Cancer

Author

Ulrike Peters, Shuji Ogino, Antoni Ribas, Charles S. Fuchs, Thomas J. Hudson, Levi A. Garraway, Eric S. Lander, Stacey B. Gabriel, Jesse M. Zaretsky, Syed H. Zaidi, Ming Yu, Catherine J. Wu, David A. Wheeler, Alexander Upfill-Brown, Jennifer Tsoi, Wei Sun, Janet L. Stanford, Sachet Shukla, Brian Shirts, Eve Shinbrot, Daniel Sanghoon Shin, Stephen J. Salipante, Ben J. Raphael, Elleanor H. Quist, Cristina Puig-Saus, Colin C. Pritchard, Matteo Pellegrini, Brian B. Nadel, Dennis J. Montoya, Mark D.M. Leiserson, Paige Krystofinski, Yeon Joo Kim, Jeroen R. Huyghe, Siwen Hu-Lieskovan, Li Hsu, William M. Grady, Milan S. Geybels, Helena Escuin-Ordinas, Charles Connolly, Gabriel Abril-Rodriguez, Katsuhiko Nosho, Teppei Morikawa, Kentaro Inamura, Zhi Rong Qian, Reiko Nishihara, Jonathan A. Nowak, Michael Quist, Xinmeng Jasmine Mu, Tsuyoshi Hamada, Daniel K. Wells, Marios Giannakis, and Catherine S. Grasso

Abstract

Supplementary Tables S1, S3 through S15, S20, and S23

Published
2023
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21. Data from Genetic Mechanisms of Immune Evasion in Colorectal Cancer

Author

Ulrike Peters, Shuji Ogino, Antoni Ribas, Charles S. Fuchs, Thomas J. Hudson, Levi A. Garraway, Eric S. Lander, Stacey B. Gabriel, Jesse M. Zaretsky, Syed H. Zaidi, Ming Yu, Catherine J. Wu, David A. Wheeler, Alexander Upfill-Brown, Jennifer Tsoi, Wei Sun, Janet L. Stanford, Sachet Shukla, Brian Shirts, Eve Shinbrot, Daniel Sanghoon Shin, Stephen J. Salipante, Ben J. Raphael, Elleanor H. Quist, Cristina Puig-Saus, Colin C. Pritchard, Matteo Pellegrini, Brian B. Nadel, Dennis J. Montoya, Mark D.M. Leiserson, Paige Krystofinski, Yeon Joo Kim, Jeroen R. Huyghe, Siwen Hu-Lieskovan, Li Hsu, William M. Grady, Milan S. Geybels, Helena Escuin-Ordinas, Charles Connolly, Gabriel Abril-Rodriguez, Katsuhiko Nosho, Teppei Morikawa, Kentaro Inamura, Zhi Rong Qian, Reiko Nishihara, Jonathan A. Nowak, Michael Quist, Xinmeng Jasmine Mu, Tsuyoshi Hamada, Daniel K. Wells, Marios Giannakis, and Catherine S. Grasso

Abstract

To understand the genetic drivers of immune recognition and evasion in colorectal cancer, we analyzed 1,211 colorectal cancer primary tumor samples, including 179 classified as microsatellite instability–high (MSI-high). This set includes The Cancer Genome Atlas colorectal cancer cohort of 592 samples, completed and analyzed here. MSI-high, a hypermutated, immunogenic subtype of colorectal cancer, had a high rate of significantly mutated genes in important immune-modulating pathways and in the antigen presentation machinery, including biallelic losses of B2M and HLA genes due to copy-number alterations and copy-neutral loss of heterozygosity. WNT/β-catenin signaling genes were significantly mutated in all colorectal cancer subtypes, and activated WNT/β-catenin signaling was correlated with the absence of T-cell infiltration. This large-scale genomic analysis of colorectal cancer demonstrates that MSI-high cases frequently undergo an immunoediting process that provides them with genetic events allowing immune escape despite high mutational load and frequent lymphocytic infiltration and, furthermore, that colorectal cancer tumors have genetic and methylation events associated with activated WNT signaling and T-cell exclusion.Significance: This multi-omic analysis of 1,211 colorectal cancer primary tumors reveals that it should be possible to better monitor resistance in the 15% of cases that respond to immune blockade therapy and also to use WNT signaling inhibitors to reverse immune exclusion in the 85% of cases that currently do not. Cancer Discov; 8(6); 730–49. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 663

Published
2023
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22. Supplementary Data and Supplementary Tables 1 and 2 from Genetic Predictors of Circulating 25-Hydroxyvitamin D and Risk of Colorectal Cancer

Author

Andrew T. Chan, Ulrike Peters, Peter Kraft, Brent W. Zanke, Kana Wu, Emily White, Jean Wactawski-Wende, Martha L. Slattery, Daniela Seminara, Fredrick R. Schumacher, Robert E. Schoen, John D. Potter, Kimmie Ng, Polly A. Newcomb, Hongmei Nan, JoAnn E. Manson, Jing Ma, Mathieu Lemire, Loic Le Marchand, Sébastien Küry, Mark A. Jenkins, Thomas J. Hudson, John L. Hopper, Michael Hoffmeister, Brian Henderson, Aditi Hazra, Richard B. Hayes, Tabitha A. Harrison, Edward L. Giovannucci, Steven Gallinger, Charles S. Fuchs, David Duggan, David V. Conti, Stephen J. Chanock, Jenny Chang-Claude, Graham Casey, Bette J. Caan, Hermann Brenner, Stéphane Bézieau, Sonja I. Berndt, John A. Baron, Carolyn M. Hutter, Conghui Qu, and Linda T. Hiraki

Abstract

Contains more detailed information on the individual cohorts contributing to the study and their genotyping results; Supplemental Tables 1 and 2

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2023
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23. Supplementary Table 2 and Supplemental Figures from Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations

Author

Rayjean J. Hung, Brian E. Henderson, Christopher A. Haiman, David J. Hunter, Douglas F. Easton, Thomas A. Sellers, Christopher I. Amos, Stephen B. Gruber, Ulrike Peters, Jian Gong, Stephen J. Chanock, Daniela Seminara, Qiyuan Li, Matthew L. Freedman, Wim Timens, David Nickle, Ma'en Obeidat, Yohan Bossé, Atsushi Takahashi, Kouya Shiraishi, Xiao-Ou Shu, Zhibin Hu, Hongbing Shen, Yongyue Wei, David C. Christiani, Jonathan P. Tyrer, Y. Ann Chen, Patrick Sulem, Kari Stefansson, Simon N. Stacey, Julius Gudmundsson, Thorunn Rafnar, Michael O. Woods, Stephen N. Thibodeau, Stephanie L. Schmit, Noralene M. Lindor, Li Li, Loïc Le Marchand, Mark Jenkins, Robert W. Haile, Steven Gallinger, Christopher K. Edlund, David V. Conti, Graham Casey, Daniel D. Buchanan, Wei Zheng, Xiaohong R. Yang, Alice S. Whittemore, Zhaoming Wang, Andre G. Uitterlinden, Clare Turnbull, Ruth C. Travis, Rulla Tamimi, Melissa C. Southey, Rita K. Schmutzler, Daniel F. Schmidt, Maria Jose Sanchez, Nazneen Rahman, Ross L. Prentice, Julian Peto, Petra H. Peeters, Heli Nevanlinna, Taru A. Muranen, Bertram Müller-Myhsok, Alfons Meindl, Enes Makalic, Eiliv Lund, Jianjun Liu, Peter Lichtner, Muhammad G. Kibriya, Rudolf Kaaks, Mattias Johansson, Astrid Irwanto, John L. Hopper, Albert Hofman, Rebecca Hein, Aditi Hazra, Per Hall, Nichola Johnson, Mia M. Gaudet, Montserrat Garcia-Closas, Olivia Fletcher, Dieter Flesch-Janys, Jonine D. Figueroa, A. Heather Eliassen, Isabel dos-Santos-Silva, Kamila Czene, Federico Canzian, Carl Blomquist, Laura Baglietto, Kristiina Aittomäki, Habibul Ahsan, Muriel A. Adank, Emily White, Martha L. Slattery, Robert E. Schoen, Polly A. Newcomb, Jonathan K. Kocarnik, Thomas J. Hudson, Jenny Chang-Claude, Andrew T. Chan, Hermann Brenner, Stephane Bezieau, Brett M. Reid, Harvey A. Risch, Jennifer B. Permuth, Ellen L. Goode, Walter C. Willett, Fredrik Wiklund, Victoria L. Stevens, Meir J. Stampfer, Kenneth Muir, Jing Ma, Zsofia Kote-Jarai, Henrik Grönberg, Edward L. Giovannucci, Sonja I. Berndt, Ali Amin Al Olama, Angela Risch, Neil Caporaso, Maria Teresa Landi, Richard S. Houlston, Heike Bickeböller, Paul Brennan, Sara Lindström, Joellen M. Schildkraut, Fredrick R. Schumacher, Nilanjan Chatterjee, Rosalind A. Eeles, Paul D. Pharoah, Peter Kraft, and Gordon Fehringer

Abstract

Table S2: Odds ratio and 95% confidence limits for cancers associated with variants with pleiotropic associations. Figure S1: Flowchart showing analysis steps. Figure S2. Manhattan plots by chromosome for individual cancer sites. Figure S3. Results for rs11571833. Figure S4: Conditional QQ-plots.

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2023
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24. Data from Genetic Predictors of Circulating 25-Hydroxyvitamin D and Risk of Colorectal Cancer

Author

Andrew T. Chan, Ulrike Peters, Peter Kraft, Brent W. Zanke, Kana Wu, Emily White, Jean Wactawski-Wende, Martha L. Slattery, Daniela Seminara, Fredrick R. Schumacher, Robert E. Schoen, John D. Potter, Kimmie Ng, Polly A. Newcomb, Hongmei Nan, JoAnn E. Manson, Jing Ma, Mathieu Lemire, Loic Le Marchand, Sébastien Küry, Mark A. Jenkins, Thomas J. Hudson, John L. Hopper, Michael Hoffmeister, Brian Henderson, Aditi Hazra, Richard B. Hayes, Tabitha A. Harrison, Edward L. Giovannucci, Steven Gallinger, Charles S. Fuchs, David Duggan, David V. Conti, Stephen J. Chanock, Jenny Chang-Claude, Graham Casey, Bette J. Caan, Hermann Brenner, Stéphane Bézieau, Sonja I. Berndt, John A. Baron, Carolyn M. Hutter, Conghui Qu, and Linda T. Hiraki

Abstract

Background: Experimental evidence has demonstrated an antineoplastic role for vitamin D in the colon, and higher circulating 25-hydroxyvitamin D [25(OH)D] levels are consistently associated with a lower risk of colorectal cancer. Genome-wide association studies have identified loci associated with levels of circulating 25(OH)D. The identified single-nucleotide polymorphisms (SNPs) from four gene regions collectively explain approximately 5% of the variance in circulating 25(OH)D.Methods: We investigated whether five polymorphisms in GC, CYP2R1, CYP24A1, and DHCR7/NADSYN1, genes previously shown to be associated with circulating 25(OH)D levels, were associated with colorectal cancer risk in 10,061 cases and 12,768 controls drawn from 13 studies included in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and Colon Cancer Family Registry (CCFR). We conducted a meta-analysis of crude and multivariate-adjusted logistic regression models to calculate odds ratios and associated confidence intervals for SNPs individually, SNPs simultaneously, and for a vitamin D additive genetic risk score (GRS).Results: We did not observe a statistically significant association between the 25(OH)D-associated SNPs and colorectal cancer marginally, conditionally, or as a GRS, or for colon or rectal cancer separately.Conclusions: Our findings do not support an association between SNPs associated with circulating 25(OH)D and risk of colorectal cancer. Additional work is warranted to investigate the complex relationship between 25(OH)D and colorectal cancer risk.Impact: There was no association observed between genetic markers of circulating 25(OH)D and colorectal cancer. These genetic markers account for a small proportion of the variance in 25(OH)D. Cancer Epidemiol Biomarkers Prev; 22(11); 2037–46. ©2013 AACR.

Published
2023
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25. Data from Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations

Author

Rayjean J. Hung, Brian E. Henderson, Christopher A. Haiman, David J. Hunter, Douglas F. Easton, Thomas A. Sellers, Christopher I. Amos, Stephen B. Gruber, Ulrike Peters, Jian Gong, Stephen J. Chanock, Daniela Seminara, Qiyuan Li, Matthew L. Freedman, Wim Timens, David Nickle, Ma'en Obeidat, Yohan Bossé, Atsushi Takahashi, Kouya Shiraishi, Xiao-Ou Shu, Zhibin Hu, Hongbing Shen, Yongyue Wei, David C. Christiani, Jonathan P. Tyrer, Y. Ann Chen, Patrick Sulem, Kari Stefansson, Simon N. Stacey, Julius Gudmundsson, Thorunn Rafnar, Michael O. Woods, Stephen N. Thibodeau, Stephanie L. Schmit, Noralene M. Lindor, Li Li, Loïc Le Marchand, Mark Jenkins, Robert W. Haile, Steven Gallinger, Christopher K. Edlund, David V. Conti, Graham Casey, Daniel D. Buchanan, Wei Zheng, Xiaohong R. Yang, Alice S. Whittemore, Zhaoming Wang, Andre G. Uitterlinden, Clare Turnbull, Ruth C. Travis, Rulla Tamimi, Melissa C. Southey, Rita K. Schmutzler, Daniel F. Schmidt, Maria Jose Sanchez, Nazneen Rahman, Ross L. Prentice, Julian Peto, Petra H. Peeters, Heli Nevanlinna, Taru A. Muranen, Bertram Müller-Myhsok, Alfons Meindl, Enes Makalic, Eiliv Lund, Jianjun Liu, Peter Lichtner, Muhammad G. Kibriya, Rudolf Kaaks, Mattias Johansson, Astrid Irwanto, John L. Hopper, Albert Hofman, Rebecca Hein, Aditi Hazra, Per Hall, Nichola Johnson, Mia M. Gaudet, Montserrat Garcia-Closas, Olivia Fletcher, Dieter Flesch-Janys, Jonine D. Figueroa, A. Heather Eliassen, Isabel dos-Santos-Silva, Kamila Czene, Federico Canzian, Carl Blomquist, Laura Baglietto, Kristiina Aittomäki, Habibul Ahsan, Muriel A. Adank, Emily White, Martha L. Slattery, Robert E. Schoen, Polly A. Newcomb, Jonathan K. Kocarnik, Thomas J. Hudson, Jenny Chang-Claude, Andrew T. Chan, Hermann Brenner, Stephane Bezieau, Brett M. Reid, Harvey A. Risch, Jennifer B. Permuth, Ellen L. Goode, Walter C. Willett, Fredrik Wiklund, Victoria L. Stevens, Meir J. Stampfer, Kenneth Muir, Jing Ma, Zsofia Kote-Jarai, Henrik Grönberg, Edward L. Giovannucci, Sonja I. Berndt, Ali Amin Al Olama, Angela Risch, Neil Caporaso, Maria Teresa Landi, Richard S. Houlston, Heike Bickeböller, Paul Brennan, Sara Lindström, Joellen M. Schildkraut, Fredrick R. Schumacher, Nilanjan Chatterjee, Rosalind A. Eeles, Paul D. Pharoah, Peter Kraft, and Gordon Fehringer

Abstract

Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103–14. ©2016 AACR.

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2023
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26. Supplementary Material: Funding, Acknowledgements, Consortia, and Bioinformatics Tools Funding sources from Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations

Author

Rayjean J. Hung, Brian E. Henderson, Christopher A. Haiman, David J. Hunter, Douglas F. Easton, Thomas A. Sellers, Christopher I. Amos, Stephen B. Gruber, Ulrike Peters, Jian Gong, Stephen J. Chanock, Daniela Seminara, Qiyuan Li, Matthew L. Freedman, Wim Timens, David Nickle, Ma'en Obeidat, Yohan Bossé, Atsushi Takahashi, Kouya Shiraishi, Xiao-Ou Shu, Zhibin Hu, Hongbing Shen, Yongyue Wei, David C. Christiani, Jonathan P. Tyrer, Y. Ann Chen, Patrick Sulem, Kari Stefansson, Simon N. Stacey, Julius Gudmundsson, Thorunn Rafnar, Michael O. Woods, Stephen N. Thibodeau, Stephanie L. Schmit, Noralene M. Lindor, Li Li, Loïc Le Marchand, Mark Jenkins, Robert W. Haile, Steven Gallinger, Christopher K. Edlund, David V. Conti, Graham Casey, Daniel D. Buchanan, Wei Zheng, Xiaohong R. Yang, Alice S. Whittemore, Zhaoming Wang, Andre G. Uitterlinden, Clare Turnbull, Ruth C. Travis, Rulla Tamimi, Melissa C. Southey, Rita K. Schmutzler, Daniel F. Schmidt, Maria Jose Sanchez, Nazneen Rahman, Ross L. Prentice, Julian Peto, Petra H. Peeters, Heli Nevanlinna, Taru A. Muranen, Bertram Müller-Myhsok, Alfons Meindl, Enes Makalic, Eiliv Lund, Jianjun Liu, Peter Lichtner, Muhammad G. Kibriya, Rudolf Kaaks, Mattias Johansson, Astrid Irwanto, John L. Hopper, Albert Hofman, Rebecca Hein, Aditi Hazra, Per Hall, Nichola Johnson, Mia M. Gaudet, Montserrat Garcia-Closas, Olivia Fletcher, Dieter Flesch-Janys, Jonine D. Figueroa, A. Heather Eliassen, Isabel dos-Santos-Silva, Kamila Czene, Federico Canzian, Carl Blomquist, Laura Baglietto, Kristiina Aittomäki, Habibul Ahsan, Muriel A. Adank, Emily White, Martha L. Slattery, Robert E. Schoen, Polly A. Newcomb, Jonathan K. Kocarnik, Thomas J. Hudson, Jenny Chang-Claude, Andrew T. Chan, Hermann Brenner, Stephane Bezieau, Brett M. Reid, Harvey A. Risch, Jennifer B. Permuth, Ellen L. Goode, Walter C. Willett, Fredrik Wiklund, Victoria L. Stevens, Meir J. Stampfer, Kenneth Muir, Jing Ma, Zsofia Kote-Jarai, Henrik Grönberg, Edward L. Giovannucci, Sonja I. Berndt, Ali Amin Al Olama, Angela Risch, Neil Caporaso, Maria Teresa Landi, Richard S. Houlston, Heike Bickeböller, Paul Brennan, Sara Lindström, Joellen M. Schildkraut, Fredrick R. Schumacher, Nilanjan Chatterjee, Rosalind A. Eeles, Paul D. Pharoah, Peter Kraft, and Gordon Fehringer

Abstract

Funding sources, acknowledgements, consortia involved in study and bioinformatics tools used

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2023
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27. Supplementary Table 1 from Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations

Author

Rayjean J. Hung, Brian E. Henderson, Christopher A. Haiman, David J. Hunter, Douglas F. Easton, Thomas A. Sellers, Christopher I. Amos, Stephen B. Gruber, Ulrike Peters, Jian Gong, Stephen J. Chanock, Daniela Seminara, Qiyuan Li, Matthew L. Freedman, Wim Timens, David Nickle, Ma'en Obeidat, Yohan Bossé, Atsushi Takahashi, Kouya Shiraishi, Xiao-Ou Shu, Zhibin Hu, Hongbing Shen, Yongyue Wei, David C. Christiani, Jonathan P. Tyrer, Y. Ann Chen, Patrick Sulem, Kari Stefansson, Simon N. Stacey, Julius Gudmundsson, Thorunn Rafnar, Michael O. Woods, Stephen N. Thibodeau, Stephanie L. Schmit, Noralene M. Lindor, Li Li, Loïc Le Marchand, Mark Jenkins, Robert W. Haile, Steven Gallinger, Christopher K. Edlund, David V. Conti, Graham Casey, Daniel D. Buchanan, Wei Zheng, Xiaohong R. Yang, Alice S. Whittemore, Zhaoming Wang, Andre G. Uitterlinden, Clare Turnbull, Ruth C. Travis, Rulla Tamimi, Melissa C. Southey, Rita K. Schmutzler, Daniel F. Schmidt, Maria Jose Sanchez, Nazneen Rahman, Ross L. Prentice, Julian Peto, Petra H. Peeters, Heli Nevanlinna, Taru A. Muranen, Bertram Müller-Myhsok, Alfons Meindl, Enes Makalic, Eiliv Lund, Jianjun Liu, Peter Lichtner, Muhammad G. Kibriya, Rudolf Kaaks, Mattias Johansson, Astrid Irwanto, John L. Hopper, Albert Hofman, Rebecca Hein, Aditi Hazra, Per Hall, Nichola Johnson, Mia M. Gaudet, Montserrat Garcia-Closas, Olivia Fletcher, Dieter Flesch-Janys, Jonine D. Figueroa, A. Heather Eliassen, Isabel dos-Santos-Silva, Kamila Czene, Federico Canzian, Carl Blomquist, Laura Baglietto, Kristiina Aittomäki, Habibul Ahsan, Muriel A. Adank, Emily White, Martha L. Slattery, Robert E. Schoen, Polly A. Newcomb, Jonathan K. Kocarnik, Thomas J. Hudson, Jenny Chang-Claude, Andrew T. Chan, Hermann Brenner, Stephane Bezieau, Brett M. Reid, Harvey A. Risch, Jennifer B. Permuth, Ellen L. Goode, Walter C. Willett, Fredrik Wiklund, Victoria L. Stevens, Meir J. Stampfer, Kenneth Muir, Jing Ma, Zsofia Kote-Jarai, Henrik Grönberg, Edward L. Giovannucci, Sonja I. Berndt, Ali Amin Al Olama, Angela Risch, Neil Caporaso, Maria Teresa Landi, Richard S. Houlston, Heike Bickeböller, Paul Brennan, Sara Lindström, Joellen M. Schildkraut, Fredrick R. Schumacher, Nilanjan Chatterjee, Rosalind A. Eeles, Paul D. Pharoah, Peter Kraft, and Gordon Fehringer

Abstract

Variants selected for replication

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2023
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28. Supplementary Table S2 from Constitutive Activation of Extracellular Signal-Regulated Kinase Predisposes Diffuse Large B-Cell Lymphoma Cell Lines to CD40-Mediated Cell Death

Author

Robert Sladek, Thomas J. Hudson, Josephine Nalbantoglu, Trevor Owens, and C. Annette Hollmann

Abstract

Supplementary Table S2 from Constitutive Activation of Extracellular Signal-Regulated Kinase Predisposes Diffuse Large B-Cell Lymphoma Cell Lines to CD40-Mediated Cell Death

Published
2023
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29. Supplementary Table 4 from Characterization of Gene–Environment Interactions for Colorectal Cancer Susceptibility Loci

Author

Ulrike Peters, Thomas J. Hudson, Andrew T. Chan, Stéphane Bézieau, Li Hsu, John D. Potter, Bette J. Caan, Richard B. Hayes, Sonja I. Berndt, Stephen J. Chanock, Robert E. Schoen, Rebecca D. Jackson, Ross L. Prentice, Andrea Z. LaCroix, Charles Kooperberg, Polly A. Newcomb, Emily White, Cornelia M. Ulrich, Jing Ma, Bernd Frank, Hermann Brenner, Brent W. Zanke, Steven Gallinger, David J. Hunter, Peter Kraft, Aditi Hazra, Edward Giovannucci, Charles S. Fuchs, Sébastien Küry, Michael Hoffmeister, Greg S. Warnick, Deanna L. Stelling, Lin S. Chen, Yan Liu, Tabitha A. Harrison, Shuo Jiao, Jane C. Figueiredo, Jagadish Rangrej, Mathieu Lemire, Hongmei Nan, David Duggan, Yi Lin, Bethann M. Pflugeisen, Martha L. Slattery, Jenny Chang-Claude, and Carolyn M. Hutter

Abstract

PDF file - 77K, All GxE interaction results.

Published
2023
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30. Data from Constitutive Activation of Extracellular Signal-Regulated Kinase Predisposes Diffuse Large B-Cell Lymphoma Cell Lines to CD40-Mediated Cell Death

Author

Robert Sladek, Thomas J. Hudson, Josephine Nalbantoglu, Trevor Owens, and C. Annette Hollmann

Abstract

CD40 promotes survival, proliferation, and differentiation of normal B cells but can cause activation-induced cell death in malignant B lymphocytes. CD40 ligand and anti-CD40 antibodies have been used successfully to induce apoptosis in lymphoma lines both in vitro and in xenograft tumor models. Although this makes CD40 an attractive target for antitumor therapies, the response of malignant B cells to CD40 signaling is variable, and CD40 stimulation can enhance proliferation and can increase chemoresistance in some cell lines. It would therefore be useful to identify markers that predict whether a specific cell line or tumor will undergo apoptosis when stimulated with CD40 and to identify targets downstream of CD40 that affect only the apoptotic arm of CD40 signaling. We have analyzed gene expression patterns in CD40-sensitive and CD40-resistant diffuse large B-cell lymphoma (DLBCL) cell lines to identify signaling pathways that are involved in CD40-mediated apoptosis. CD40-resistant lines expressed pre-B-cell markers, including RAG and VPREB, whereas CD40-sensitive cells resembled mature B cells and expressed higher levels of transcripts encoding several members of the CD40 signaling pathway, including LCK and VAV. In addition, CD40-sensitive DLBCL cell lines also displayed constitutive activation of extracellular signal-regulated kinase (ERK) and failed to undergo apoptosis when ERK phosphorylation was inhibited. In contrast, CD40-resistant lines showed no constitutive activation of ERK and no increase in ERK activity in response to CD40 stimulation. Our results suggest that constitutive activation of ERK may be required for death signaling by CD40. (Cancer Res 2006; 66(77):3550-7)

Published
2023
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31. Supplementary Table 2 from Characterization of Gene–Environment Interactions for Colorectal Cancer Susceptibility Loci

Author

Ulrike Peters, Thomas J. Hudson, Andrew T. Chan, Stéphane Bézieau, Li Hsu, John D. Potter, Bette J. Caan, Richard B. Hayes, Sonja I. Berndt, Stephen J. Chanock, Robert E. Schoen, Rebecca D. Jackson, Ross L. Prentice, Andrea Z. LaCroix, Charles Kooperberg, Polly A. Newcomb, Emily White, Cornelia M. Ulrich, Jing Ma, Bernd Frank, Hermann Brenner, Brent W. Zanke, Steven Gallinger, David J. Hunter, Peter Kraft, Aditi Hazra, Edward Giovannucci, Charles S. Fuchs, Sébastien Küry, Michael Hoffmeister, Greg S. Warnick, Deanna L. Stelling, Lin S. Chen, Yan Liu, Tabitha A. Harrison, Shuo Jiao, Jane C. Figueiredo, Jagadish Rangrej, Mathieu Lemire, Hongmei Nan, David Duggan, Yi Lin, Bethann M. Pflugeisen, Martha L. Slattery, Jenny Chang-Claude, and Carolyn M. Hutter

Abstract

PDF file - 55K, Study specific definitions of regular aspirin/NSAID use.

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2023
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32. Supplementary Table 7 from Characterization of Gene–Environment Interactions for Colorectal Cancer Susceptibility Loci

Author

Ulrike Peters, Thomas J. Hudson, Andrew T. Chan, Stéphane Bézieau, Li Hsu, John D. Potter, Bette J. Caan, Richard B. Hayes, Sonja I. Berndt, Stephen J. Chanock, Robert E. Schoen, Rebecca D. Jackson, Ross L. Prentice, Andrea Z. LaCroix, Charles Kooperberg, Polly A. Newcomb, Emily White, Cornelia M. Ulrich, Jing Ma, Bernd Frank, Hermann Brenner, Brent W. Zanke, Steven Gallinger, David J. Hunter, Peter Kraft, Aditi Hazra, Edward Giovannucci, Charles S. Fuchs, Sébastien Küry, Michael Hoffmeister, Greg S. Warnick, Deanna L. Stelling, Lin S. Chen, Yan Liu, Tabitha A. Harrison, Shuo Jiao, Jane C. Figueiredo, Jagadish Rangrej, Mathieu Lemire, Hongmei Nan, David Duggan, Yi Lin, Bethann M. Pflugeisen, Martha L. Slattery, Jenny Chang-Claude, and Carolyn M. Hutter

Abstract

PDF file - 96K, All GxE interactions stratified by cancer site.

Published
2023
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33. Supplementary Figure 1 from Characterization of Gene–Environment Interactions for Colorectal Cancer Susceptibility Loci

Author

Ulrike Peters, Thomas J. Hudson, Andrew T. Chan, Stéphane Bézieau, Li Hsu, John D. Potter, Bette J. Caan, Richard B. Hayes, Sonja I. Berndt, Stephen J. Chanock, Robert E. Schoen, Rebecca D. Jackson, Ross L. Prentice, Andrea Z. LaCroix, Charles Kooperberg, Polly A. Newcomb, Emily White, Cornelia M. Ulrich, Jing Ma, Bernd Frank, Hermann Brenner, Brent W. Zanke, Steven Gallinger, David J. Hunter, Peter Kraft, Aditi Hazra, Edward Giovannucci, Charles S. Fuchs, Sébastien Küry, Michael Hoffmeister, Greg S. Warnick, Deanna L. Stelling, Lin S. Chen, Yan Liu, Tabitha A. Harrison, Shuo Jiao, Jane C. Figueiredo, Jagadish Rangrej, Mathieu Lemire, Hongmei Nan, David Duggan, Yi Lin, Bethann M. Pflugeisen, Martha L. Slattery, Jenny Chang-Claude, and Carolyn M. Hutter

Abstract

PDF file - 52K, Forest plots for meta-analysis results with GxE interaction p < 0.01

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2023
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34. Supplementary Table 3 from Characterization of Gene–Environment Interactions for Colorectal Cancer Susceptibility Loci

Author

Ulrike Peters, Thomas J. Hudson, Andrew T. Chan, Stéphane Bézieau, Li Hsu, John D. Potter, Bette J. Caan, Richard B. Hayes, Sonja I. Berndt, Stephen J. Chanock, Robert E. Schoen, Rebecca D. Jackson, Ross L. Prentice, Andrea Z. LaCroix, Charles Kooperberg, Polly A. Newcomb, Emily White, Cornelia M. Ulrich, Jing Ma, Bernd Frank, Hermann Brenner, Brent W. Zanke, Steven Gallinger, David J. Hunter, Peter Kraft, Aditi Hazra, Edward Giovannucci, Charles S. Fuchs, Sébastien Küry, Michael Hoffmeister, Greg S. Warnick, Deanna L. Stelling, Lin S. Chen, Yan Liu, Tabitha A. Harrison, Shuo Jiao, Jane C. Figueiredo, Jagadish Rangrej, Mathieu Lemire, Hongmei Nan, David Duggan, Yi Lin, Bethann M. Pflugeisen, Martha L. Slattery, Jenny Chang-Claude, and Carolyn M. Hutter

Abstract

PDF file - 67K, Descriptives for smoking, BMI, height, dietary variables, alcohol, sex, and NSAID use.

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2023
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35. Supplementary Table 6 from Characterization of Gene–Environment Interactions for Colorectal Cancer Susceptibility Loci

Author

Ulrike Peters, Thomas J. Hudson, Andrew T. Chan, Stéphane Bézieau, Li Hsu, John D. Potter, Bette J. Caan, Richard B. Hayes, Sonja I. Berndt, Stephen J. Chanock, Robert E. Schoen, Rebecca D. Jackson, Ross L. Prentice, Andrea Z. LaCroix, Charles Kooperberg, Polly A. Newcomb, Emily White, Cornelia M. Ulrich, Jing Ma, Bernd Frank, Hermann Brenner, Brent W. Zanke, Steven Gallinger, David J. Hunter, Peter Kraft, Aditi Hazra, Edward Giovannucci, Charles S. Fuchs, Sébastien Küry, Michael Hoffmeister, Greg S. Warnick, Deanna L. Stelling, Lin S. Chen, Yan Liu, Tabitha A. Harrison, Shuo Jiao, Jane C. Figueiredo, Jagadish Rangrej, Mathieu Lemire, Hongmei Nan, David Duggan, Yi Lin, Bethann M. Pflugeisen, Martha L. Slattery, Jenny Chang-Claude, and Carolyn M. Hutter

Abstract

PDF file - 55K, Further information about main finding

Published
2023
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36. Supplementary Table 1 from Characterization of Gene–Environment Interactions for Colorectal Cancer Susceptibility Loci

Author

Ulrike Peters, Thomas J. Hudson, Andrew T. Chan, Stéphane Bézieau, Li Hsu, John D. Potter, Bette J. Caan, Richard B. Hayes, Sonja I. Berndt, Stephen J. Chanock, Robert E. Schoen, Rebecca D. Jackson, Ross L. Prentice, Andrea Z. LaCroix, Charles Kooperberg, Polly A. Newcomb, Emily White, Cornelia M. Ulrich, Jing Ma, Bernd Frank, Hermann Brenner, Brent W. Zanke, Steven Gallinger, David J. Hunter, Peter Kraft, Aditi Hazra, Edward Giovannucci, Charles S. Fuchs, Sébastien Küry, Michael Hoffmeister, Greg S. Warnick, Deanna L. Stelling, Lin S. Chen, Yan Liu, Tabitha A. Harrison, Shuo Jiao, Jane C. Figueiredo, Jagadish Rangrej, Mathieu Lemire, Hongmei Nan, David Duggan, Yi Lin, Bethann M. Pflugeisen, Martha L. Slattery, Jenny Chang-Claude, and Carolyn M. Hutter

Abstract

PDF file - 168K, SNP details by study.

Published
2023
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38. Genotoxic colibactin mutational signature in colorectal cancer is associated with clinicopathological features, specific genomic alterations and better survival

Author

Peter Georgeson, Robert S. Steinfelder, Tabitha A. Harrison, Bernard J. Pope, Syed H. Zaidi, Conghui Qu, Yi Lin, Jihoon E. Joo, Khalid Mahmood, Mark Clendenning, Romy Walker, Elom K Aglago, Sonja I. Berndt, Hermann Brenner, Peter T. Campbell, Yin Cao, Andrew T. Chan, Jenny Chang-Claude, Niki Dimou, Kimberly F. Doheny, David A. Drew, Jane C. Figueiredo, Amy J. French, Steven Gallinger, Marios Giannakis, Graham G. Giles, Ellen L Goode, Stephen B Gruber, Andrea Gsur, Marc J. Gunter, Sophia Harlid, Michael Hoffmeister, Li Hsu, Wen-Yi Huang, Jeroen R Huyghe, JoAnn E. Manson, Victor Moreno, Neil Murphy, Rami Nassir, Christina C. Newton, Jonathan A. Nowak, Mireia Obón-Santacana, Shuji Ogino, Rish K. Pai, Nikos Papadimitrou, John D. Potter, Robert E. Schoen, Mingyang Song, Wei Sun, Amanda E. Toland, Quang M. Trinh, Kostas Tsilidis, Tomotaka Ugai, Caroline Y Um, Finlay A. Macrae, Christophe Rosty, Thomas J. Hudson, Ingrid M. Winship, Amanda I. Phipps, Mark A. Jenkins, Ulrike Peters, and Daniel D. Buchanan

Abstract

Background and AimsThe microbiome has long been suspected of a role in colorectal cancer (CRC) tumorigenesis. The mutational signature SBS88 mechanistically links CRC development with the strain ofEscherichia coliharboring thepksisland that produces the genotoxin colibactin, but the genomic, pathological and survival characteristics associated with SBS88-positive tumors are unknown.MethodsSBS88-positive CRCs were identified from targeted sequencing data from 5,292 CRCs from 17 studies and tested for their association with clinico-pathological features, oncogenic pathways, genomic characteristics and survival.ResultsIn total, 7.5% (398/5,292) of the CRCs were SBS88-positive, of which 98.7% (392/398) were microsatellite stable/microsatellite instability low (MSS/MSI-L), compared with 80% (3916/4894) of SBS88 negative tumors (p=1.5×10-28). Analysis of MSS/MSI-L CRCs demonstrated that SBS88 positive CRCs were associated with the distal colon (OR=1.84, 95% CI=1.40-2.42, p=1×10-5) and rectum (OR=1.90, 95% CI=1.44-2.51, p=6×10-6) tumor sites compared with the proximal colon. The top seven recurrent somatic mutations associated with SBS88-positive CRCs demonstrated mutational contexts associated with colibactin-induced DNA damage, the strongest of which was theAPC:c.835-8A>G mutation (OR=65.5, 95%CI=39.0-110.0, p=3×10-80). Large copy number alterations (CNAs) including CNA loss on 14q and gains on 13q, 16q and 20p were significantly enriched in SBS88- positive CRCs. SBS88-positive CRCs were associated with better CRC-specific survival (p=0.007; hazard ratio of 0.69, 95% CI=0.52-0.90) when stratified by age, sex, study, and by stage.ConclusionSBS88-positivity, a biomarker of colibactin-induced DNA damage, can identify a novel subtype of CRC characterized by recurrent somatic mutations, copy number alterations and better survival. These findings provide new insights for treatment and prevention strategies for this subtype of CRC.

Published
2023
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39. Same-Day Thyroidectomy Outcomes: A Canadian Multi-Center Retrospective Cohort Study

Author

Mélyssa Fortin, Maxine Noik, Thomas J. Hudson, Sabrina D. da Silva, Véronique-Isabelle Forest, Michael P. Hier, Alex M. Mlynarek, and Richard J. Payne

Abstract

Background The American Thyroid Association supports same-day thyroid surgery (SDT) in select patients. In practice, it is common for thyroid surgeons to monitor patients overnight for postoperative complications such as cervical hematoma, recurrent laryngeal nerve injury (RLN) and symptomatic hypocalcemia. We sought to determine the safety profile and predictive factors of adverse postoperative outcomes for SDT based on the experience of three large institutions. Methods A retrospective cohort study was conducted for all thyroidectomies performed at three McGill University tertiary and quaternary care centers in Montreal, Canada between January 1st, 2016 and November 13th, 2020. Patient characteristics were associated with outcomes by bivariate and multivariate analyses. Results A total of 2297 records were surveyed and 1983 patients (1513 females, 470 males) met the inclusion criteria. Amongst them, 603 (30.4%) patients were discharged the same day. The overall postoperative complication rate amongst SDT was 3.6% compared with 10.7% for inpatients (p p = 0.061). RLN injury occurred in 7 SDT (1.2%), compared with 35 (2.5%) inpatients (p = 0.050). Symptomatic hypocalcemia occurred in 3 SDT (0.5%) compared with 73 (5.3%) inpatients (p p p p = 0.041) and reoperation (p = 0.037) rates compared with the inpatient group. Conclusion This study demonstrates that SDT are safe in a select group of patients under the care of experienced thyroid surgeons at high volume thyroid surgery centers. SDT can also lead to significant cost savings in a publicly funded health care system. Further exploration is needed to clarify patient profiles most amenable to SDT and inform clinical decision-making.

Published
2022
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40. Association between germline variants and somatic mutations in colorectal cancer

Author

Richard Barfield, Conghui Qu, Robert S. Steinfelder, Chenjie Zeng, Tabitha A. Harrison, Stefanie Brezina, Daniel D. Buchanan, Peter T. Campbell, Graham Casey, Steven Gallinger, Marios Giannakis, Stephen B. Gruber, Andrea Gsur, Li Hsu, Jeroen R. Huyghe, Victor Moreno, Polly A. Newcomb, Shuji Ogino, Amanda I. Phipps, Martha L. Slattery, Stephen N. Thibodeau, Quang M. Trinh, Amanda E. Toland, Thomas J. Hudson, Wei Sun, Syed H. Zaidi, and Ulrike Peters

Subjects
Multidisciplinary, Germ Cells, Càncer colorectal, Polimorfisme genètic, Humans, Genetic Predisposition to Disease, Allelic Imbalance, Colorectal Neoplasms, Genetic polymorphisms, Polymorphism, Single Nucleotide, Colorectal cancer, Germ-Line Mutation
Abstract

Colorectal cancer (CRC) is a heterogeneous disease with evidence of distinct tumor types that develop through different somatically altered pathways. To better understand the impact of the host genome on somatically mutated genes and pathways, we assessed associations of germline variations with somatic events via two complementary approaches. We first analyzed the association between individual germline genetic variants and the presence of non-silent somatic mutations in genes in 1375 CRC cases with genome-wide SNPs data and a tumor sequencing panel targeting 205 genes. In the second analysis, we tested if germline variants located within previously identified regions of somatic allelic imbalance were associated with overall CRC risk using summary statistics from a recent large scale GWAS (n≃125 k CRC cases and controls). The first analysis revealed that a variant (rs78963230) located within a CNA region associated with TLR3 was also associated with a non-silent mutation within gene FBXW7. In the secondary analysis, the variant rs2302274 located in CDX1/PDGFRB frequently gained/lost in colorectal tumors was associated with overall CRC risk (OR = 0.96, p = 7.50e-7). In summary, we demonstrate that an integrative analysis of somatic and germline variation can lead to new insights about CRC.

Published
2022

42. Intrinsic Measures and Shape Analysis of the Intratemporal Facial Nerve

Author

Bradley Gare, Hanif M. Ladak, Thomas J. Hudson, Daniel G. Allen, and Sumit K. Agrawal

Subjects
Ear, Middle, Mastoid, 03 medical and health sciences, 0302 clinical medicine, Temporal bone, Humans, Medicine, Segmentation, 030223 otorhinolaryngology, Landmark, business.industry, Temporal Bone, Pattern recognition, Facial nerve, Sensory Systems, Facial Nerve, Otorhinolaryngology, Ear, Inner, Principal component analysis, Neurology (clinical), Artificial intelligence, business, Cadaveric spasm, Fiducial marker, 030217 neurology & neurosurgery, Shape analysis (digital geometry)
Abstract

Hypothesis To characterize anatomical measurements and shape variation of the facial nerve within the temporal bone, and to create statistical shape models (SSMs) to enhance knowledge of temporal bone anatomy and aid in automated segmentation. Background The facial nerve is a fundamental structure in otologic surgery, and detailed anatomic knowledge with surgical experience are needed to avoid its iatrogenic injury. Trainees can use simulators to practice surgical techniques, however manual segmentation required to develop simulations can be time consuming. Consequently, automated segmentation algorithms have been developed that use atlas registration, SSMs, and deep learning. Methods Forty cadaveric temporal bones were evaluated using three dimensional microCT (μCT) scans. The image sets were aligned using rigid fiducial registration, and the facial nerve canals were segmented and analyzed. Detailed measurements were performed along the various sections of the nerve. Shape variability was then studied using two SSMs: one involving principal component analysis (PCA) and a second using the Statismo framework. Results Measurements of the nerve canal revealed mean diameters and lengths of the labyrinthine, tympanic, and mastoid segments. The landmark PCA analysis demonstrated significant shape variation along one mode at the distal tympanic segment, and along three modes at the distal mastoid segment. The Statismo shape model was consistent with this analysis, emphasizing the variability at the mastoid segment. The models were made publicly available to aid in future research and foster collaborative work. Conclusion The facial nerve exhibited statistical variation within the temporal bone. The models used form a framework for automated facial nerve segmentation and simulation for trainees.

Published
2020
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43. Genetic regulation of DNA methylation yields novel discoveries in GWAS of colorectal cancer

Author

Richard Barfield, Jeroen R. Huyghe, Mathieu Lemire, Xinyuan Dong, Yu-Ru Su, Stefanie Brezina, Daniel D. Buchanan, Jane C. Figueiredo, Steven Gallinger, Marios Giannakis, Andrea Gsur, Marc J. Gunter, Heather Hampel, Tabitha A. Harrison, John L. Hopper, Thomas J. Hudson, Christopher I. Li, Victor Moreno, Polly A. Newcomb, Rish K. Pai, Paul D.P. Pharoah, Amanda I. Phipps, Conghui Qu, Robert S. Steinfelder, Wei Sun, Aung Ko Win, Syed H. Zaidi, Peter T. Campbell, Ulrike Peters, and Li Hsu

Subjects
Epigenomics, Oncology, Epidemiology, Quantitative Trait Loci, Humans, Proteins, Genetic Predisposition to Disease, DNA Methylation, Colorectal Neoplasms, Polymorphism, Single Nucleotide, Article, Genome-Wide Association Study
Abstract

Background: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.Methods: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.Results: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.Conclusions: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.Impact: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.

Published
2022

44. Molecular and pathology features of colorectal tumors and patient outcomes are associated with Fusobacterium nucleatum and its subspecies animalis

Author

Quang M. Trinh, Tabitha A. Harrison, Jeremy Adams, Stephen Lee, Syed H.E. Zaidi, Emma E.G. Reid, Sophia Harlid, Barbara L. Banbury, Thomas J. Hudson, Robert S. Steinfelder, Susan Bullman, Steven Gallinger, Wei Sun, Amanda I. Phipps, Vincent Ferretti, Andrea Gsur, Li Hsu, Conghui Qu, Xuemei Luo, Yin Cao, Peter T. Campbell, John L. Hopper, Ulrike Peters, Ivan Borozan, Stephen N. Thibodeau, Jane C. Figueiredo, Lawrence E. Heisler, Jiayin Zheng, Polly A. Newcomb, Nickolas Papadopoulos, Yi Lin, Sonja I. Berndt, Daniel D. Buchanan, Caroline Y. Um, Alton B. Farris, Marios Giannakis, Shuji Ogino, Stefanie Brezina, Elaine R. Mardis, and Reiko Nishihara

Subjects
Chemotherapy, biology, Epidemiology, business.industry, Somatic cell, Colorectal cancer, medicine.medical_treatment, Cancer, Subspecies, medicine.disease, biology.organism_classification, Article, stomatognathic diseases, Oncology, stomatognathic system, Cancer research, Medicine, ERBB3, Fusobacterium nucleatum, business, Gene
Abstract

Background: Fusobacterium nucleatum (F. nucleatum) activates oncogenic signaling pathways and induces inflammation to promote colorectal carcinogenesis. Methods: We characterized F. nucleatum and its subspecies in colorectal tumors and examined associations with tumor characteristics and colorectal cancer–specific survival. We conducted deep sequencing of nusA, nusG, and bacterial 16s rRNA genes in tumors from 1,994 patients with colorectal cancer and assessed associations between F. nucleatum presence and clinical characteristics, colorectal cancer–specific mortality, and somatic mutations. Results: F. nucleatum, which was present in 10.3% of tumors, was detected in a higher proportion of right-sided and advanced-stage tumors, particularly subspecies animalis. Presence of F. nucleatum was associated with higher colorectal cancer–specific mortality (HR, 1.97; P = 0.0004). This association was restricted to nonhypermutated, microsatellite-stable tumors (HR, 2.13; P = 0.0002) and those who received chemotherapy [HR, 1.92; confidence interval (CI), 1.07–3.45; P = 0.029). Only F. nucleatum subspecies animalis, the main subspecies detected (65.8%), was associated with colorectal cancer–specific mortality (HR, 2.16; P = 0.0016), subspecies vincentii and nucleatum were not (HR, 1.07; P = 0.86). Additional adjustment for tumor stage suggests that the effect of F. nucleatum on mortality is partly driven by a stage shift. Presence of F. nucleatum was associated with microsatellite instable tumors, tumors with POLE exonuclease domain mutations, and ERBB3 mutations, and suggestively associated with TP53 mutations. Conclusions: F. nucleatum, and particularly subspecies animalis, was associated with a higher colorectal cancer–specific mortality and specific somatic mutated genes. Impact: Our findings identify the F. nucleatum subspecies animalis as negatively impacting colorectal cancer mortality, which may occur through a stage shift and its effect on chemoresistance.

Published
2021

45. Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures

Author

Peter Georgeson, Tabitha A. Harrison, Bernard J. Pope, Syed H. Zaidi, Conghui Qu, Robert S. Steinfelder, Yi Lin, Jihoon E. Joo, Khalid Mahmood, Mark Clendenning, Romy Walker, Efrat L. Amitay, Sonja I. Berndt, Hermann Brenner, Peter T. Campbell, Yin Cao, Andrew T. Chan, Jenny Chang-Claude, Kimberly F. Doheny, David A. Drew, Jane C. Figueiredo, Amy J. French, Steven Gallinger, Marios Giannakis, Graham G. Giles, Andrea Gsur, Marc J. Gunter, Michael Hoffmeister, Li Hsu, Wen-Yi Huang, Paul Limburg, JoAnn E. Manson, Victor Moreno, Rami Nassir, Jonathan A. Nowak, Mireia Obón-Santacana, Shuji Ogino, Amanda I. Phipps, John D. Potter, Robert E. Schoen, Wei Sun, Amanda E. Toland, Quang M. Trinh, Tomotaka Ugai, Finlay A. Macrae, Christophe Rosty, Thomas J. Hudson, Mark A. Jenkins, Stephen N. Thibodeau, Ingrid M. Winship, Ulrike Peters, and Daniel D. Buchanan

Subjects
Heterozygote, Multidisciplinary, DNA Mutational Analysis, General Physics and Astronomy, General Chemistry, Colorectal cancer, General Biochemistry, Genetics and Molecular Biology, DNA Glycosylases, Càncer colorectal, Mutation, Genetics, Humans, Genetic Predisposition to Disease, Colorectal Neoplasms, Genètica, Germ-Line Mutation
Abstract

Carriers of germline biallelic pathogenic variants in the MUTYH gene have a high risk of colorectal cancer. We test 5649 colorectal cancers to evaluate the discriminatory potential of a tumor mutational signature specific to MUTYH for identifying biallelic carriers and classifying variants of uncertain clinical significance (VUS). Using a tumor and matched germline targeted multi-gene panel approach, our classifier identifies all biallelic MUTYH carriers and all known non-carriers in an independent test set of 3019 colorectal cancers (accuracy = 100% (95% confidence interval 99.87–100%)). All monoallelic MUTYH carriers are classified with the non-MUTYH carriers. The classifier provides evidence for a pathogenic classification for two VUS and a benign classification for five VUS. Somatic hotspot mutations KRAS p.G12C and PIK3CA p.Q546K are associated with colorectal cancers from biallelic MUTYH carriers compared with non-carriers (p = 2 × 10−23 and p = 6 × 10−11, respectively). Here, we demonstrate the potential application of mutational signatures to tumor sequencing workflows to improve the identification of biallelic MUTYH carriers.

Published
2021

46. Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk

Author

Alicja Wolk, Edward Giovannucci, Li Li, Polly A. Newcomb, Kenneth Offit, Clemens Schafmayer, Vicente Martín, Sergi Castellví-Bel, Daniel D. Buchanan, Mingyang Song, Qianchuan He, Martha L. Slattery, Volker Arndt, Anna H. Wu, Amit Joshi, David A. Drew, D. Timothy Bishop, Annika Lindblom, Temitope O. Keku, Jochen Hampe, Ozan Dikilitas, Douglas A. Corley, John B. Harley, Hakon Hakonarson, Steven Gallinger, Noralane M. Lindor, Ian B. Stanaway, Jeffrey K. Lee, Sonja I. Berndt, Veronika Vymetalkova, Syed H.E. Zaidi, Jessica Minnier, Daniel J. Schaid, Ludmila Vodickova, John D. Potter, Heather Hampel, Christopher I. Li, Frank D. Mentch, Wei-Qi Wei, Cornelia M. Ulrich, Marc J. Gunter, Robert E. Schoen, Catherine M. Tangen, Victor Moreno, Shuji Ogino, Tabitha A. Harrison, Albert de la Chapelle, Pavel Vodicka, Andrew T. Chan, Keith R. Curtis, Elisabeth A. Rosenthal, Jenny Chang-Claude, David C. Muller, Paul D.P. Pharoah, Roger L. Milne, David Duggan, Eric B. Larson, David R. Crosslin, Andrea Gsur, Stéphane Bézieau, Graham G. Giles, Robert J. MacInnis, Bahram Namjou, Christopher H. Dampier, Gail P. Jarvik, Andrea N. Burnett-Hartman, Richard B. Hayes, Fränzel J.B. Van Duijnhoven, Wendy K. Chung, Michael Hoffmeister, Mark A. Jenkins, Mathieu Lemire, Thomas J. Hudson, Elizabeth A. Platz, Neil Murphy, Graham Casey, Michael O. Woods, Aung Ko Win, Flora Qu, Li Hsu, Emily White, Peter T. Campbell, Lori C. Sakoda, Jane C. Figueiredo, Minta Thomas, Jeroen R. Huyghe, Bethany Van Guelpen, Kala Visvanathan, Loic Le Marchand, Corinne E. Joshu, Yu Ru Su, Ulrike Peters, Stephen B. Gruber, Demetrius Albanes, Stephen N. Thibodeau, Antoni Castells, and Hermann Brenner

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Linkage disequilibrium, Nutrition and Disease, Population, Genome-wide association study, colorectal cancer, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Voeding en Ziekte, Genetics, Medicine, Family history, education, cancer risk prediction, Genetics (clinical), Genetic association, VLAG, education.field_of_study, business.industry, 030104 developmental biology, machine learning, 030220 oncology & carcinogenesis, Relative risk, Cohort, polygenic risk score, business, Risk assessment
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.

Published
2020
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47. Response to Li and Hopper

Author

Roger L. Milne, Jane C. Figueiredo, Kenneth Offit, Daniel D. Buchanan, Wendy K. Chung, Robert J. MacInnis, Marc J. Gunter, Catherine M. Tangen, Li Hsu, Emily White, Peter T. Campbell, Stéphane Bézieau, Andrew T. Chan, David C. Muller, Lori C. Sakoda, Bahram Namjou, Annika Lindblom, Temitope O. Keku, Vicente Martín, D. Timothy Bishop, Amit Joshi, Robert E. Schoen, Ludmila Vodickova, Mark A. Jenkins, Pavel Vodicka, Richard B. Hayes, Antoni Castells, Hermann Brenner, Daniel J. Schaid, David Duggan, Christopher I. Li, Mingyang Song, John B. Harley, Jeffrey K. Lee, Ozan Dikilitas, Douglas A. Corley, Neil Murphy, Steven Gallinger, Cornelia M. Ulrich, Victor Moreno, Clemens Schafmayer, Elizabeth A. Platz, Noralane M. Lindor, Elisabeth A. Rosenthal, Alicja Wolk, Yu Ru Su, Martha L. Slattery, Hakon Hakonarson, Stephen B. Gruber, Eric B. Larson, Graham G. Giles, Demetrius Albanes, Jenny Chang-Claude, Christopher H. Dampier, David R. Crosslin, Michael Hoffmeister, Andrea Gsur, Stephen N. Thibodeau, Shuji Ogino, Frank D. Mentch, Sonja I. Berndt, Bethany Van Guelpen, Kala Visvanathan, Loic Le Marchand, John D. Potter, Jeroen R. Huyghe, Heather Hampel, Gail P. Jarvik, Jochen Hampe, Graham Casey, Wei-Qi Wei, David A. Drew, Corinne E. Joshu, Aung Ko Win, Qianchuan He, Paul D.P. Pharoah, Michael O. Woods, Flora Qu, Ulrike Peters, Minta Thomas, Fränzel J.B. Van Duijnhoven, Ian B. Stanaway, Keith R. Curtis, Tabitha A. Harrison, Andrea N. Burnett-Hartman, Anna H. Wu, Edward Giovannucci, Li Li, Volker Arndt, Mathieu Lemire, Thomas J. Hudson, Albert de la Chapelle, Veronika Vymetalkova, Syed H.E. Zaidi, Jessica Minnier, Polly A. Newcomb, and Sergi Castellví-Bel

Subjects
Male, Multifactorial Inheritance, Nutrition and Disease, MEDLINE, Polymorphism, Single Nucleotide, Risk Assessment, Text mining, Asian People, Risk Factors, Voeding en Ziekte, Genetics, Humans, Medicine, Life Science, Genetic Predisposition to Disease, Letter to the Editor, Genetics (clinical), Aged, Information retrieval, Genome, Human, business.industry, Bayes Theorem, Middle Aged, Female, Colorectal Neoplasms, business, Genome-Wide Association Study
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.

Published
2021

48. Genetic architectures of proximal and distal colorectal cancer are partly distinct

Author

Stephanie J. Weinstein, Rami Nassir, Fredrick R. Schumacher, Neil Murphy, M. Henar Alonso, Satu Männistö, Hedy S. Rennert, Manish Gala, Phyllis J. Goodman, Albert de la Chapelle, Tilman Kühn, Fränzel J.B. Van Duijnhoven, Paul D.P. Pharoah, Anshul Kundaje, Juergen Boehm, W. James Gauderman, Mark A. Jenkins, Vittorio Perduca, Polly A. Newcomb, Amanda I. Phipps, Christopher I. Li, Douglas F. Easton, Antonia Trichopoulou, Kristin E. Anderson, Daniel D. Buchanan, Peter C. Scacheri, William M. Grady, Liher Imaz, Veronika Vymetalkova, Wan-Ling Hsu, Prudence R. Carr, Martha L. Slattery, Keith R. Curtis, Elizabeth A. Platz, Sai Chen, Graham G. Giles, D. Timothy Bishop, David M. Levine, Michael Hoffmeister, Duncan C. Thomas, Roger L. Milne, Michael O. Woods, Michael C. Bassik, Andrea Gsur, Dallas R. English, David V. Conti, Sébastien Küry, Wolfgang Lieb, Jochen Hampe, Coral Arnau-Collell, Steven Gallinger, Emily White, John S. Grove, Antoni Castells, Hermann Brenner, Amanda E. Toland, Noralane M. Lindor, Aurora Perez-Cornago, David Duggan, Temitope O. Keku, Edith J. M. Feskens, Heather Hampel, Korbinian Weigl, Li Li, Li Hsu, Conghui Qu, Peter T. Campbell, John L. Hopper, Volker Arndt, Jenny Chang-Claude, Lorena Moreno, John A. Baron, Stephen N. Thibodeau, Robert E. Schoen, Jeroen R. Huyghe, Rachel Pearlman, Sanford D. Markowitz, Amanda J. Cross, Stephan Buch, Barbara L. Banbury, Thomas J. Hudson, Yu Ru Su, Marc J. Gunter, Stephen B. Gruber, Heiner Boeing, Demetrius Albanes, Wen Yi Huang, Sergi Castellví-Bel, Jane C. Figueiredo, Catherine M. Tangen, Andrew T. Chan, Annika Lindblom, Deborah A. Nickerson, Richard B. Hayes, Lori C. Sakoda, Flavio Lejbkowicz, Salvatore Panico, Alicja Wolk, Kenneth Offit, John D. Potter, Leon Raskin, Bette J. Caan, Clemens Schafmayer, Mingyang Song, Lihong Qi, Elio Riboli, Hyun Min Kang, Sophia Harlid, Pavel Vodicka, Ludmila Vodickova, Cornelia M. Ulrich, Stephanie L. Schmit, Victor Moreno, Anna H. Wu, Brenda Diergaarde, Bethany Van Guelpen, Kala Visvanathan, Loic Le Marchand, Mazda Jenab, Amit Joshi, Stefanie Brezina, Stephanie A. Bien, Charles Kooperberg, Shuji Ogino, Daniela Seminara, Graham Casey, Andrea N. Burnett-Hartman, Robert W. Haile, Ulrike Peters, Gad Rennert, Tabitha A. Harrison, Ross L. Prentice, Yi Lin, Antonio Agudo, Gonçalo R. Abecasis, Sonja I. Berndt, Stephen J. Chanock, Stéphane Bézieau, Patrick S. Parfrey, Richard Barfield, Marie-Christine Boutron-Ruault, Huyghe, Jeroen R [0000-0001-6027-9806], Brenner, Hermann [0000-0002-6129-1572], Buchanan, Daniel D [0000-0003-2225-6675], Chan, Andrew T [0000-0001-7284-6767], Gsur, Andrea [0000-0002-9795-1528], Hampe, Jochen [0000-0002-2421-6127], Hoffmeister, Michael [0000-0002-8307-3197], Huang, Wen-Yi [0000-0002-4440-3368], Jenab, Mazda [0000-0002-0573-1852], Murphy, Neil [0000-0003-3347-8249], Peters, Ulrike [0000-0001-5666-9318], and Apollo - University of Cambridge Repository

Subjects
Male, 0301 basic medicine, Oncology, Candidate gene, Nutrition and Disease, Colorectal cancer, Genome-wide association study, Bioinformatics, medicine.disease_cause, Germline, colon carcinogenesis, Transcriptome, 0302 clinical medicine, Risk Factors, Voeding en Ziekte, Genotype, Age of Onset, Cecum, Aged, 80 and over, Gastroenterology, Middle Aged, cancer susceptibility, Primary tumor, Colon, Descending, 030220 oncology & carcinogenesis, Colonic Neoplasms, Female, Medical Genetics, Colon, Transverse, Adult, medicine.medical_specialty, Colon, cancer genetics, colorectal cancer, Biology, Polymorphism, Single Nucleotide, White People, Colon, Ascending, Genetic Heterogeneity, Young Adult, 03 medical and health sciences, Age Distribution, Medicina preventiva, genetic polymorphisms, Colon, Sigmoid, Càncer colorectal, Internal medicine, medicine, Genetics, Humans, Alleles, VLAG, Genetic association, Medicinsk genetik, Aged, Global Nutrition, Preventive medicine, Wereldvoeding, Cancer och onkologi, Gastroenterology & Hepatology, Rectal Neoplasms, Cancer, 1103 Clinical Sciences, medicine.disease, digestive system diseases, 030104 developmental biology, Cancer and Oncology, Case-Control Studies, 1114 Paediatrics and Reproductive Medicine, Human genome, Carcinogenesis, Genètica, Genome-Wide Association Study
Abstract

ObjectiveAn 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 sporadic CRC differs by anatomical subsite of the primary tumor has not been examined.DesignTo 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 characterized effect heterogeneity at CRC risk loci using multinomial modeling.ResultsWe identified 13 loci that reached genome-wide significance (P−8) and that were not reported by previous GWAS 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.ConclusionGenetic 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 tumor.Significance of this studyWhat is already known about this subject?Heterogeneity among colorectal cancer (CRC) tumors originating at different locations of the colorectum has been revealed in somatic genomes, epigenomes, and transcriptomes, and in some established environmental risk factors for CRC.Genome-wide association studies (GWAS) have identified over 100 genetic variants for overall CRC risk; however, a comprehensive analysis of the extent to which genetic risk factors differ by the anatomical sublocation of the primary tumor is lacking.What are the new findings?In this large consortium-based study, we analyzed clinical and genome-wide genotype data of 112,373 CRC cases and controls of European ancestry to comprehensively examine whether CRC case subgroups defined by anatomical sublocation have distinct germline genetic etiologies.We discovered 13 new loci at genome-wide significance (P−8) that were specific to certain anatomical sublocations and that were not reported by previous GWAS for overall CRC risk; multiple lines of evidence support strong candidate target genes at several of these loci, including PTGER3, LCT, MLH1, CDX1, KLF14, PYGL, BCL11B, and BMP7.Systematic heterogeneity analysis of genetic risk variants for CRC identified thus far, revealed that the genetic architectures of proximal and distal CRC are partly distinct.Taken together, our results further support the idea that tumors arising in different anatomical sublocations of the colorectum may have distinct etiologies.How might it impact on clinical practice in the foreseeable future?Our results provide an informative resource for understanding the differential role that genes and pathways may play in the mechanisms of proximal and distal CRC carcinogenesis.The new insights into the etiologies of proximal and distal CRC may inform the development of new precision prevention strategies, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention.Our findings suggest that future studies of etiological risk factors for CRC and molecular mechanisms of carcinogenesis should take into consideration the anatomical sublocation of the colorectal tumor.

Published
2021

49. Novel Common Genetic Susceptibility Loci for Colorectal Cancer

Author

Katja Butterbach, Julyann Pérez-Mayoral, Douglas F. Easton, Stefanie Brezina, Ben Zhang, Frank J. Manion, Hansong Wang, Sanford D. Markowitz, Liesel M. FitzGerald, Sun Ha Jee, Michelle Cotterchio, Daniel D. Buchanan, Timothy R. Church, Wolfgang Lieb, Xiao-Ou Shu, John L. Hopper, Stephanie A. Bien, Manuela Gago-Dominguez, Jian Gong, Laurence N. Kolonel, Graham G. Giles, Leon Raskin, Yingchang Lu, Kristen Anton, Charles S. Fuchs, Fränzel J.B. van Duijnhoven, Hermann Brenner, Yi Lin, Clicerio Gonzalez-Villalpando, Yong-Bing Xiang, Aaron K. Aragaki, Daniela Seminara, Stephanie M. Gogarten, Gad Rennert, Jose E. Castelao, Rocky Fischer, Antonio J. Molina, Jarmo Virtamo, Tabitha A. Harrison, Volker Arndt, Lee Soo Chin, Michael Hoffmeister, Mark A. Jenkins, Shu Chen Huang, Chris S. Carlson, Stéphane Bézieau, Rebecca D. Jackson, Bhramar Mukherjee, Darin Taverna, Bridget M. Riggs, Christopher K. Edlund, Christopher A. Haiman, Melissa C. Southey, Anna H. Wu, Marilena Melas, Antonia Trichopoulou, Hedy S. Rennert, Gianluca Severi, Stephen B. Gruber, Noralane M. Lindor, Gerhard A. Coetzee, Richard B. Hayes, Sarah J. Plummer, Keitaro Matsuo, Mathieu Lemire, Philipp Hofer, Neil Murphy, José María Huerta, Paul D.P. Pharoah, Erin M. Siegel, Sébastien Küry, Thomas J. Hudson, Annika Lindblom, Marcia Cruz Correa, Michael O. Woods, Sophia Harlid, Tilman Kuehn, David Shibata, Christopher I. Li, Stephen N. Thibodeau, Stephen J. Chanock, Jochen Hampe, Flavio Lejbkowicz, Jeroen R. Huyghe, Suminori Kono, Jenny Chang-Claude, Aung Ko Win, Brent W. Zanke, Alicja Wolk, David V. Conti, Elena M. Gonzalez-Villalpando, Christopher I. Amos, Shuo Jiao, Domenico Palli, Vicente Martín, Jesus P. Paredes Cotoré, Stephanie J. Weinstein, Andrea Gsur, William M. Grady, Koichi Matsuda, Loic Le Marchand, Hanane Omichessan, Marc J. Gunter, Graham Casey, Li Li, Zsofia K. Stadler, Eric J. Jacobs, Kevin McDonnell, Dallas R. English, Demetrius Albanes, Amit Joshi, Wei Zheng, Mariana C. Stern, Cecelia A. Laurie, Jing Ma, Cornelia M. Ulrich, Stephanie L. Schmit, Victor Moreno, John D. Potter, Chenxu Qu, Bette J. Caan, Heinz-Josef Lenz, M. Henar Alonso, Andrea Z. LaCroix, Christoph Mancao, John F. Harju, Yun Ru Liu, Jane C. Figueiredo, Gregory Idos, Kana Wu, Duncan C. Thomas, Motoki Iwasaki, W. James Gauderman, Thomas A. Sellers, David Van Den Berg, Barbara K. Fortini, David N. Levine, James M. Church, Ya Wen Cheng, Edith J. M. Feskens, Edward Giovannucci, Manish Gala, Polly A. Newcomb, Charles Kooperberg, Iona Cheng, David J. Hunter, Martha L. Slattery, Roger L. Milne, Lars G. Fritsche, Niha Zubair, Steven Gallinger, Yi Xin Zeng, Wei Shi, Andrew T. Chan, Fotios Loupakis, Vittorio Krogh, Clemens Schafmayer, Sun-Seog Kweon, Bethany van Guelpan, Amanda Bloomer, Kenneth Offit, Stephanie Tring, Shoichiro Tsugane, David Duggan, Fredrick R. Schumacher, Joseph Vijai, Weihua Jia, Marie-Christine Boutron-Ruault, Joel K. Greenson, Frank Luh, Ulrike Peters, Keith R. Curtis, Juergen Boehm, Robert E. Schoen, Sonja I. Berndt, Elizabeth L. Barry, Sebastian Stintzing, Li Hsu, Emily White, Conghui Qu, Peter T. Campbell, Caroline McNeil, and Yun Yen

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Genotype, Nutrition and Disease, Colorectal cancer, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Càncer colorectal, Internal medicine, Voeding en Ziekte, Ethnicity, medicine, Genetic predisposition, Genetics, Humans, Life Science, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Allele, Allele frequency, Genetic association, VLAG, Global Nutrition, Wereldvoeding, Oncology And Carcinogenesis, Case-control study, Articles, Prognosis, medicine.disease, United States, 3. Good health, Genetic Loci, Case-Control Studies, 030220 oncology & carcinogenesis, Colorectal Neoplasms, Genètica, Follow-Up Studies, Genome-Wide Association Study
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.

Published
2019
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50. Discovery of common and rare genetic risk variants for colorectal cancer

Author

Charles M. Connolly, Deborah A. Nickerson, Jian Gong, Sébastien Küry, Barbara Pardini, Brent W. Zanke, Andrea Gsur, Jochen Hampe, Coral Arnau-Collell, M. Henar Alonso, Elio Riboli, Annika Lindblom, Ulrike Peters, Gad Rennert, Tabitha A. Harrison, Lori C. Sakoda, Caroline McNeil, Flavio Lejbkowicz, Hyun Min Kang, David J. Hunter, Martha L. Slattery, Miguel Rodríguez-Barranco, Christina Bamia, Satu Männistö, Timothy J. Key, W. James Gauderman, Gonçalo R. Abecasis, Sanford D. Markowitz, Laurence N. Kolonel, Mark A. Jenkins, Yi Lin, Robin Myte, Hedy S. Rennert, Neil Murphy, Antonia Trichopoulou, Christopher I. Li, Ross L. Prentice, Sai Chen, Stephanie J. Weinstein, Kristin E. Anderson, Hua Ling, Mitul Shah, Philipp Hofer, Wen Yi Huang, Sergi Castellví-Bel, Susanna C. Larsson, Maria Dolores Chirlaque, Wei Zheng, Stephanie L. Schmit, Cecelia A. Laurie, Soo-Chin Lee, David Forman, Andrea N. Burnett-Hartman, Giovanna Masala, Sarah C. Nelson, Michael O. Woods, Charles Kooperberg, Qing Zhang, Sonja I. Berndt, Christopher S. Carlson, Katja Butterbach, Hyeong Rok Kim, Rebecca D. Jackson, David Van Den Berg, Michael C. Bassik, Amanda J. Cross, Sushma S. Thomas, Clemens Schafmayer, Anna H. Wu, Douglas F. Easton, Robert W. Haile, Ludmila Vodickova, Graham G. Giles, Yu Ru Su, Jenny Chang-Claude, Lorena Moreno, Peter C. Scacheri, Stefanie Brezina, Min-Ho Shin, Steven Gallinger, Bethany Van Guelpen, Daniel D. Buchanan, Roger L. Milne, Stephen J. Chanock, Tin Louie, Tameka Shelford, Emily White, Kala Visvanathan, Loic Le Marchand, Veronika Vymetalkova, Roxann G. Ingersoll, Temitope O. Keku, Stephanie A. Bien, Fredrick R. Schumacher, Wan-Ling Hsu, Amanda E. Toland, John S. Grove, Noralane M. Lindor, Faye Elliott, Leon Raskin, Heather Hampel, Joshua D. Smith, Vicente Martín, David V. Conti, Sjoerd G. Elias, Henk J. van Kranen, Manish Gala, Daniela Seminara, Syed H.E. Zaidi, Suzanne M. Leal, Tilman Kühn, Korbinian Weigl, Marc J. Gunter, Cornelia M. Ulrich, Peyton Greenside, Victor Moreno, John D. Potter, Michael Hoffmeister, Eric J. Jacobs, Catherine M. Tangen, Jihyoun Jeon, Fränzel J.B. Van Duijnhoven, Andrew T. Chan, Stephen B. Gruber, John A. Baron, Alicja Wolk, Edith J. M. Feskens, Demetrius Albanes, Amit Joshi, Bette J. Caan, Polly A. Newcomb, Stéphane Bézieau, Elizabeth M. Gillanders, Anshul Kundaje, Elizabeth A. Platz, Michael Wainberg, Sun-Seog Kweon, C. Roland Wolf, Gemma Ibáñez-Sanz, Shuji Ogino, Emiko Kobayashi, Richard B. Hayes, Patrick S. Parfrey, Katarina Cuk, Stephen N. Thibodeau, Kenneth Offit, David Duggan, Sophia Harlid, Pavel Vodicka, Juergen Boehm, Christa Stegmaier, Jeroen R. Huyghe, Joseph Vijai, Sang-Hee Cho, Elizabeth W. Pugh, Rachel Pearlman, Alessio Naccarati, Marilena Melas, Graham Casey, Jane Romm, Stephan Buch, Phyllis J. Goodman, Albert de la Chapelle, John L. Hopper, Zsofia K. Stadler, Corinne E. Joshu, Liesel M. FitzGerald, Wolfgang Lieb, Aung Ko Win, Keith R. Curtis, Hermann Brenner, Christopher K. Edlund, Li Hsu, Conghui Qu, Peter T. Campbell, Robert E. Schoen, Heiner Boeing, D. Timothy Bishop, Kimberly F. Doheny, Sabina Sieri, Barbara L. Banbury, Mathieu Lemire, Jane C. Figueiredo, Gregory Idos, Katerina Shulman, Thomas J. Hudson, Melissa C. Southey, Duncan C. Thomas, Paul D.P. Pharoah, Mila Pinchev, Vittorio Perduca, Rocky Fischer, Volker Arndt, William M. Grady, Nasa Sinnott-Armstrong, N. Charlotte Onland-Moret, David M. Levine, Li Li, Dallas R. English, Health Research Board - Ireland, Department of Medical Genetics, HMNC Brain Health, Case Western Reserve University [Cleveland], National Cancer Institute, NIH, Division of Clinical Epidemiology and Aging Research, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Service de Génétique, Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Division of Cancer Epidemiology, Cancer Genome Project, The Wellcome Trust Sanger Institute [Cambridge], Division of Signaling Biology, Ontario Cancer Institute, Consorcio de Investigación Biomédica en Red especializado en Epidemiología y Salud Pública (CIBERESP), Los Centros de Investigación Biomédica en Red (CIBER), National Institute of Standards and Technology [Gaithersburg] (NIST), Ohio State University [Columbus] (OSU), Centre for Cancer Genetic Epidemiology, University of Cambridge [UK] (CAM), Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, Cancer Epidemiology Centre, Cancer Council Victoria, Division of Human Nutrition, Wageningen University and Research [Wageningen] (WUR), Division of Public Health Sciences, Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Northern and Yorkshire Cancer Registry and Information Service, Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital [Toronto, Canada] (MSH), University of Melbourne, Nutrition and Metabolism Section, International Agency for Cancer Research (IACR), Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, London School of Hygiene and Tropical Medicine (LSHTM), Fraunhofer Institute for Manufacturing Engineering and Automation (Fraunhofer IPA), Fraunhofer (Fraunhofer-Gesellschaft), Centre for Molecular , Environmental, Genetic and Analytic (MEGA) Epidemiology, University of Melbourne-Centre for Molecular, Melbourne School of Population Health, Department of Mathematics, University of Warwick, Warwick Mathematics Institute (WMI), University of Warwick [Coventry]-University of Warwick [Coventry], Department of Statistics, Penn State University, University of Pennsylvania [Philadelphia], Tata Memorial Centre, Cancer Epidemiology Unit, University of Oxford [Oxford], Thermo Fisher Scientific, Thermo Fisher Scientific Inc., Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, National University Health System, Department of Community Medicine and Epidemiology, CHS National Cancer Control Center, Ontario Institute for Cancer Research [Canada] (OICR), Ontario Institute for Cancer Research, Laboratoire de Génie Electrique de Grenoble (G2ELab), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Chronic Disease Epidemiology and Prevention Unit, National Institute for Health and Welfare [Helsinki], Dell-EMC, Molecular and Nutritional Epidemiology Unit (ISPO), Cancer Research and Prevention Institute, Clinical Genetics Service, Memorial Sloane Kettering Cancer Center [New York], Department of Pathology, Brigham and Women's Hospital [Boston], University Medical Center [Utrecht], Mathématiques Appliquées Paris 5 (MAP5 - UMR 8145), Université Paris Descartes - Paris 5 (UPD5)-Institut National des Sciences Mathématiques et de leurs Interactions (INSMI)-Centre National de la Recherche Scientifique (CNRS), Department of Oncology, Department of Epidemiology and Biostatistics, Imperial College London, Department of Visceral and Thoracic Surgery [Kiel, Germany], University Hospital Schleswig-Holstein [Kiel, Germany], Nutritional Epidemiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, entre for Molecular, Environmental, Genetic and Analytic (MEGA) Epidemiology, Department of Laboratory Medicine and Department of Pathology, Mayo Clinic College of Medicine, Department of Molecular Virology, Immunology and Medical Genetics [Colombus], Ohio State University [Columbus] (OSU)-College of Medicine and Public Health [Colombus], Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School [Athens], Department of Medical Biosciences and Pathology, Umeå University, Institute of Experimental Medicine, Czech Academy of Sciences [Prague] (CAS), Dundee Technopole, CXR Biosciences Ltd, Karolinska Institutet [Stockholm], CINTRA / SEEE Nanyang Technological University, Nanyang Technological University [Singapour], Center for Astrophysical Sciences [Baltimore], Johns Hopkins University (JHU), Computer Science and Artificial Intelligence Laboratory (CSAIL), Massachusetts Institute of Technology (MIT), Department of Preventive Medicine, University of Southern California (USC), Biomedical Research Centre Network for Rare Diseases, CIBER de Enfermedades Raras (CIBERER), Medstar Research Institute, Department of Genome Sciences [Seattle] (GS), University of Washington [Seattle], Department of Internal Medicine, Epidemiology, Human Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Wageningen University and Research Centre [Wageningen] (WUR), Mount Sinai Hospital (MSH), Fraunhofer Institute for Manufacturing Engineering and Automation [Stuttgart] (IPA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Czech Academy of Sciences [Prague] (ASCR), Huyghe, Jeroen R [0000-0001-6027-9806], Harrison, Tabitha A [0000-0002-4173-7530], Chen, Sai [0000-0003-3106-5643], Schmit, Stephanie L [0000-0001-5931-1194], Jeon, Jihyoun [0000-0001-7003-3412], Schumacher, Fredrick R [0000-0002-3073-7463], Nelson, Sarah C [0000-0002-2109-6465], Sinnott-Armstrong, Nasa A [0000-0003-4490-0601], Alonso, M Henar [0000-0003-0285-5451], Arndt, Volker [0000-0001-9320-8684], Bézieau, Stéphane [0000-0003-0095-1319], Bishop, D Timothy [0000-0002-8752-8785], Brezina, Stefanie [0000-0001-5238-6900], Buchanan, Daniel D [0000-0003-2225-6675], Chanock, Stephen J [0000-0002-2324-3393], de la Chapelle, Albert [0000-0001-9345-9248], Easton, Douglas F [0000-0003-2444-3247], Hampe, Jochen [0000-0002-2421-6127], Hayes, Richard B [0000-0002-0918-661X], Hofer, Philipp [0000-0003-2550-6019], Huang, Wen-Yi [0000-0002-4440-3368], Hudson, Thomas J [0000-0002-1376-4849], Jacobs, Eric J [0000-0002-8458-7659], Jenkins, Mark A [0000-0002-8964-6160], Joshi, Amit D [0000-0001-7581-6934], Küry, Sébastien [0000-0001-5497-0465], Larsson, Susanna C [0000-0003-0118-0341], Laurie, Cecelia A [0000-0001-6569-2501], Martín, Vicente [0000-0003-0552-2804], Masala, Giovanna [0000-0002-5758-9069], Milne, Roger L [0000-0001-5764-7268], Naccarati, Alessio [0000-0001-5774-0905], Newcomb, Polly A [0000-0001-8786-0043], Pardini, Barbara [0000-0001-9571-4257], Perduca, Vittorio [0000-0003-0339-0473], Pharoah, Paul DP [0000-0001-8494-732X], Raskin, Leon [0000-0003-1195-7214], Rennert, Gad [0000-0002-8512-068X], Shin, Min-Ho [0000-0002-2217-5624], Toland, Amanda E [0000-0002-0271-1792], Vijai, Joseph [0000-0002-7933-151X], Weigl, Korbinian [0000-0003-4453-2036], Win, Aung Ko [0000-0002-2794-5261], Wolk, Alicja [0000-0001-7387-6845], Zheng, Wei [0000-0003-1226-070X], Bassik, Michael C [0000-0001-5185-8427], Moreno, Victor [0000-0002-2818-5487], Peters, Ulrike [0000-0001-5666-9318], and Apollo - University of Cambridge Repository

Subjects
Male, Nutrition and Disease, Colorectal cancer, IDENTIFIES 6, Genome-wide association study, 0302 clinical medicine, Risk Factors, Voeding en Ziekte, Genotype, ComputingMilieux_MISCELLANEOUS, Avaluació del risc per la salut, Genetics & Heredity, Genetics, 0303 health sciences, COLON-CANCER, 11 Medical And Health Sciences, Middle Aged, 3. Good health, Medical genetics, Female, RNA, Long Noncoding, Colorectal Neoplasms, Life Sciences & Biomedicine, Signal Transduction, EXPRESSION, medicine.medical_specialty, SUSCEPTIBILITY LOCI, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Polymorphism, Single Nucleotide, Article, Health risk assessment, 03 medical and health sciences, QUALITY-CONTROL, Càncer colorectal, Journal Article, medicine, Life Science, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, VLAG, Aged, 030304 developmental biology, Global Nutrition, [SDV.GEN]Life Sciences [q-bio]/Genetics, Wereldvoeding, Science & Technology, ORGAN SIZE, MUTATIONS, Haplotype, Case-control study, 06 Biological Sciences, medicine.disease, Genetic architecture, Case-Control Studies, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Human genome, LYSOPHOSPHATIDIC ACID, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
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, Reporting Summary. Further information on experimental design is available in the Life Sciences Reporting Summary linked to this article.

Published
2018
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