Author: "Maggie Gorman" - Searchworks@Jio Institute Digital Library Search Results

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1. Identification of nine new susceptibility loci for endometrial cancer

Author: Tracy A. O’Mara, Dylan M. Glubb, Frederic Amant, Daniela Annibali, Katie Ashton, John Attia, Paul L. Auer, Matthias W. Beckmann, Amanda Black, Manjeet K. Bolla, Hiltrud Brauch, Hermann Brenner, Louise Brinton, Daniel D. Buchanan, Barbara Burwinkel, Jenny Chang-Claude, Stephen J. Chanock, Chu Chen, Maxine M. Chen, Timothy H. T. Cheng, Christine L. Clarke, Mark Clendenning, Linda S. Cook, Fergus J. Couch, Angela Cox, Marta Crous-Bous, Kamila Czene, Felix Day, Joe Dennis, Jeroen Depreeuw, Jennifer Anne Doherty, Thilo Dörk, Sean C. Dowdy, Matthias Dürst, Arif B. Ekici, Peter A. Fasching, Brooke L. Fridley, Christine M. Friedenreich, Lin Fritschi, Jenny Fung, Montserrat García-Closas, Mia M. Gaudet, Graham G. Giles, Ellen L. Goode, Maggie Gorman, Christopher A. Haiman, Per Hall, Susan E. Hankison, Catherine S. Healey, Alexander Hein, Peter Hillemanns, Shirley Hodgson, Erling A. Hoivik, Elizabeth G. Holliday, John L. Hopper, David J. Hunter, Angela Jones, Camilla Krakstad, Vessela N. Kristensen, Diether Lambrechts, Loic Le Marchand, Xiaolin Liang, Annika Lindblom, Jolanta Lissowska, Jirong Long, Lingeng Lu, Anthony M. Magliocco, Lynn Martin, Mark McEvoy, Alfons Meindl, Kyriaki Michailidou, Roger L. Milne, Miriam Mints, Grant W. Montgomery, Rami Nassir, Håkan Olsson, Irene Orlow, Geoffrey Otton, Claire Palles, John R. B. Perry, Julian Peto, Loreall Pooler, Jennifer Prescott, Tony Proietto, Timothy R. Rebbeck, Harvey A. Risch, Peter A. W. Rogers, Matthias Rübner, Ingo Runnebaum, Carlotta Sacerdote, Gloria E. Sarto, Fredrick Schumacher, Rodney J. Scott, V. Wendy Setiawan, Mitul Shah, Xin Sheng, Xiao-Ou Shu, Melissa C. Southey, Anthony J. Swerdlow, Emma Tham, Jone Trovik, Constance Turman, Jonathan P. Tyrer, Celine Vachon, David VanDen Berg, Adriaan Vanderstichele, Zhaoming Wang, Penelope M. Webb, Nicolas Wentzensen, Henrica M. J. Werner, Stacey J. Winham, Alicja Wolk, Lucy Xia, Yong-Bing Xiang, Hannah P. Yang, Herbert Yu, Wei Zheng, Paul D. P. Pharoah, Alison M. Dunning, Peter Kraft, Immaculata De Vivo, Ian Tomlinson, Douglas F. Easton, Amanda B. Spurdle, and Deborah J. Thompson
Subjects: Science
Abstract: Endometrial cancer is the most common invasive gynaecological cancer in developed countries. Here a meta-analysis identifies an additional nine novel endometrial cancer risk loci and eQTL analysis reveals risk variants associate with reduced expression of negative regulators of oncogenic signal transduction proteins.
Published: 2018
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2. Genetic overlap between endometriosis and endometrial cancer: evidence from cross‐disease genetic correlation and GWAS meta‐analyses

Author: Jodie N. Painter, Tracy A. O'Mara, Andrew P. Morris, Timothy H. T. Cheng, Maggie Gorman, Lynn Martin, Shirley Hodson, Angela Jones, Nicholas G. Martin, Scott Gordon, Anjali K. Henders, John Attia, Mark McEvoy, Elizabeth G. Holliday, Rodney J. Scott, Penelope M. Webb, Peter A. Fasching, Matthias W. Beckmann, Arif B. Ekici, Alexander Hein, Matthias Rübner, Per Hall, Kamila Czene, Thilo Dörk, Matthias Dürst, Peter Hillemanns, Ingo Runnebaum, Diether Lambrechts, Frederic Amant, Daniela Annibali, Jeroen Depreeuw, Adriaan Vanderstichele, Ellen L. Goode, Julie M. Cunningham, Sean C. Dowdy, Stacey J. Winham, Jone Trovik, Erling Hoivik, Henrica M. J. Werner, Camilla Krakstad, Katie Ashton, Geoffrey Otton, Tony Proietto, Emma Tham, Miriam Mints, Shahana Ahmed, Catherine S. Healey, Mitul Shah, Paul D. P. Pharoah, Alison M. Dunning, Joe Dennis, Manjeet K. Bolla, Kyriaki Michailidou, Qin Wang, Jonathan P. Tyrer, John L. Hopper, Julian Peto, Anthony J. Swerdlow, Barbara Burwinkel, Hermann Brenner, Alfons Meindl, Hiltrud Brauch, Annika Lindblom, Jenny Chang‐Claude, Fergus J. Couch, Graham G. Giles, Vessela N. Kristensen, Angela Cox, Krina T. Zondervan, Dale R. Nyholt, Stuart MacGregor, Grant W. Montgomery, Ian Tomlinson, Douglas F. Easton, Deborah J. Thompson, and Amanda B. Spurdle
Subjects: Cross‐disease analysis, endometrial cancer, endometriosis, genome‐wide association study, genetic correlation, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Epidemiological, biological, and molecular data suggest links between endometriosis and endometrial cancer, with recent epidemiological studies providing evidence for an association between a previous diagnosis of endometriosis and risk of endometrial cancer. We used genetic data as an alternative approach to investigate shared biological etiology of these two diseases. Genetic correlation analysis of summary level statistics from genomewide association studies (GWAS) using LD Score regression revealed moderate but significant genetic correlation (rg = 0.23, P = 9.3 × 10−3), and SNP effect concordance analysis provided evidence for significant SNP pleiotropy (P = 6.0 × 10−3) and concordance in effect direction (P = 2.0 × 10−3) between the two diseases. Cross‐disease GWAS meta‐analysis highlighted 13 distinct loci associated at P ≤ 10−5 with both endometriosis and endometrial cancer, with one locus (SNP rs2475335) located within PTPRD associated at a genomewide significant level (P = 4.9 × 10−8, OR = 1.11, 95% CI = 1.07–1.15). PTPRD acts in the STAT3 pathway, which has been implicated in both endometriosis and endometrial cancer. This study demonstrates the value of cross‐disease genetic analysis to support epidemiological observations and to identify biological pathways of relevance to multiple diseases.
Published: 2018
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3. Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer.

Author: Ian P M Tomlinson, Luis G Carvajal-Carmona, Sara E Dobbins, Albert Tenesa, Angela M Jones, Kimberley Howarth, Claire Palles, Peter Broderick, Emma E M Jaeger, Susan Farrington, Annabelle Lewis, James G D Prendergast, Alan M Pittman, Evropi Theodoratou, Bianca Olver, Marion Walker, Steven Penegar, Ella Barclay, Nicola Whiffin, Lynn Martin, Stephane Ballereau, Amy Lloyd, Maggie Gorman, Steven Lubbe, COGENT Consortium, CORGI Collaborators, EPICOLON Consortium, Bryan Howie, Jonathan Marchini, Clara Ruiz-Ponte, Ceres Fernandez-Rozadilla, Antoni Castells, Angel Carracedo, Sergi Castellvi-Bel, David Duggan, David Conti, Jean-Baptiste Cazier, Harry Campbell, Oliver Sieber, Lara Lipton, Peter Gibbs, Nicholas G Martin, Grant W Montgomery, Joanne Young, Paul N Baird, Steven Gallinger, Polly Newcomb, John Hopper, Mark A Jenkins, Lauri A Aaltonen, David J Kerr, Jeremy Cheadle, Paul Pharoah, Graham Casey, Richard S Houlston, and Malcolm G Dunlop
Subjects: Genetics, QH426-470
Abstract: Genome-wide association studies (GWAS) have identified 14 tagging single nucleotide polymorphisms (tagSNPs) that are associated with the risk of colorectal cancer (CRC), and several of these tagSNPs are near bone morphogenetic protein (BMP) pathway loci. The penalty of multiple testing implicit in GWAS increases the attraction of complementary approaches for disease gene discovery, including candidate gene- or pathway-based analyses. The strongest candidate loci for additional predisposition SNPs are arguably those already known both to have functional relevance and to be involved in disease risk. To investigate this proposition, we searched for novel CRC susceptibility variants close to the BMP pathway genes GREM1 (15q13.3), BMP4 (14q22.2), and BMP2 (20p12.3) using sample sets totalling 24,910 CRC cases and 26,275 controls. We identified new, independent CRC predisposition SNPs close to BMP4 (rs1957636, P = 3.93×10(-10)) and BMP2 (rs4813802, P = 4.65×10(-11)). Near GREM1, we found using fine-mapping that the previously-identified association between tagSNP rs4779584 and CRC actually resulted from two independent signals represented by rs16969681 (P = 5.33×10(-8)) and rs11632715 (P = 2.30×10(-10)). As low-penetrance predisposition variants become harder to identify-owing to small effect sizes and/or low risk allele frequencies-approaches based on informed candidate gene selection may become increasingly attractive. Our data emphasise that genetic fine-mapping studies can deconvolute associations that have arisen owing to independent correlation of a tagSNP with more than one functional SNP, thus explaining some of the apparently missing heritability of common diseases.
Published: 2011
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4. Data from Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Author: Amanda B. Spurdle, Deborah J. Thompson, Douglas F. Easton, Alison M. Dunning, Ian Tomlinson, Paul D.P. Pharoah, Angela Cox, Vessela N. Kristensen, Graham G. Giles, Fergus J. Couch, Jenny Chang-Claude, Annika Lindblom, Hiltrud Brauch, Alfons Meindl, Hermann Brenner, Barbara Burwinkel, Anthony J. Swerdlow, Julian Peto, John L. Hopper, Jonathan P. Tyrer, Qin Wang, Kyriaki Michailidou, Manjeet K. Bolla, Emma Tham, Miriam Mints, Anthony Proietto, Geoffrey Otton, Katie A. Ashton, Henrica M.J. Werner, Jone Trovik, Helga B. Salvesen, Tormund S. Njølstad, Stacey J. Winham, Brooke L. Fridley, Ellen L. Goode, Sean C. Dowdy, Julie M. Cunningham, Patrick Neven, Diether Lambrechts, Jeroen Depreeuw, Daniela Annibali, Frederic Amant, Ingo B. Runnebaum, Peter Hillemanns, Matthias Dürst, Thilo Dörk, Jingmei Li, Per Hall, Hatef Darabi, Kamila Czene, Matthias Rübner, Alexander Hein, Peter A. Fasching, Arif B. Ekici, Matthias W. Beckmann, Shirley V. Hodgson, Lynn Martin, Maggie Gorman, Mitul Shah, Catherine S. Healey, Shahana Ahmed, Rodney J. Scott, Mark McEvoy, Elizabeth G. Holliday, Joe Dennis, Timothy Cheng, Sarah E. Medland, John Attia, Penelope M. Webb, Louise Marquart, Tracy A. O'Mara, and Jodie N. Painter
Abstract: Background: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist–hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls.Methods: Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable.Results: The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10−17). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m2 of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89–2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55; 95% CI, 1.44–1.68, per 5 kg/m2). The association attenuated but remained significant after adjusting for BMI (OR = 1.22; 95% CI, 1.10–1.39; P = 5.3 × 10−4). There was evidence of directional pleiotropy (P = 1.5 × 10−4). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P < 4.0 × 10−4), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS.Conclusions: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI.Impact: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling. Cancer Epidemiol Biomarkers Prev; 25(11); 1503–10. ©2016 AACR.
Published: 2023

5. Supplementary Figure 1 from Genome-Wide Association Study Identifies a Possible Susceptibility Locus for Endometrial Cancer

Author: Xiao-Ou Shu, Amanda B. Spurdle, Qiuyin Cai, Yu-Tang Gao, Douglas Easton, Alison Dunning, Wei Lu, Hui Cai, Anthony Proietto, Alexander Hein, Mari K. Halle, Rayna K. Matsuno, An Coosemans, Louise Brinton, Maggie Gorman, Ben Zhang, Jiajun Shi, Geoffrey Otton, Arif B. Ekici, Camilla Krakstad, Pamela J. Thompson, Matthias Dürst, Dilyara Kaidarova, Lieve Coenegrachts, Jolanta Lissowska, Lingeng Lu, Kimberly Howarth, Ping-Ping Bao, Bu-Tian Ji, Katie Ashton, Matthias W. Beckmann, Jone Trovik, Galina Lurie, Anita Schwake, Nurzhan Turmanov, Frederic Amant, Hannah P. Yang, Harvey Risch, Shirley Hodgson, Catherine S. Healey, Tracy O'Mara, Ying Zheng, Ryan Delahanty, Rodney J. Scott, Peter A. Fasching, Helga B. Salvesen, Marc T. Goodman, Natalia Dubrowinskaja, Thilo Dörk, Diether Lambrechts, Nicolas Wentzensen, Herbert Yu, Ian Tomlinson, Deborah Thompson, Felicity Lose, Yong-Bing Xiang, Wei Zheng, and Jirong Long
Abstract: PDF file, 53KB.
Published: 2023

6. Supplemental Table 1. Details of cases and controls included in the endometrial cancer analyses from Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Author: Amanda B. Spurdle, Deborah J. Thompson, Douglas F. Easton, Alison M. Dunning, Ian Tomlinson, Paul D.P. Pharoah, Angela Cox, Vessela N. Kristensen, Graham G. Giles, Fergus J. Couch, Jenny Chang-Claude, Annika Lindblom, Hiltrud Brauch, Alfons Meindl, Hermann Brenner, Barbara Burwinkel, Anthony J. Swerdlow, Julian Peto, John L. Hopper, Jonathan P. Tyrer, Qin Wang, Kyriaki Michailidou, Manjeet K. Bolla, Emma Tham, Miriam Mints, Anthony Proietto, Geoffrey Otton, Katie A. Ashton, Henrica M.J. Werner, Jone Trovik, Helga B. Salvesen, Tormund S. Njølstad, Stacey J. Winham, Brooke L. Fridley, Ellen L. Goode, Sean C. Dowdy, Julie M. Cunningham, Patrick Neven, Diether Lambrechts, Jeroen Depreeuw, Daniela Annibali, Frederic Amant, Ingo B. Runnebaum, Peter Hillemanns, Matthias Dürst, Thilo Dörk, Jingmei Li, Per Hall, Hatef Darabi, Kamila Czene, Matthias Rübner, Alexander Hein, Peter A. Fasching, Arif B. Ekici, Matthias W. Beckmann, Shirley V. Hodgson, Lynn Martin, Maggie Gorman, Mitul Shah, Catherine S. Healey, Shahana Ahmed, Rodney J. Scott, Mark McEvoy, Elizabeth G. Holliday, Joe Dennis, Timothy Cheng, Sarah E. Medland, John Attia, Penelope M. Webb, Louise Marquart, Tracy A. O'Mara, and Jodie N. Painter
Abstract: Excel file detailing case-control populations
Published: 2023

7. Supplemental Table 2. Average BMIs in the ANECS, SEARCH and iCOGS endometrial cancer datasets. from Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Author: Amanda B. Spurdle, Deborah J. Thompson, Douglas F. Easton, Alison M. Dunning, Ian Tomlinson, Paul D.P. Pharoah, Angela Cox, Vessela N. Kristensen, Graham G. Giles, Fergus J. Couch, Jenny Chang-Claude, Annika Lindblom, Hiltrud Brauch, Alfons Meindl, Hermann Brenner, Barbara Burwinkel, Anthony J. Swerdlow, Julian Peto, John L. Hopper, Jonathan P. Tyrer, Qin Wang, Kyriaki Michailidou, Manjeet K. Bolla, Emma Tham, Miriam Mints, Anthony Proietto, Geoffrey Otton, Katie A. Ashton, Henrica M.J. Werner, Jone Trovik, Helga B. Salvesen, Tormund S. Njølstad, Stacey J. Winham, Brooke L. Fridley, Ellen L. Goode, Sean C. Dowdy, Julie M. Cunningham, Patrick Neven, Diether Lambrechts, Jeroen Depreeuw, Daniela Annibali, Frederic Amant, Ingo B. Runnebaum, Peter Hillemanns, Matthias Dürst, Thilo Dörk, Jingmei Li, Per Hall, Hatef Darabi, Kamila Czene, Matthias Rübner, Alexander Hein, Peter A. Fasching, Arif B. Ekici, Matthias W. Beckmann, Shirley V. Hodgson, Lynn Martin, Maggie Gorman, Mitul Shah, Catherine S. Healey, Shahana Ahmed, Rodney J. Scott, Mark McEvoy, Elizabeth G. Holliday, Joe Dennis, Timothy Cheng, Sarah E. Medland, John Attia, Penelope M. Webb, Louise Marquart, Tracy A. O'Mara, and Jodie N. Painter
Abstract: Excel file detailing average BMI per study population
Published: 2023

8. Supplementary Figure 1 from Polymorphisms in Inflammation Pathway Genes and Endometrial Cancer Risk

Author: Xiao-Ou Shu, Wei Zheng, Qiuyin Cai, Wei Lu, Wanqing Wen, Nurzhan Turmanov, Jone Trovik, Madeleine Corssen, Harvey Risch, Paul Pharoah, Rayna K. Matsuno, Tracy O'Mara, Galina Lurie, Lingeng Lu, Felicity Lose, Camilla Krakstad, Dylyara Kaydarova, Maggie Gorman, Kimberly Howarth, Alexander Hein, Mari K. Halle, Peter A. Fasching, Arif B. Ekici, Douglas Easton, Ingo B. Runnebaum, Alison Dunning, Natalia Dubrowinskaja, An Coosemans, Lieve Coenegrachts, Matthias W. Beckmann, Frederic Amant, Ping-Ping Bao, Helga B. Salvesen, Ying Zheng, Marc T. Goodman, Thilo Dörk, Diether Lambrechts, Herbert Yu, Ian Tomlinson, Deborah Thompson, Jirong Long, Alicia Beeghly-Fadiel, Amanda Spurdle, Yong-Bing Xiang, and Ryan J. Delahanty
Abstract: PDF file - 99K, LocusZoom plots of the top two loci using stage 1 P values.
Published: 2023

9. Data from Genome-Wide Association Study Identifies a Possible Susceptibility Locus for Endometrial Cancer

Author: Xiao-Ou Shu, Amanda B. Spurdle, Qiuyin Cai, Yu-Tang Gao, Douglas Easton, Alison Dunning, Wei Lu, Hui Cai, Anthony Proietto, Alexander Hein, Mari K. Halle, Rayna K. Matsuno, An Coosemans, Louise Brinton, Maggie Gorman, Ben Zhang, Jiajun Shi, Geoffrey Otton, Arif B. Ekici, Camilla Krakstad, Pamela J. Thompson, Matthias Dürst, Dilyara Kaidarova, Lieve Coenegrachts, Jolanta Lissowska, Lingeng Lu, Kimberly Howarth, Ping-Ping Bao, Bu-Tian Ji, Katie Ashton, Matthias W. Beckmann, Jone Trovik, Galina Lurie, Anita Schwake, Nurzhan Turmanov, Frederic Amant, Hannah P. Yang, Harvey Risch, Shirley Hodgson, Catherine S. Healey, Tracy O'Mara, Ying Zheng, Ryan Delahanty, Rodney J. Scott, Peter A. Fasching, Helga B. Salvesen, Marc T. Goodman, Natalia Dubrowinskaja, Thilo Dörk, Diether Lambrechts, Nicolas Wentzensen, Herbert Yu, Ian Tomlinson, Deborah Thompson, Felicity Lose, Yong-Bing Xiang, Wei Zheng, and Jirong Long
Abstract: Background: Genome-wide association studies (GWAS) have identified more than 100 genetic loci for various cancers. However, only one is for endometrial cancer.Methods: We conducted a three-stage GWAS including 8,492 endometrial cancer cases and 16,596 controls. After analyzing 585,963 single-nucleotide polymorphisms (SNP) in 832 cases and 2,682 controls (stage I) from the Shanghai Endometrial Cancer Genetics Study, we selected the top 106 SNPs for in silico replication among 1,265 cases and 5,190 controls from the Australian/British Endometrial Cancer GWAS (stage II). Nine SNPs showed results consistent in direction with stage I with P < 0.1. These nine SNPs were investigated among 459 cases and 558 controls (stage IIIa) and six SNPs showed a direction of association consistent with stages I and II. These six SNPs, plus two additional SNPs selected on the basis of linkage disequilibrium and P values in stage II, were investigated among 5,936 cases and 8,166 controls from an additional 11 studies (stage IIIb).Results: SNP rs1202524, near the CAPN9 gene on chromosome 1q42.2, showed a consistent association with endometrial cancer risk across all three stages, with ORs of 1.09 [95% confidence interval (CI), 1.03–1.16] for the A/G genotype and 1.17 (95% CI, 1.05–1.30) for the G/G genotype (P = 1.6 × 10−4 in combined analyses of all samples). The association was stronger when limited to the endometrioid subtype, with ORs (95% CI) of 1.11 (1.04–1.18) and 1.21 (1.08–1.35), respectively (P = 2.4 × 10−5).Conclusions: Chromosome 1q42.2 may host an endometrial cancer susceptibility locus.Impact: This study identified a potential genetic locus for endometrial cancer risk. Cancer Epidemiol Biomarkers Prev; 21(6); 980–7. ©2012 AACR.
Published: 2023

10. Supplementary Table 3: Association of 77 body mass index (BMI) SNPs with endometrial cancer risk and BMI in the endometrial cancer dataset from Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Author: Amanda B. Spurdle, Deborah J. Thompson, Douglas F. Easton, Alison M. Dunning, Ian Tomlinson, Paul D.P. Pharoah, Angela Cox, Vessela N. Kristensen, Graham G. Giles, Fergus J. Couch, Jenny Chang-Claude, Annika Lindblom, Hiltrud Brauch, Alfons Meindl, Hermann Brenner, Barbara Burwinkel, Anthony J. Swerdlow, Julian Peto, John L. Hopper, Jonathan P. Tyrer, Qin Wang, Kyriaki Michailidou, Manjeet K. Bolla, Emma Tham, Miriam Mints, Anthony Proietto, Geoffrey Otton, Katie A. Ashton, Henrica M.J. Werner, Jone Trovik, Helga B. Salvesen, Tormund S. Njølstad, Stacey J. Winham, Brooke L. Fridley, Ellen L. Goode, Sean C. Dowdy, Julie M. Cunningham, Patrick Neven, Diether Lambrechts, Jeroen Depreeuw, Daniela Annibali, Frederic Amant, Ingo B. Runnebaum, Peter Hillemanns, Matthias Dürst, Thilo Dörk, Jingmei Li, Per Hall, Hatef Darabi, Kamila Czene, Matthias Rübner, Alexander Hein, Peter A. Fasching, Arif B. Ekici, Matthias W. Beckmann, Shirley V. Hodgson, Lynn Martin, Maggie Gorman, Mitul Shah, Catherine S. Healey, Shahana Ahmed, Rodney J. Scott, Mark McEvoy, Elizabeth G. Holliday, Joe Dennis, Timothy Cheng, Sarah E. Medland, John Attia, Penelope M. Webb, Louise Marquart, Tracy A. O'Mara, and Jodie N. Painter
Abstract: Excel file detailing single BMI SNP associations with EC risk and BMI
Published: 2023

11. Supplementary Tables 1 - 4 from Genome-Wide Association Study Identifies a Possible Susceptibility Locus for Endometrial Cancer

Author: Xiao-Ou Shu, Amanda B. Spurdle, Qiuyin Cai, Yu-Tang Gao, Douglas Easton, Alison Dunning, Wei Lu, Hui Cai, Anthony Proietto, Alexander Hein, Mari K. Halle, Rayna K. Matsuno, An Coosemans, Louise Brinton, Maggie Gorman, Ben Zhang, Jiajun Shi, Geoffrey Otton, Arif B. Ekici, Camilla Krakstad, Pamela J. Thompson, Matthias Dürst, Dilyara Kaidarova, Lieve Coenegrachts, Jolanta Lissowska, Lingeng Lu, Kimberly Howarth, Ping-Ping Bao, Bu-Tian Ji, Katie Ashton, Matthias W. Beckmann, Jone Trovik, Galina Lurie, Anita Schwake, Nurzhan Turmanov, Frederic Amant, Hannah P. Yang, Harvey Risch, Shirley Hodgson, Catherine S. Healey, Tracy O'Mara, Ying Zheng, Ryan Delahanty, Rodney J. Scott, Peter A. Fasching, Helga B. Salvesen, Marc T. Goodman, Natalia Dubrowinskaja, Thilo Dörk, Diether Lambrechts, Nicolas Wentzensen, Herbert Yu, Ian Tomlinson, Deborah Thompson, Felicity Lose, Yong-Bing Xiang, Wei Zheng, and Jirong Long
Abstract: PDF file, 112KB.
Published: 2023

12. Supplementary Tables 1 - 2 from Polymorphisms in Inflammation Pathway Genes and Endometrial Cancer Risk

Author: Xiao-Ou Shu, Wei Zheng, Qiuyin Cai, Wei Lu, Wanqing Wen, Nurzhan Turmanov, Jone Trovik, Madeleine Corssen, Harvey Risch, Paul Pharoah, Rayna K. Matsuno, Tracy O'Mara, Galina Lurie, Lingeng Lu, Felicity Lose, Camilla Krakstad, Dylyara Kaydarova, Maggie Gorman, Kimberly Howarth, Alexander Hein, Mari K. Halle, Peter A. Fasching, Arif B. Ekici, Douglas Easton, Ingo B. Runnebaum, Alison Dunning, Natalia Dubrowinskaja, An Coosemans, Lieve Coenegrachts, Matthias W. Beckmann, Frederic Amant, Ping-Ping Bao, Helga B. Salvesen, Ying Zheng, Marc T. Goodman, Thilo Dörk, Diether Lambrechts, Herbert Yu, Ian Tomlinson, Deborah Thompson, Jirong Long, Alicia Beeghly-Fadiel, Amanda Spurdle, Yong-Bing Xiang, and Ryan J. Delahanty
Abstract: PDF file - 70K, Candidate inflammation genes selected for stage 1 study, Annotation of potentially functional SNPs in linkage disequilibrium (r2 > 0.2) with rs352038 (CXCL3) or rs3918249 (MMP9)
Published: 2023

13. Supplementary Table 4. Association of 47 waist-hip ratio (WHR) SNPs with endometrial cancer risk from Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Author: Amanda B. Spurdle, Deborah J. Thompson, Douglas F. Easton, Alison M. Dunning, Ian Tomlinson, Paul D.P. Pharoah, Angela Cox, Vessela N. Kristensen, Graham G. Giles, Fergus J. Couch, Jenny Chang-Claude, Annika Lindblom, Hiltrud Brauch, Alfons Meindl, Hermann Brenner, Barbara Burwinkel, Anthony J. Swerdlow, Julian Peto, John L. Hopper, Jonathan P. Tyrer, Qin Wang, Kyriaki Michailidou, Manjeet K. Bolla, Emma Tham, Miriam Mints, Anthony Proietto, Geoffrey Otton, Katie A. Ashton, Henrica M.J. Werner, Jone Trovik, Helga B. Salvesen, Tormund S. Njølstad, Stacey J. Winham, Brooke L. Fridley, Ellen L. Goode, Sean C. Dowdy, Julie M. Cunningham, Patrick Neven, Diether Lambrechts, Jeroen Depreeuw, Daniela Annibali, Frederic Amant, Ingo B. Runnebaum, Peter Hillemanns, Matthias Dürst, Thilo Dörk, Jingmei Li, Per Hall, Hatef Darabi, Kamila Czene, Matthias Rübner, Alexander Hein, Peter A. Fasching, Arif B. Ekici, Matthias W. Beckmann, Shirley V. Hodgson, Lynn Martin, Maggie Gorman, Mitul Shah, Catherine S. Healey, Shahana Ahmed, Rodney J. Scott, Mark McEvoy, Elizabeth G. Holliday, Joe Dennis, Timothy Cheng, Sarah E. Medland, John Attia, Penelope M. Webb, Louise Marquart, Tracy A. O'Mara, and Jodie N. Painter
Abstract: Excel file detailing single WHR SNP associations with EC risk
Published: 2023

14. Supplementary Figure 2 from Genome-Wide Association Study Identifies a Possible Susceptibility Locus for Endometrial Cancer

Author: Xiao-Ou Shu, Amanda B. Spurdle, Qiuyin Cai, Yu-Tang Gao, Douglas Easton, Alison Dunning, Wei Lu, Hui Cai, Anthony Proietto, Alexander Hein, Mari K. Halle, Rayna K. Matsuno, An Coosemans, Louise Brinton, Maggie Gorman, Ben Zhang, Jiajun Shi, Geoffrey Otton, Arif B. Ekici, Camilla Krakstad, Pamela J. Thompson, Matthias Dürst, Dilyara Kaidarova, Lieve Coenegrachts, Jolanta Lissowska, Lingeng Lu, Kimberly Howarth, Ping-Ping Bao, Bu-Tian Ji, Katie Ashton, Matthias W. Beckmann, Jone Trovik, Galina Lurie, Anita Schwake, Nurzhan Turmanov, Frederic Amant, Hannah P. Yang, Harvey Risch, Shirley Hodgson, Catherine S. Healey, Tracy O'Mara, Ying Zheng, Ryan Delahanty, Rodney J. Scott, Peter A. Fasching, Helga B. Salvesen, Marc T. Goodman, Natalia Dubrowinskaja, Thilo Dörk, Diether Lambrechts, Nicolas Wentzensen, Herbert Yu, Ian Tomlinson, Deborah Thompson, Felicity Lose, Yong-Bing Xiang, Wei Zheng, and Jirong Long
Abstract: PDF file, 45KB.
Published: 2023

15. Supplementary Figure Legend from Polymorphisms in Inflammation Pathway Genes and Endometrial Cancer Risk

Author: Xiao-Ou Shu, Wei Zheng, Qiuyin Cai, Wei Lu, Wanqing Wen, Nurzhan Turmanov, Jone Trovik, Madeleine Corssen, Harvey Risch, Paul Pharoah, Rayna K. Matsuno, Tracy O'Mara, Galina Lurie, Lingeng Lu, Felicity Lose, Camilla Krakstad, Dylyara Kaydarova, Maggie Gorman, Kimberly Howarth, Alexander Hein, Mari K. Halle, Peter A. Fasching, Arif B. Ekici, Douglas Easton, Ingo B. Runnebaum, Alison Dunning, Natalia Dubrowinskaja, An Coosemans, Lieve Coenegrachts, Matthias W. Beckmann, Frederic Amant, Ping-Ping Bao, Helga B. Salvesen, Ying Zheng, Marc T. Goodman, Thilo Dörk, Diether Lambrechts, Herbert Yu, Ian Tomlinson, Deborah Thompson, Jirong Long, Alicia Beeghly-Fadiel, Amanda Spurdle, Yong-Bing Xiang, and Ryan J. Delahanty
Abstract: PDF file - 48K
Published: 2023

16. Data from Polymorphisms in Inflammation Pathway Genes and Endometrial Cancer Risk

Author: Xiao-Ou Shu, Wei Zheng, Qiuyin Cai, Wei Lu, Wanqing Wen, Nurzhan Turmanov, Jone Trovik, Madeleine Corssen, Harvey Risch, Paul Pharoah, Rayna K. Matsuno, Tracy O'Mara, Galina Lurie, Lingeng Lu, Felicity Lose, Camilla Krakstad, Dylyara Kaydarova, Maggie Gorman, Kimberly Howarth, Alexander Hein, Mari K. Halle, Peter A. Fasching, Arif B. Ekici, Douglas Easton, Ingo B. Runnebaum, Alison Dunning, Natalia Dubrowinskaja, An Coosemans, Lieve Coenegrachts, Matthias W. Beckmann, Frederic Amant, Ping-Ping Bao, Helga B. Salvesen, Ying Zheng, Marc T. Goodman, Thilo Dörk, Diether Lambrechts, Herbert Yu, Ian Tomlinson, Deborah Thompson, Jirong Long, Alicia Beeghly-Fadiel, Amanda Spurdle, Yong-Bing Xiang, and Ryan J. Delahanty
Abstract: Background: Experimental and epidemiologic evidence have suggested that chronic inflammation may play a critical role in endometrial carcinogenesis.Methods: To investigate this hypothesis, a two-stage study was carried out to evaluate single-nucleotide polymorphisms (SNP) in inflammatory pathway genes in association with endometrial cancer risk. In stage I, 64 candidate pathway genes were identified and 4,542 directly genotyped or imputed SNPs were analyzed among 832 endometrial cancer cases and 2,049 controls, using data from the Shanghai Endometrial Cancer Genetics Study. Linkage disequilibrium of stage I SNPs significantly associated with endometrial cancer (P < 0.05) indicated that the majority of associations could be linked to one of 24 distinct loci. One SNP from each of the 24 loci was then selected for follow-up genotyping. Of these, 21 SNPs were successfully designed and genotyped in stage II, which consisted of 10 additional studies including 6,604 endometrial cancer cases and 8,511 controls.Results: Five of the 21 SNPs had significant allelic odds ratios (ORs) and 95% confidence intervals (CI) as follows: FABP1, 0.92 (0.85–0.99); CXCL3, 1.16 (1.05–1.29); IL6, 1.08 (1.00–1.17); MSR1, 0.90 (0.82–0.98); and MMP9, 0.91 (0.87–0.97). Two of these polymorphisms were independently significant in the replication sample (rs352038 in CXCL3 and rs3918249 in MMP9). The association for the MMP9 polymorphism remained significant after Bonferroni correction and showed a significant association with endometrial cancer in both Asian- and European-ancestry samples.Conclusions: These findings lend support to the hypothesis that genetic polymorphisms in genes involved in the inflammatory pathway may contribute to genetic susceptibility to endometrial cancer.Impact statement: This study adds to the growing evidence that inflammation plays an important role in endometrial carcinogenesis. Cancer Epidemiol Biomarkers Prev; 22(2); 216–23. ©2012 AACR.
Published: 2023

17. Supplementary Methods from Genome-Wide Association Study Identifies a Possible Susceptibility Locus for Endometrial Cancer

Author: Xiao-Ou Shu, Amanda B. Spurdle, Qiuyin Cai, Yu-Tang Gao, Douglas Easton, Alison Dunning, Wei Lu, Hui Cai, Anthony Proietto, Alexander Hein, Mari K. Halle, Rayna K. Matsuno, An Coosemans, Louise Brinton, Maggie Gorman, Ben Zhang, Jiajun Shi, Geoffrey Otton, Arif B. Ekici, Camilla Krakstad, Pamela J. Thompson, Matthias Dürst, Dilyara Kaidarova, Lieve Coenegrachts, Jolanta Lissowska, Lingeng Lu, Kimberly Howarth, Ping-Ping Bao, Bu-Tian Ji, Katie Ashton, Matthias W. Beckmann, Jone Trovik, Galina Lurie, Anita Schwake, Nurzhan Turmanov, Frederic Amant, Hannah P. Yang, Harvey Risch, Shirley Hodgson, Catherine S. Healey, Tracy O'Mara, Ying Zheng, Ryan Delahanty, Rodney J. Scott, Peter A. Fasching, Helga B. Salvesen, Marc T. Goodman, Natalia Dubrowinskaja, Thilo Dörk, Diether Lambrechts, Nicolas Wentzensen, Herbert Yu, Ian Tomlinson, Deborah Thompson, Felicity Lose, Yong-Bing Xiang, Wei Zheng, and Jirong Long
Abstract: PDF file, 123KB, Detailed Description of the Case and Control Sample Sets.
Published: 2023

18. Supplementary Text for: Genetic risk score Mendelian randomization shows that obesity measured as body mass index, but not waist:hip ratio, is causal for endometrial cancer from Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Author: Amanda B. Spurdle, Deborah J. Thompson, Douglas F. Easton, Alison M. Dunning, Ian Tomlinson, Paul D.P. Pharoah, Angela Cox, Vessela N. Kristensen, Graham G. Giles, Fergus J. Couch, Jenny Chang-Claude, Annika Lindblom, Hiltrud Brauch, Alfons Meindl, Hermann Brenner, Barbara Burwinkel, Anthony J. Swerdlow, Julian Peto, John L. Hopper, Jonathan P. Tyrer, Qin Wang, Kyriaki Michailidou, Manjeet K. Bolla, Emma Tham, Miriam Mints, Anthony Proietto, Geoffrey Otton, Katie A. Ashton, Henrica M.J. Werner, Jone Trovik, Helga B. Salvesen, Tormund S. Njølstad, Stacey J. Winham, Brooke L. Fridley, Ellen L. Goode, Sean C. Dowdy, Julie M. Cunningham, Patrick Neven, Diether Lambrechts, Jeroen Depreeuw, Daniela Annibali, Frederic Amant, Ingo B. Runnebaum, Peter Hillemanns, Matthias Dürst, Thilo Dörk, Jingmei Li, Per Hall, Hatef Darabi, Kamila Czene, Matthias Rübner, Alexander Hein, Peter A. Fasching, Arif B. Ekici, Matthias W. Beckmann, Shirley V. Hodgson, Lynn Martin, Maggie Gorman, Mitul Shah, Catherine S. Healey, Shahana Ahmed, Rodney J. Scott, Mark McEvoy, Elizabeth G. Holliday, Joe Dennis, Timothy Cheng, Sarah E. Medland, John Attia, Penelope M. Webb, Louise Marquart, Tracy A. O'Mara, and Jodie N. Painter
Abstract: Supplementary Text for manuscript.
Published: 2023

19. Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer

Author: Timothy H.T. Cheng, V. Wendy Setiawan, Jolanta Lissowska, Kamila Czene, Zhaoming Wang, Linda S. Cook, Shirley Hodgson, Mitul Shah, Matthias W. Beckmann, Douglas F. Easton, Annika Lindblom, Daniel D. Buchanan, Wei Zheng, Constance Turman, Gloria E. Sarto, Susan E. Hankinson, Chu Chen, Joe Dennis, Christine M. Friedenreich, Dylan M. Glubb, Peter Hillemanns, Tracy A. O'Mara, Camilla Krakstad, Yong-Bing Xiang, Arif B. Ekici, Maxine M. Chen, Marta Crous-Bous, Montserrat Garcia-Closas, David Van Den Berg, Amanda Black, Immaculata De Vivo, Roger L. Milne, Geoffrey Otton, Frédéric Amant, Timothy R. Rebbeck, Carlotta Sacerdote, Erling A. Hoivik, Xiao-Ou Shu, Melissa C. Southey, Paul L. Auer, Brooke L. Fridley, Thilo Dörk, Elizabeth G. Holliday, Fredrick R. Schumacher, Loreall Pooler, Daniela Annibali, Mia M. Gaudet, Maggie Gorman, Peter A. Fasching, Matthias Rübner, Hannah P. Yang, Graham G. Giles, Stefan P. Renner, Jirong Long, Ellen L. Goode, Katie A. Ashton, Claire Palles, Emma Tham, Diether Lambrechts, Xin Sheng, Rodney J. Scott, Angela M. Jones, Alexander Hein, Amanda B. Spurdle, Nicolas Wentzensen, David J. Hunter, Rami Nassir, Peter Kraft, Lynn Martin, Christopher A. Haiman, Alison M. Dunning, Stephen J. Chanock, Jone Trovik, Loic Le Marchand, Harvey A. Risch, Tony Proietto, Matthias Dürst, Sean C. Dowdy, Lucy Xia, Miriam Mints, Anthony M. Magliocco, Pik Fang Kho, Herbert Yu, Lingeng Lu, Mark McEvoy, Xiaolin Liang, Louise A. Brinton, Per Hall, Jonathan Tyrer, Ingo B. Runnebaum, Penelope M. Webb, John Attia, Ian Tomlinson, Deborah J. Thompson, Buchanan, Daniel D [0000-0003-2225-6675], Chen, Chu [0000-0003-2267-8050], De Vivo, Immaculata [0000-0002-7185-7402], Dörk, Thilo [0000-0002-9458-0282], Fasching, Peter A [0000-0003-4885-8471], Friedenreich, Christine M [0000-0002-4783-1966], Gaudet, Mia M [0000-0002-6429-4007], Goode, Ellen L [0000-0002-9094-8326], Lu, Lingeng [0000-0001-9871-0809], Sacerdote, Carlotta [0000-0002-8008-5096], Shu, Xiao-Ou [0000-0002-0711-8314], Wang, Zhaoming [0000-0001-7556-3869], Wentzensen, Nicolas [0000-0003-1251-0836], Xiang, Yong-Bing [0000-0002-3840-9915], Yu, Herbert [0000-0003-3950-4815], Spurdle, Amanda B [0000-0003-1337-7897], O'Mara, Tracy A [0000-0002-5436-3232], Apollo - University of Cambridge Repository, ARD - Amsterdam Reproduction and Development, Obstetrics and Gynaecology, and CCA - Imaging and biomarkers
Subjects: Oncology, Cancer Research, Colorectal cancer, Blood lipids, chemistry.chemical_compound, 0302 clinical medicine, HDL cholesterol, Medicine, triglycerides, METABOLIC SYNDROME, 2. Zero hunger, Mendelian Randomization Analysis, ASSOCIATION, 3. Good health, 030220 oncology & carcinogenesis, LDL cholesterol, SERUM-LIPIDS, Female, lipids (amino acids, peptides, and proteins), Life Sciences & Biomedicine, Risk, medicine.medical_specialty, endometrial cancer risk, Article, 03 medical and health sciences, INFLAMMATION, Internal medicine, Mendelian randomization, CAUSAL, Humans, Science & Technology, Cholesterol, business.industry, Endometrial cancer, Cholesterol, HDL, Case-control study, Cholesterol, LDL, medicine.disease, Endometrial Neoplasms, BODY-MASS INDEX, LIPOPROTEIN, chemistry, Case-Control Studies, RISK-FACTORS, Metabolic syndrome, business, Genome-Wide Association Study
Abstract: Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two-sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P
Published: 2021

20. Identification of nine new susceptibility loci for endometrial cancer

Author: Chu Chen, Angela Cox, Marta Crous-Bous, Sean C. Dowdy, Lucy Xia, Herbert Yu, Mark McEvoy, Catherine S. Healey, Xiaolin Liang, V. Wendy Setiawan, Christine L. Clarke, Jeroen Depreeuw, Camilla Krakstad, Christine M. Friedenreich, Brooke L. Fridley, John R. B. Perry, Jolanta Lissowska, Thilo Dörk, Fredrick R. Schumacher, Jennifer A. Doherty, Rodney J. Scott, Jenny Chang-Claude, David Van Den Berg, Manjeet K. Bolla, Ingo B. Runnebaum, Jirong Long, Nicolas Wentzensen, Harvey A. Risch, Jennifer Prescott, Vessela N. Kristensen, Jonathan Tyrer, Penelope M. Webb, Lingeng Lu, Louise A. Brinton, Shirley Hodgson, Felix R. Day, Lin Fritschi, Matthias Rübner, Gloria E. Sarto, Anthony J. Swerdlow, Melissa C. Southey, Hannah P. Yang, Graham G. Giles, Julian Peto, Christopher A. Haiman, Mitul Shah, Matthias W. Beckmann, Kyriaki Michailidou, John Attia, Katie A. Ashton, Hiltrud Brauch, Loic Le Marchand, Joe Dennis, Håkan Olsson, Mia M. Gaudet, Ellen L. Goode, Celine M. Vachon, Paul D.P. Pharoah, Barbara Burwinkel, Alexander Hein, Stephen J. Chanock, Emma Tham, Douglas F. Easton, Wei Zheng, Ian Tomlinson, Jenny N. Fung, Maxine M. Chen, Zhaoming Wang, Alicja Wolk, Paul L. Auer, Daniel D. Buchanan, Deborah J. Thompson, Arif B. Ekici, Henrica M.J. Werner, Elizabeth G. Holliday, Timothy R. Rebbeck, Maggie Gorman, Per Hall, Tracy A. O'Mara, Peter Rogers, Miriam Mints, Anthony M. Magliocco, Xiao-Ou Shu, Tony Proietto, Matthias Dürst, Stacey J. Winham, Linda S. Cook, Annika Lindblom, Susan E. Hankison, Irene Orlow, Constance Turman, Dylan M. Glubb, Peter Hillemanns, Roger L. Milne, Geoffrey Otton, Carlotta Sacerdote, Erling A. Hoivik, Adriaan Vanderstichele, Daniela Annibali, Angela M. Jones, Amanda B. Spurdle, Peter Kraft, Hermann Brenner, Grant W. Montgomery, Alison M. Dunning, Jone Trovik, Amanda Black, Mark Clendenning, Immaculata De Vivo, Fergus J. Couch, David J. Hunter, Lynn Martin, Kamila Czene, John L. Hopper, Timothy H.T. Cheng, Montserrat Garcia-Closas, Frédéric Amant, Loreall Pooler, Peter A. Fasching, Diether Lambrechts, Xin Sheng, Rami Nassir, Claire Palles, Alfons Meindl, Yong-Bing Xiang, ARD - Amsterdam Reproduction and Development, CCA - Cancer biology and immunology, and Obstetrics and Gynaecology
Subjects: 0301 basic medicine, LD SCORE REGRESSION, General Physics and Astronomy, Genome-wide association study, VARIANTS, FAMILY-HISTORY, Gene Frequency, Risk Factors, Genotype, lcsh:Science, Genetics, Multidisciplinary, Chromatin, 3. Good health, Multidisciplinary Sciences, MENDELIAN RANDOMIZATION, Science & Technology - Other Topics, Female, Signal Transduction, Science, Quantitative Trait Loci, Locus (genetics), Biology, Quantitative trait locus, GENOTYPE IMPUTATION, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Breast cancer, medicine, Biomarkers, Tumor, BREAST-CANCER, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Allele frequency, METAANALYSIS, Alleles, Cancer och onkologi, Science & Technology, Endometrial cancer, General Chemistry, medicine.disease, RISK LOCI, Endometrial Neoplasms, BODY-MASS INDEX, 030104 developmental biology, Cancer and Oncology, Expression quantitative trait loci, lcsh:Q, Genome-Wide Association Study
Abstract: Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study., Endometrial cancer is the most common invasive gynaecological cancer in developed countries. Here a meta-analysis identifies an additional nine novel endometrial cancer risk loci and eQTL analysis reveals risk variants associate with reduced expression of negative regulators of oncogenic signal transduction proteins.
Published: 2018

21. Identification of susceptibility loci for colorectal cancer in a genome-wide meta-analysis

Author: Yufei Wang, Ben Kinnersley, Fay J. Hosking, Ian Tomlinson, Noralane M. Lindor, Nicola Whiffin, Steve Gallinger, Ella Barclay, Richard S. Houlston, Claire Palles, Graham Casey, Fred Schumacher, Mark A. Jenkins, Tao Liu, Daniel D. Buchanan, Lynn Martin, Malcolm G. Dunlop, Caroline Hayward, Maggie Gorman, Amy Lloyd, Lina Zgaga, John L. Hopper, Susan M. Farrington, Peter Broderick, Polly A. Newcomb, Harry Campbell, Annika Lindblom, Aung Ko Win, Albert Tenesa, David V. Conti, and Sara E. Dobbins
Subjects: Male, Quantitative Trait Loci, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, White People, Asian People, Genetics, Genetic predisposition, Odds Ratio, Humans, Genetic Predisposition to Disease, Molecular Biology, Genetics (clinical), Genetic association, Association Studies Articles, General Medicine, Odds ratio, Middle Aged, Genetic Loci, Meta-analysis, Female, Colorectal Neoplasms, Genome-Wide Association Study
Abstract: To identify common variants influencing colorectal cancer (CRC) risk, we performed a meta-analysis of five genome-wide association studies, comprising 5626 cases and 7817 controls of European descent. We conducted replication of top ranked single nucleotide polymorphisms (SNPs) in additional series totalling 14 037 cases and 15 937 controls, identifying a new CRC risk locus at 10q24.2 [rs1035209; odds ratio (OR) = 1.13, P = 4.54 × 10(-11)]. We also performed meta-analysis of our studies, with previously published data, of several recently purported CRC risk loci. We failed to find convincing evidence for a previously reported genome-wide association at rs11903757 (2q32.3). Of the three additional loci for which evidence of an association in Europeans has been previously described we failed to show an association between rs59336 (12q24.21) and CRC risk. However, for the other two SNPs, our analyses demonstrated new, formally significant associations with CRC. These are rs3217810 intronic in CCND2 (12p13.32; OR = 1.19, P = 2.16 × 10(-10)) and rs10911251 near LAMC1 (1q25.3; OR = 1.09, P = 1.75 × 10(-8)). Additionally, we found some evidence to support a relationship between, rs647161, rs2423297 and rs10774214 and CRC risk originally identified in East Asians in our European datasets. Our findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC.
Published: 2016

22. Deciphering the genetics of hereditary non-syndromic colorectal cancer

Author: Peter Propping, Eamonn R. Maher, Richard S. Houlston, Hans K. Schackert, D. Timothy Bishop, Jean-Baptiste Cazier, Anneke Lucassen, Juul T. Wijnen, Zoe Kemp, Huw Thomas, Gabrielle S. Sellick, Luis G. Carvajal-Carmona, Steven J. Lubbe, Elke Holinski-Feder, Nils Rahner, Maggie Gorman, Ian Tomlinson, Emma Jaeger, Ella Barclay, Verena Steinke, Timm O. Goecke, Peter Broderick, D. Gareth Evans, Kate Sullivan, Tom van Wezel, Jayaram Vijayakrishnan, Emily L. Webb, Eli Papaemmanuil, Sarah L. Spain, and Lynn Martin
Subjects: Adenoma, Candidate gene, Genetic Linkage, DNA Mutational Analysis, Gene Dosage, Locus (genetics), Genome-wide association study, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Gene mapping, Genetic linkage, Genetics, Humans, Family, Genetics (clinical), Family Health, Linkage Disequilibrium Mapping, Chromosome Mapping, Case-Control Studies, Chromosomes, Human, Pair 3, Lod Score, Colorectal Neoplasms, SNP array, Genome-Wide Association Study
Abstract: Previously we have localized to chromosome 3q21-q24, a predisposition locus for colorectal cancer (CRC), through a genome-wide linkage screen (GWLS) of 69 families without familial adenomatous polyposis or hereditary non-polyposis CRC. To further investigate Mendelian susceptibility to CRC, we extended our screen to include a further GWLS of an additional 34 CRC families. We also searched for a disease gene at 3q21-q24 by linkage disequilibrium mapping in 620 familial CRC cases and 960 controls by genotyping 1676 tagging SNPs and sequencing 30 candidate genes from the region. Linkage analysis was conducted using the Affymetrix 10K SNP array. Data from both GWLSs were pooled and multipoint linkage statistics computed. The maximum NPL score (3.01; P=0.0013) across all families was at 3q22, maximal evidence for linkage coming from families segregating rectal CRC. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) score under a dominant model (HLOD=2.79; P=0.00034), with an estimated 43% of families linked. In the case-control analysis, the strongest association was obtained at rs698675 (P=0.0029), but this was not significant after adjusting for multiple testing. Analysis of candidate gene mapping to the region of maximal linkage on 3q22 failed to identify a causal mutation. There was no evidence for linkage to the previously reported 9q CRC locus (NPL=0.95, P=0.23; HLOD(dominant)=0.40, HLOD(recessive)=0.20). Our findings are consistent with the hypothesis that variation at 3q22 contributes to the risk of CRC, but this is unlikely to be mediated through a restricted set of alleles.
Published: 2016

23. GWAS meta-analysis of 16 852 women identifies new susceptibility locus for endometrial cancer

Author: Jodie N. Painter, Herbert Yu, Mark McEvoy, Xiaolin Liang, Xin Sheng, Zhaoming Wang, Tracy A. O'Mara, Timothy R. Rebbeck, Douglas F. Easton, Chu Chen, Christopher A. Haiman, Jirong Long, Montserrat Garcia-Closas, Lynn Martin, Patricia Hartge, David J. Hunter, Louise A. Brinton, Mia M. Gaudet, Paul D.P. Pharoah, Loreall Pooler, Elizabeth G. Holliday, Ian Tomlinson, Veronica Wendy Setiawan, Shirley Hodgson, Jennifer Prescott, Wei Zhang, Deborah J. Thompson, Amanda Black, Immaculata De Vivo, Noel S. Weiss, Jolanta Lissowska, Christine M. Friedenreich, Frederick Schumacher, Maxine M. Chen, Timothy H.T. Cheng, Pamela L. Horn-Ross, Maggie Gorman, Amanda B. Spurdle, Alison M. Dunning, Peter Kraft, John Attia, Carlotta Sacerdote, Irene Orlow, Nicholas Wentzensen, Linda S. Cook, Brian E. Henderson, David Van Den Berg, Constance Turman, Radhai Rastogi, Susan E. Hankinson, Sara H. Olson, Yong-Bing Xiang, Loic Le Marchand, Stephen J. Chanock, Jennifer A. Doherty, Anthony M. Magliocco, Hannah P. Yang, Xiao-Ou Shu, Rodney J. Scott, Harvey A. Risch, Lucy Xia, Marta Crous-Bou, and Lingeng Lu
Subjects: 0301 basic medicine, Genotype, Genome-wide association study, Single-nucleotide polymorphism, Locus (genetics), Disease, Biology, Bioinformatics, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, 0302 clinical medicine, Genetics, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, Molecular Biology, Genetics (clinical), Genetic association, Endometrial cancer, Association Studies Articles, General Medicine, medicine.disease, Endometrial Neoplasms, 030104 developmental biology, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 6, Female, Genome-Wide Association Study
Abstract: Endometrial cancer is the most common gynecological malignancy in the developed world. Although there is evidence of genetic predisposition to the disease, most of the genetic risk remains unexplained. We present the meta-analysis results of four genome-wide association studies (4907 cases and 11 945 controls total) in women of European ancestry. We describe one new locus reaching genome-wide significance (P < 5 × 10 -8) at 6p22.3 (rs1740828; P = 2.29 × 10 -8, OR = 1.20), providing evidence of an additional region of interest for genetic susceptibility to endometrial cancer.
Published: 2016

24. Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist: Hip Ratio, Is Causal for Endometrial Cancer

Author: Jodie N. Painter, Brooke L. Fridley, Sean C. Dowdy, Thilo Dörk, Hiltrud Brauch, Matthias Dürst, Vessela N. Kristensen, Jonathan Tyrer, Peter Hillemanns, Paul D.P. Pharoah, Douglas F. Easton, Penelope M. Webb, Manjeet K. Bolla, Henrica M.J. Werner, Geoffrey Otton, Hermann Brenner, Amanda B. Spurdle, Miriam Mints, Patrick Neven, Sarah E. Medland, Stacey J. Winham, Lynn Martin, Anthony Proietto, Matthias Rübner, Ellen L. Goode, Graham G. Giles, Katie A. Ashton, Tracy A. O'Mara, Helga B. Salvesen, Emma Tham, Elizabeth G. Holliday, Alexander Hein, Maggie Gorman, Ingo B. Runnebaum, Mark McEvoy, Julie M. Cunningham, Tormund S. Njolstad, Arif B. Ekici, Shirley Hodgson, Mitul Shah, Annika Lindblom, Matthias W. Beckmann, Jingmei Li, Rodney J. Scott, Louise Marquart, Daniela Annibali, Peter A. Fasching, Alison M. Dunning, Catherine S. Healey, Joe Dennis, Jone Trovik, Diether Lambrechts, Jeroen Depreeuw, Alfons Meindl, Jenny Chang-Claude, Julian Peto, Angela Cox, Kyriaki Michailidou, John Attia, Barbara Burwinkel, Frédéric Amant, Ian Tomlinson, Deborah J. Thompson, Per Hall, Shahana Ahmed, Qin Wang, Kamila Czene, John L. Hopper, Fergus J. Couch, Hatef Darabi, Anthony J. Swerdlow, Timothy H.T. Cheng, and Other departments
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Epidemiology, Colorectal cancer, Polymorphism, Single Nucleotide, Article, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Waist–hip ratio, Internal medicine, Mendelian randomization, Humans, Medicine, Genetic Predisposition to Disease, Obesity, Risk factor, 2. Zero hunger, Genetics, Waist-Hip Ratio, business.industry, Endometrial cancer, Cancer, nutritional and metabolic diseases, Mendelian Randomization Analysis, medicine.disease, Confidence interval, Endometrial Neoplasms, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, business, Body mass index
Abstract: Background: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist–hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls. Methods: Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable. Results: The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10−17). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m2 of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89–2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55; 95% CI, 1.44–1.68, per 5 kg/m2). The association attenuated but remained significant after adjusting for BMI (OR = 1.22; 95% CI, 1.10–1.39; P = 5.3 × 10−4). There was evidence of directional pleiotropy (P = 1.5 × 10−4). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P < 4.0 × 10−4), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS. Conclusions: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI. Impact: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling. Cancer Epidemiol Biomarkers Prev; 25(11); 1503–10. ©2016 AACR.
Published: 2016

25. Five endometrial cancer risk loci identified through genome-wide association analysis

Author: Graham G. Giles, Katie A. Ashton, Vessela N. Kristensen, Stacey L. Edwards, Jonathan Tyrer, Alexander Hein, Kamila Czene, Maggie Gorman, Hiltrud Brauch, Rodney J. Scott, Penelope M. Webb, Paul D.P. Pharoah, John L. Hopper, Elizabeth G. Holliday, Nicholas G. Martin, Ingo B. Runnebaum, Jodie N. Painter, Tony Proietto, Matthias Dürst, Rendocas, Brooke L. Fridley, Thilo Dörk, Douglas F. Easton, Miriam Mints, Anjali K. Henders, Kyriaki Michailidou, John Attia, Fergus J. Couch, Tormund S. Njolstad, Tracy A. O'Mara, Qin Wang, Shun H. Yip, Richard S. Houlston, Timothy H.T. Cheng, Mark McEvoy, Per Hall, Malcolm G. Dunlop, Shahana Ahmed, Lynn Martin, Manjeet K. Bolla, Ellen L. Goode, Susanne Flach, Joe Dennis, Julie M. Cunningham, Grant W. Montgomery, Emma Tham, Luke Freeman-Mills, Hui Zhao, Hatef Darabi, Amanda B. Spurdle, Sean C. Dowdy, Shirley Hodgson, Angela Cox, Arif B. Ekici, Catherine S. Healey, Mitul Shah, Matthias W. Beckmann, Julian Peto, Tao Liu, Jenny Chang-Claude, Junwen Wang, Annika Lindblom, Ian Tomlinson, Dylan M. Glubb, Barbara Burwinkel, Peter Hillemanns, Deborah J. Thompson, Geoffrey Otton, Stefanie Schrauwen, Annabelle Lewis, David N. Church, Hermann Brenner, Jingmei Li, Mulin Jun Li, Alison M. Dunning, Claire Palles, Jone Trovik, Alfons Meindl, Anthony J. Swerdlow, Jeroen Depreeuw, Frédéric Amant, Peter A. Fasching, Diether Lambrechts, Dale R. Nyholt, Helga B. Salvesen, Juliet D. French, Henrica M.J. Werner, Stacey J. Winham, and Other departments
Subjects: 0301 basic medicine, Genome-wide association study, Locus (genetics), Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Genetics, medicine, Humans, Genetic Predisposition to Disease, Allele, Promoter Regions, Genetic, Gene, Genetic association, Endometrial cancer, Promoter, medicine.disease, humanities, Endometrial Neoplasms, 3. Good health, 030104 developmental biology, Cancer research, Female, Carcinogenesis, Chromosomes, Human, Pair 8, Genome-Wide Association Study
Abstract: We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r2 = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.
Published: 2016

26. Cumulative impact of common genetic variants and other risk factors on colorectal cancer risk in 42 103 individuals

Author: Graham Casey, Henry Völzke, Hermann Brenner, Thomas J. Hudson, Albert Tenesa, David J. Kerr, Clara Ruiz-Ponte, Stephane Ballereau, Luis G. Carvajal-Carmona, Anna Abulí, Jenny Chang-Claude, Lynn Martin, Maggie Gorman, Clemens Schafmayer, Steven Gallinger, John L. Hopper, Ian Tomlinson, Iina Niittymäki, Richard S. Houlston, Simone Picelli, Ella Barclay, Jochen Hampe, Xavier Bessa, Alan M. Pittman, Lauri A. Aaltonen, Susanna von Holst, Auli Karhu, Brent W. Zanke, Malcolm G. Dunlop, Michael Hoffmeister, Polly A. Newcomb, Harry Campbell, Steven Penegar, Sari Tuupanen, Steven J. Lubbe, Annika Lindblom, Axel Walther, Ian Chandler, David Duggan, Paul D.P. Pharoah, Peter Broderick, Mark A. Jenkins, Sergi Castellví-Bel, Susan M. Farrington, David H. Brewster, and Thibaud Koessler
Subjects: Male, Genotype, Population, Genome-wide association study, Bioinformatics, Logistic regression, Risk Assessment, Article, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Humans, Medicine, Genetic Predisposition to Disease, Risk factor, 10. No inequality, education, Alleles, 030304 developmental biology, 0303 health sciences, education.field_of_study, business.industry, Gastroenterology, Case-control study, Absolute risk reduction, Genetic Variation, 3. Good health, Logistic Models, Scotland, Case-Control Studies, 030220 oncology & carcinogenesis, Feasibility Studies, Female, Colorectal Neoplasms, business, Risk assessment, Demography
Abstract: OBJECTIVE: Colorectal cancer (CRC) has a substantial heritable component. Common genetic variation has been shown to contribute to CRC risk. A study was conducted in a large multi-population study to assess the feasibility of CRC risk prediction using common genetic variant data combined with other risk factors. A risk prediction model was built and applied to the Scottish population using available data. DESIGN: Nine populations of European descent were studied to develop and validate CRC risk prediction models. Binary logistic regression was used to assess the combined effect of age, gender, family history (FH) and genotypes at 10 susceptibility loci that individually only modestly influence CRC risk. Risk models were generated from case-control data incorporating genotypes alone (n=39,266) and in combination with gender, age and FH (n=11,324). Model discriminatory performance was assessed using 10-fold internal cross-validation and externally using 4187 independent samples. The 10-year absolute risk was estimated by modelling genotype and FH with age- and gender-specific population risks. RESULTS: The median number of risk alleles was greater in cases than controls (10 vs 9, p5% predicted 10-year absolute risk. CONCLUSION: Genotype data provide additional information that complements age, gender and FH as risk factors, but individualised genetic risk prediction is not currently feasible. Nonetheless, the modelling exercise suggests public health potential since it is possible to stratify the population into CRC risk categories, thereby informing targeted prevention and surveillance.
Published: 2012

27. Breast cancer susceptibility polymorphisms and endometrial cancer risk: a Collaborative Endometrial Cancer Study

Author: Ignace Vergote, Diether Lambrechts, Maggie Gorman, Paul D.P. Pharoah, Timothy R. Rebbeck, Sasbac, Les, Tracy A. O'Mara, Anecs, Amanda B. Spurdle, Jolanta Lissowska, Ian Tomlinson, Stephen J. Chanock, Nsecg, Diego A. Garcia-Dios, Deborah J. Thompson, Jianjun Liu, Kimberley Howarth, Montserrat Garcia-Closas, Frédéric Amant, Catherine S. Healey, Louise A. Brinton, Brian L. Strom, Pecs, Hannah P. Yang, Shahana Ahmed, Per Hall, Kaltin Ferguson, Shirley Hodgson, Mitul Shah, Douglas F. Easton, Alison M. Dunning, Other departments, Amsterdam institute for Infection and Immunity, Graduate School, and Ear, Nose and Throat
Subjects: Adult, Oncology, Cancer Research, medicine.medical_specialty, Candidate gene, Adolescent, Breast Neoplasms, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Young adult, Aged, 030304 developmental biology, Genetic association, Molecular Epidemiology, 0303 health sciences, business.industry, Endometrial cancer, Case-control study, Cancer, General Medicine, Middle Aged, medicine.disease, Endometrial Neoplasms, 3. Good health, Case-Control Studies, 030220 oncology & carcinogenesis, Female, business
Abstract: Recent large--scale association studies, both of genome-wide and candidate gene design, have revealed several single-nucleotide polymorphisms (SNPs) which are significantly associated with risk of developing breast cancer. As both breast and endometrial cancers are considered to be hormonally driven and share multiple risk factors, we investigated whether breast cancer risk alleles are also associated with endometrial cancer risk. We genotyped nine breast cancer risk SNPs in up to 4188 endometrial cases and 11,928 controls, from between three and seven Caucasian populations. None of the tested SNPs showed significant evidence of association with risk of endometrial cancer.
Published: 2011

28. Refinement of the basis and impact of common 11q23.1 variation to the risk of developing colorectal cancer

Author: Lara Lipton, Amy Price, Enric Domingo, Trinidad Caldés, Gianluca Severi, Emma Jaeger, Sarah Fielding, Auli Karhu, José M. Ladero, Alan M. Pittman, David J. Kerr, Axel Walther, Mobshra Qureshi, Ian Tomlinson, Sergi Castellví-Bel, King Yip Cheng, Miguel de la Hoya, Wendy Wood, Emily L. Webb, John M. Luk, G Evans, Philip Twiss, Timothy Bishop, Hans Morreau, Steven Penegar, Pak C. Sham, Angel Carracedo, Melissa C. Southey, Eamonn R. Maher, Maria Chiara Di Bernardo, Sarah L. Spain, Julian Peto, Anneke Lucassen, Kari Hemminki, Lynn Martin, Richard Gray, Ian Chandler, Luis G. Carvajal-Carmona, Jean-Baptiste Cazier, Steven J. Lubbe, Kimberley Howarth, Richard S. Houlston, Graham G. Giles, Maggie Gorman, Kate Sullivan, Zoe Kemp, Pavel Vodicka, Judy W. C. Ho, Lauri A. Aaltonen, Clara Ruiz-Ponte, Jayaram Vijayakrishnan, Asta Försti, Huw Thomas, Alessio Naccarati, Peter Broderick, Juul T. Wijnen, Antoni Castells, Tom van Wezel, John L. Hopper, Iina Niittymäki, José A. G. Agúndez, Sari Tuupanen, Andrew Rowan, and Ella Barclay
Subjects: Adult, Male, Genotype, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Genetics, Humans, SNP, Genetic Predisposition to Disease, Allele, Molecular Biology, Genetics (clinical), Aged, 030304 developmental biology, 0303 health sciences, Chromosomes, Human, Pair 11, Case-control study, Genetic Variation, General Medicine, Middle Aged, 3. Good health, Case-Control Studies, 030220 oncology & carcinogenesis, Mutation, Female, Colorectal Neoplasms, Imputation (genetics)
Abstract: The common single-nucleotide polymorphism (SNP) rs3802842 at 11q23.1 has recently been reported to be associated with risk of colorectal cancer (CRC). To examine this association in detail we genotyped rs3802842 in eight independent case-control series comprising a total of 10 638 cases and 10 457 healthy individuals. A significant association between the C allele of rs3802842 and CRC risk was found (per allele OR = 1.17; 95% confidence interval [CI]: 1.12-1.22; P = 1.08 x 10(-12)) with the risk allele more frequent in rectal than colonic disease (P = 0.02). In combination with 8q21, 8q24, 10p14, 11q, 15q13.3 and 18q21 variants, the risk of CRC increases with an increasing numbers of variant alleles for the six loci (OR(per allele) = 1.19; 95% CI: 1.15-1.23; P(trend) = 7.4 x 10(-24)). Using the data from our genome-wide association study of CRC, LD mapping and imputation, we were able to refine the location of the causal locus to a 60 kb region and screened for coding changes. The absence of exonic mutations in any of the transcripts (FLJ45803, LOC120376, C11orf53 and POU2AF1) mapping to this region makes the association likely to be a consequence of non-coding effects on gene expression.
Published: 2008

29. A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3

Author: Sari Tuupanen, Melissa C. Southey, Ian Chandler, Enric Domingo, Paul D.P. Pharoah, Luis G. Carvajal-Carmona, D. Gareth Evans, Malcolm G. Dunlop, Trinidad Caldés, Graham G. Giles, Zoe Kemp, Harry Campbell, David J. Kerr, Alan M. Pittman, Eamonn R. Maher, D. Timothy Bishop, Jayaram Vijayakrishnan, Hans Morreau, Albert Tenesa, Asta Försti, Jean-Baptiste Cazier, Kimberley Howarth, Ella Barclay, Rebecca A. Barnetson, Tom van Wezel, Juul T. Wijnen, James G. D. Prendergast, Maggie Gorman, Julian Peto, Anneke Lucassen, Antoni Castells, Jochen Hampe, José A. G. Agúndez, Susan M. Farrington, Kate Sullivan, Henry Völzke, Richard Gray, Ulrich John, King Yip Cheng, Pavel Vodicka, Emma Jaeger, Peter Broderick, Judy W. C. Ho, Mobshra Qureshi, Lauri A. Aaltonen, Stephan Buch, Sarah Fielding, Sarah L. Spain, Lynn Martin, Andrew Rowan, Wendy Wood, Emily L. Webb, John M. Luk, Angel Carracedo, Clara Ruiz-Ponte, Alessio Naccarati, Steven J. Lubbe, Ian Tomlinson, Lara Lipton, John L. Hopper, Iina Niittymäki, Axel Walther, José M. Ladero, Pak C. Sham, Stefan Schreiber, Sergi Castellví-Bel, Miguel de la Hoya, Clemens Schafmayer, Gianluca Severi, Auli Karhu, Steven Penegar, Thibaud Koessler, Kari Hemminki, Richard S. Houlston, and Huw Thomas
Subjects: Adult, Male, Genetic Linkage, Colorectal cancer, Eukaryotic Initiation Factor-3, Single-nucleotide polymorphism, Genome-wide association study, Locus (genetics), Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Genetic linkage, Genetics, medicine, Humans, Genetic Predisposition to Disease, Allele, Genotyping, Alleles, Aged, 030304 developmental biology, 0303 health sciences, Chromosomes, Human, Pair 10, Genome, Human, Cancer, Middle Aged, medicine.disease, Pedigree, 3. Good health, 030220 oncology & carcinogenesis, Female, Colorectal Neoplasms, Chromosomes, Human, Pair 8
Abstract: To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10(-4) in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping (10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P = 2.5 x 10(-13) overall; P = 6.9 x 10(-12) replication), and rs16892766, at 8q23.3 (P = 3.3 x 10(-18) overall; P = 9.6 x 10(-17) replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition.
Published: 2008

30. Investigation of pathogenic mechanisms in multiple colorectal adenoma patients without germline APC or MYH/MUTYH mutations

Author: R. K. S. Phillips, Ian Tomlinson, Stefania Segditsas, Kimberley Howarth, Marco Novelli, Ian C. Talbot, Maggie Gorman, Oliver M. Sieber, Christina Thirlwell, G Guerra, and Huw Thomas
Subjects: Adenoma, Adult, Cancer Research, Genes, APC, Adenomatous polyposis coli, Loss of Heterozygosity, Somatic hypermutation, Colorectal adenoma, Germline, DNA Glycosylases, Familial adenomatous polyposis, Germline mutation, Gene Frequency, MUTYH, medicine, Humans, Genetic Predisposition to Disease, APC mutations, Molecular Diagnostics, Germ-Line Mutation, beta Catenin, Aged, Genetics, biology, multiple colorectal adenoma, MYH/MUTYH mutations, Middle Aged, medicine.disease, Gene Expression Regulation, Neoplastic, Adenomatous Polyposis Coli, Oncology, biology.protein, Colorectal Neoplasms
Abstract: Patients with multiple (5-100) colorectal adenomas (MCRAs) often have no germline mutation in known predisposition genes, but probably have a genetic origin. We collected a set of 25 MCRA patients with no detectable germline mutation in APC, MYH/MUTYH or the mismatch repair genes. Extracolonic tumours were absent in these cases. No vertical transmission of the MCRA phenotype was found. Based on the precedent of MYH-associated polyposis (MAP), we searched for a mutational signature in 241 adenomatous polyps from our MCRA cases. Somatic mutation frequencies and spectra at APC, K-ras and BRAF were, however, similar to those in sporadic colorectal adenomas. Our data suggest that the genetic pathway of tumorigenesis in the MCRA patients' tumours is very similar to the classical pathway in sporadic adenomas. In sharp contrast to MAP tumours, we did not find evidence of a specific mutational signature in any individual patient or in the overall set of MCRA cases. These results suggest that hypermutation of APC does not cause our patients' disease and strongly suggests that MAP is not a paradigm for the remaining MCRA patients. Our MCRA patients' colons showed no evidence of microadenomas, unlike in MAP and familial adenomatous polyposis (FAP). However, nuclear beta-catenin expression was significantly greater in MCRA patients' tumours than in sporadic adenomas. We suggest that, at least in some cases, the MCRA phenotype results from germline variation that acts subsequent to tumour initiation, perhaps by causing more rapid or more likely progression from microadenoma to macroadenoma.
Published: 2007

31. Recurrent Coding Sequence Variation Explains Only A Small Fraction of the Genetic Architecture of Colorectal Cancer

Author: Frederik J. Hes, Richard S. Houlston, Ceres Fernandez-Rozadilla, Maggie Gorman, Harry Campbell, Ben Kinnersley, Albert Tenesa, Carli M. J. Tops, Melanie Schrumpf, Nicola Whiffin, Asta Försti, D. Timothy Bishop, Ella Barclay, Robert M.W. Hofstra, Fay J. Hosking, L. Y. Ooi, Claire Smillie, Graeme R. Grimes, Caroline Hayward, Arnoud Boot, Amy Lloyd, Stephan Buch, Manuela Pinheiro, Sara E. Dobbins, Clemens Schafmayer, Jennifer H. Barrett, Kari Hemminki, Helga Westers, Tom van Wezel, David J. Porteous, Archie Campbell, Sergi Castellví-Bel, Carla M. A. Pinto, Evropi Theodoratou, Lina Zgaga, Antoni Castells, Roland Wolf, Juul T. Wijnen, Hans Morreau, Peter Broderick, Susan M. Farrington, Victoria Svinti, Sarah E. Harris, Emma Northwood, Angel Carracedo, Andre Franke, Lynn Martin, Gillian Smith, Peter Propping, David Forman, Hans F. A. Vasen, Malcolm G. Dunlop, Ian Tomlinson, Dina Ruano, Wolgang Lieb, Claire Palles, Manuel R. Teixeira, Ian J. Deary, Clara Ruiz-Ponte, Maria Timofeeva, Jochen Hampe, Neurology, Internal Medicine, and Medical Genetics
Subjects: Activating Transcription Factor 1/genetics, EXPRESSION, Linkage disequilibrium, SUSCEPTIBILITY LOCI, Genotype, VARIANT, European Continental Ancestry Group, IDENTIFIES 6, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, Linkage Disequilibrium, White People, SDG 3 - Good Health and Well-being, Gene Frequency, Genetic variation, Odds Ratio, Coding region, Humans, HETEROGENEITY, European Continental Ancestry Group/genetics, Allele, GENOME-WIDE ASSOCIATION, Allele frequency, Gene, METAANALYSIS, Alleles, Adaptor Proteins, Signal Transducing, Medicine(all), Genetics, RISK, Activating Transcription Factor 1, Multidisciplinary, Cadherins/genetics, Intracellular Signaling Peptides and Proteins, Genetic Variation, Proteins, Cadherins, Colorectal Neoplasms/genetics, 3. Good health, DISCOVERY, Case-Control Studies, Proteins/genetics, Colorectal Neoplasms, SCAN, Genome-Wide Association Study
Abstract: Whilst common genetic variation in many non-coding genomic regulatory regions are known to impart risk of colorectal cancer (CRC), much of the heritability of CRC remains unexplained. To examine the role of recurrent coding sequence variation in CRC aetiology, we genotyped 12,638 CRCs cases and 29,045 controls from six European populations. Single-variant analysis identified a coding variant (rs3184504) in SH2B3 (12q24) associated with CRC risk (OR = 1.08, P = 3.9 × 10−7) and novel damaging coding variants in 3 genes previously tagged by GWAS efforts; rs16888728 (8q24) in UTP23 (OR = 1.15, P = 1.4 × 10−7); rs6580742 and rs12303082 (12q13) in FAM186A (OR = 1.11, P = 1.2 × 10−7 and OR = 1.09, P = 7.4 × 10−8); rs1129406 (12q13) in ATF1 (OR = 1.11, P = 8.3 × 10−9), all reaching exome-wide significance levels. Gene based tests identified associations between CRC and PCDHGA genes (P −6). We found an excess of rare, damaging variants in base-excision (P = 2.4 × 10−4) and DNA mismatch repair genes (P = 6.1 × 10−4) consistent with a recessive mode of inheritance. This study comprehensively explores the contribution of coding sequence variation to CRC risk, identifying associations with coding variation in 4 genes and PCDHG gene cluster and several candidate recessive alleles. However, these findings suggest that recurrent, low-frequency coding variants account for a minority of the unexplained heritability of CRC.
Published: 2015

32. Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer

Author: Dylan M. Glubb, Peter Hillemanns, Geoffrey Otton, Tracy A. O'Mara, Catherine S. Healey, Alison M. Dunning, Jone Trovik, Helga B. Salvesen, Jingmei Li, Daniela Annibali, Jenny Chang-Claude, Tony Proietto, Matthias Dürst, Brooke L. Fridley, Rendocas, Qin Wang, Hatef Darabi, Thilo Dörk, Douglas F. Easton, Arif B. Ekici, Amanda B. Spurdle, Joe Dennis, Jeroen Depreeuw, Tao Liu, Jodie N. Painter, Lynn Martin, Annika Lindblom, Graham G. Giles, Hiltrud Brauch, Angela Cox, Ellen L. Goode, Katie A. Ashton, Paul D.P. Pharoah, Kamila Czene, John L. Hopper, Henrica M.J. Werner, Hui Zhao, Emma Tham, Fergus J. Couch, Alexander Hein, Stacey J. Winham, Ian Tomlinson, Shirley Hodgson, Deborah J. Thompson, Mitul Shah, Matthias W. Beckmann, Anthony J. Swerdlow, Ingo B. Runnebaum, Manjeet K. Bolla, Tormund S. Njolstad, Hermann Brenner, Kyriaki Michailidou, John Attia, Timothy H.T. Cheng, Per Hall, Alfons Meindl, Elizabeth G. Holliday, Mark McEvoy, Maggie Gorman, Rodney J. Scott, Shahana Ahmed, Sean C. Dowdy, Vessela N. Kristensen, Jonathan Tyrer, Peter A. Fasching, Frédéric Amant, Diether Lambrechts, Julian Peto, Barbara Burwinkel, Miriam Mints, and Other departments
Subjects: Cancer Research, Genotype, Endocrinology, Diabetes and Metabolism, Single-nucleotide polymorphism, Locus (genetics), Genome-wide association study, Breast Neoplasms, Nerve Tissue Proteins, Biology, Polymorphism, Single Nucleotide, Article, Endocrinology, Breast cancer, Meta-Analysis as Topic, Risk Factors, Databases, Genetic, medicine, SNP, Humans, Genetic Predisposition to Disease, Promoter Regions, Genetic, Genetics, Endometrial cancer, Estrogen Receptor alpha, Computational Biology, Nuclear Proteins, medicine.disease, Prognosis, Endometrial Neoplasms, Cytoskeletal Proteins, Oncology, Genetic Loci, Case-Control Studies, Expression quantitative trait loci, Cancer research, Female, Estrogen receptor alpha
Abstract: Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded byESR1. Consequently, several studies have investigated whether variation at theESR1locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3633 genotyped and imputed single nucleotide polymorphisms (SNPs) in 6607 EC cases and 37 925 controls. There was evidence of an EC risk signal located at a potential alternative promoter of theESR1gene (lead SNP rs79575945,P=1.86×10−5), which was stronger for cancers of endometrioid subtype (P=3.76×10−6). Bioinformatic analysis suggests that this risk signal is in a functionally important region targetingESR1, and eQTL analysis found that rs79575945 was associated with expression ofSYNE1, a neighbouring gene. In summary, we have identified a single EC risk signal located atESR1, at study-wide significance. Given SNPs located at this locus have been associated with risk for breast cancer, also a hormonally driven cancer, this study adds weight to the rationale for performing informed candidate fine-scale genetic studies across cancer types.
Published: 2015

33. Erratum: A new GWAS and meta-analysis with 1000Genomes imputation identifies novel risk variants for colorectal cancer

Author: Salma M. Wakil, Maggie Gorman, Harry Campbell, Sara E. Dobbins, Lynn Martin, Jeremy Peter Cheadle, Shelley Idziaszczyk, Ben Kinnersley, David J. Kerr, Graham Casey, Rebecca Harris, Fay J. Hosking, Ella Barclay, Nicola Whiffin, Aung Ko Win, Malcolm G. Dunlop, Albert Tenesa, Nada Al-Tassan, Fred Schumacher, Susan M. Farrington, John L. Hopper, Steve Gallinger, Tim Maughan, Mark A. Jenkins, Ian Tomlinson, Noralane M. Lindor, David V. Conti, Claire Palles, Polly A. Newcomb, Richard Kaplan, Brian F. Meyer, Christopher Smith, Richard S. Houlston, Daniel D. Buchanan, and Rachel Kerr
Subjects: Male, Multidisciplinary, business.industry, Colorectal cancer, Chromosome Mapping, Genome-wide association study, Forkhead Transcription Factors, Receptors, Cell Surface, Middle Aged, Bioinformatics, medicine.disease, Polymorphism, Single Nucleotide, Gene Frequency, Meta-analysis, Biomarkers, Tumor, Medicine, Humans, Female, Genetic Predisposition to Disease, Erratum, business, Colorectal Neoplasms, Imputation (genetics), Genome-Wide Association Study
Abstract: Genome-wide association studies (GWAS) of colorectal cancer (CRC) have identified 23 susceptibility loci thus far. Analyses of previously conducted GWAS indicate additional risk loci are yet to be discovered. To identify novel CRC susceptibility loci, we conducted a new GWAS and performed a meta-analysis with five published GWAS (totalling 7,577 cases and 9,979 controls of European ancestry), imputing genotypes utilising the 1000 Genomes Project. The combined analysis identified new, significant associations with CRC at 1p36.2 marked by rs72647484 (minor allele frequency [MAF] = 0.09) near CDC42 and WNT4 (P = 1.21 × 10(-8), odds ratio [OR] = 1.21 ) and at 16q24.1 marked by rs16941835 (MAF = 0.21, P = 5.06 × 10(-8); OR = 1.15) within the long non-coding RNA (lncRNA) RP11-58A18.1 and ~500 kb from the nearest coding gene FOXL1. Additionally we identified a promising association at 10p13 with rs10904849 intronic to CUBN (MAF = 0.32, P = 7.01 × 10(-8); OR = 1.14). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC. Additionally, our analysis further demonstrates that imputation can be used to exploit GWAS data to identify novel disease-causing variants.
Published: 2015

34. A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk

Author: Jayaram Vijayakrishnan, Ella Barclay, Maggie Gorman, Julian Peto, Andrew Rowan, Peter Broderick, Richard S. Houlston, Zoe Kemp, Luis G. Carvajal-Carmona, Sarah L. Spain, Emily L. Webb, Enric Domingo, Ian Chandler, Kate Sullivan, Steven J. Lubbe, Alan M. Pittman, Kimberley Howarth, Elli Papaemmanuil, Lynn Martin, Richard Gray, Gabrielle S. Sellick, Oliver M. Sieber, Sarah Fielding, Wendy Wood, Emma Jaeger, David J. Kerr, Steven Penegar, Ian Tomlinson, Jean-Baptiste Cazier, Mobshra Qureshi, and Ana Teixeira
Subjects: Genetics, Genotype, Genetic Linkage, Genome, Human, Colorectal cancer, Case-control study, Cancer, Single-nucleotide polymorphism, Genome-wide association study, Biology, medicine.disease, Polymorphism, Single Nucleotide, digestive system diseases, Smad7 Protein, Risk Factors, Polymorphism (computer science), Case-Control Studies, medicine, Humans, Genetic Predisposition to Disease, Colorectal Neoplasms, Genotyping, Alleles
Abstract: To identify risk variants for colorectal cancer (CRC), we conducted a genome-wide association study, genotyping 550,163 tag SNPs in 940 individuals with familial colorectal tumor (627 CRC, 313 advanced adenomas) and 965 controls. We evaluated selected SNPs in three replication sample sets (7,473 cases, 5,984 controls) and identified three SNPs in SMAD7 (involved in TGF-beta and Wnt signaling) associated with CRC. Across the four sample sets, the association between rs4939827 and CRC was highly statistically significant (P(trend) = 1.0 x 10(-12)).
Published: 2007

35. Polymorphisms in Inflammation Pathway Genes and Endometrial Cancer Risk

Author: Herbert Yu, Maggie Gorman, Tracy A. O'Mara, Harvey A. Risch, Nurzhan Turmanov, Ingo B. Runnebaum, Helga B. Salvesen, Dylyara Kaydarova, Yong-Bing Xiang, Camilla Krakstad, Wei Zheng, An Coosemans, Rayna K. Matsuno, Thilo Dörk, Ying Zheng, Paul D.P. Pharoah, Amanda B. Spurdle, Mari K. Halle, Qiuyin Cai, Kimberley Howarth, Ian Tomlinson, Alison M. Dunning, Galina Lurie, Deborah J. Thompson, Wei Lu, Peter A. Fasching, Ryan J. Delahanty, Jone Trovik, Diether Lambrechts, Jirong Long, Natalia Dubrowinskaja, Matthias W. Beckmann, Ping-Ping Bao, Douglas F. Easton, Marc T. Goodman, Madeleine Corssen, Frédéric Amant, Alicia Beeghly-Fadiel, Lieve Coenegrachts, Felicity Lose, Alexander Hein, Arif B. Ekici, Xiao-Ou Shu, Lingeng Lu, Wanqing Wen, and Other departments
Subjects: China, Linkage disequilibrium, Epidemiology, Single-nucleotide polymorphism, Biology, Bioinformatics, Polymorphism, Single Nucleotide, Article, Linkage Disequilibrium, MSR1, Asian People, Risk Factors, Biomarkers, Tumor, medicine, Genetic predisposition, Humans, SNP, Genetic Predisposition to Disease, Neoplasm Staging, Oligonucleotide Array Sequence Analysis, Inflammation, Gene Expression Profiling, Endometrial cancer, Case-control study, Odds ratio, Middle Aged, Prognosis, medicine.disease, Endometrial Neoplasms, Oncology, Case-Control Studies, Female, Follow-Up Studies
Abstract: Background: Experimental and epidemiologic evidence have suggested that chronic inflammation may play a critical role in endometrial carcinogenesis. Methods: To investigate this hypothesis, a two-stage study was carried out to evaluate single-nucleotide polymorphisms (SNP) in inflammatory pathway genes in association with endometrial cancer risk. In stage I, 64 candidate pathway genes were identified and 4,542 directly genotyped or imputed SNPs were analyzed among 832 endometrial cancer cases and 2,049 controls, using data from the Shanghai Endometrial Cancer Genetics Study. Linkage disequilibrium of stage I SNPs significantly associated with endometrial cancer (P < 0.05) indicated that the majority of associations could be linked to one of 24 distinct loci. One SNP from each of the 24 loci was then selected for follow-up genotyping. Of these, 21 SNPs were successfully designed and genotyped in stage II, which consisted of 10 additional studies including 6,604 endometrial cancer cases and 8,511 controls. Results: Five of the 21 SNPs had significant allelic odds ratios (ORs) and 95% confidence intervals (CI) as follows: FABP1, 0.92 (0.85–0.99); CXCL3, 1.16 (1.05–1.29); IL6, 1.08 (1.00–1.17); MSR1, 0.90 (0.82–0.98); and MMP9, 0.91 (0.87–0.97). Two of these polymorphisms were independently significant in the replication sample (rs352038 in CXCL3 and rs3918249 in MMP9). The association for the MMP9 polymorphism remained significant after Bonferroni correction and showed a significant association with endometrial cancer in both Asian- and European-ancestry samples. Conclusions: These findings lend support to the hypothesis that genetic polymorphisms in genes involved in the inflammatory pathway may contribute to genetic susceptibility to endometrial cancer. Impact statement: This study adds to the growing evidence that inflammation plays an important role in endometrial carcinogenesis. Cancer Epidemiol Biomarkers Prev; 22(2); 216–23. ©2012 AACR.
Published: 2013

36. Genome-wide association study identifies a possible susceptibility locus for endometrial cancer

Author: Wei Lu, Qiuyin Cai, Helga B. Salvesen, Camilla Krakstad, Douglas F. Easton, Ying Zheng, Dilyara Kaidarova, Thilo Dörk, Rayna K. Matsuno, Nicolas Wentzensen, Galina Lurie, Yu-Tang Gao, Amanda B. Spurdle, Herbert Yu, Felicity Lose, Kimberley Howarth, Matthias Dürst, Rodney J. Scott, Maggie Gorman, Ryan J. Delahanty, Ian Tomlinson, Geoffrey Otton, Harvey A. Risch, Jolanta Lissowska, Marc T. Goodman, Deborah J. Thompson, Shirley Hodgson, Wei Zheng, Matthias W. Beckmann, Jirong Long, Yong-Bing Xiang, Bu-Tian Ji, Frédéric Amant, Catherine S. Healey, Louise A. Brinton, Arif B. Ekici, Jiajun Shi, Pamela J. Thompson, Ben Zhang, Hui Cai, Tracy A. O'Mara, Lieve Coenegrachts, Diether Lambrechts, Anthony Proietto, Alison M. Dunning, Jone Trovik, An Coosemans, Peter A. Fasching, Xiao-Ou Shu, Hannah P. Yang, Katie A. Ashton, Alexander Hein, Natalia Dubrowinskaja, Mari K. Halle, Ping-Ping Bao, Lingeng Lu, Nurzhan Turmanov, Anita Schwake, and Other departments
Subjects: Oncology, Linkage disequilibrium, medicine.medical_specialty, Epidemiology, Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, Risk Factors, Internal medicine, Genotype, medicine, SNP, Humans, Genetic Predisposition to Disease, Genetic association, Neoplasm Staging, Genetics, Chromosomes, Human, Pair 14, Endometrial cancer, Cancer, medicine.disease, Endometrial Neoplasms, Genetic Loci, Case-Control Studies, Female, Genome-Wide Association Study
Abstract: Background: Genome-wide association studies (GWAS) have identified more than 100 genetic loci for various cancers. However, only one is for endometrial cancer. Methods: We conducted a three-stage GWAS including 8,492 endometrial cancer cases and 16,596 controls. After analyzing 585,963 single-nucleotide polymorphisms (SNP) in 832 cases and 2,682 controls (stage I) from the Shanghai Endometrial Cancer Genetics Study, we selected the top 106 SNPs for in silico replication among 1,265 cases and 5,190 controls from the Australian/British Endometrial Cancer GWAS (stage II). Nine SNPs showed results consistent in direction with stage I with P < 0.1. These nine SNPs were investigated among 459 cases and 558 controls (stage IIIa) and six SNPs showed a direction of association consistent with stages I and II. These six SNPs, plus two additional SNPs selected on the basis of linkage disequilibrium and P values in stage II, were investigated among 5,936 cases and 8,166 controls from an additional 11 studies (stage IIIb). Results: SNP rs1202524, near the CAPN9 gene on chromosome 1q42.2, showed a consistent association with endometrial cancer risk across all three stages, with ORs of 1.09 [95% confidence interval (CI), 1.03–1.16] for the A/G genotype and 1.17 (95% CI, 1.05–1.30) for the G/G genotype (P = 1.6 × 10−4 in combined analyses of all samples). The association was stronger when limited to the endometrioid subtype, with ORs (95% CI) of 1.11 (1.04–1.18) and 1.21 (1.08–1.35), respectively (P = 2.4 × 10−5). Conclusions: Chromosome 1q42.2 may host an endometrial cancer susceptibility locus. Impact: This study identified a potential genetic locus for endometrial cancer risk. Cancer Epidemiol Biomarkers Prev; 21(6); 980–7. ©2012 AACR.
Published: 2012

37. Genome-wide association study identifies a common variant associated with risk of endometrial cancer

Author: Douglas F. Easton, Penelope M. Webb, Hannah P. Yang, Rodney J. Scott, Stephen B. Montgomery, Katie A. Ashton, Paul D.P. Pharoah, Shirley Hodgson, Alexander Hein, Harald Helland, Jianjun Liu, Kyriaki Michailidou, Amanda B. Spurdle, Maggie Gorman, Logan C. Walker, Tormund S. Njolstad, Mitul Shah, Matthias W. Beckmann, Arif B. Ekici, Stephen J. Chanock, Tracy A. O'Mara, Yong-Bing Xiang, Wei Zheng, Emmanouil T. Dermitzakis, Kaltin Ferguson, Montserrat Garcia-Closas, Xiao-Ou Shu, Helga B. Salvesen, Per Hall, Ignace Vergote, Frédéric Amant, Grant W. Montgomery, Kimberley Howarth, Tony Proietto, Diether Lambrechts, Nicolas Wentzensen, Kamila Czene, Catherine S. Healey, Jirong Long, Ian Tomlinson, Deborah J. Thompson, Peter A. Fasching, Lieve Coenegrachts, Shahana Ahmed, Paul Fahey, Jonathan J. Morrison, Jingmei Li, Geoffrey Otton, Alison M. Dunning, Jone Trovik, and Other departments
Subjects: Oncology, Adult, Male, medicine.medical_specialty, Adolescent, Genome-wide association study, Single-nucleotide polymorphism, Biology, Malignancy, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Prostate cancer, Young Adult, 0302 clinical medicine, Risk Factors, Internal medicine, Genetics, medicine, Odds Ratio, Humans, ddc:576.5, Genetic Predisposition to Disease, 030304 developmental biology, Aged, Hepatocyte Nuclear Factor 1-beta, Aged, 80 and over, 0303 health sciences, Prostatic Neoplasms/genetics, Endometrial cancer, Case-control study, Genetic Variation, Prostatic Neoplasms, Hepatocyte Nuclear Factor 1-beta/genetics, Odds ratio, Middle Aged, medicine.disease, 3. Good health, Genotype frequency, Endometrial Neoplasms, Diabetes Mellitus, Type 2, 030220 oncology & carcinogenesis, Case-Control Studies, Diabetes Mellitus, Type 2/genetics, Female, Endometrial Neoplasms/genetics, Genome-Wide Association Study
Abstract: Endometrial cancer is the most common malignancy of the female genital tract in developed countries. To identify genetic variants associated with endometrial cancer risk, we performed a genome-wide association study involving 1,265 individuals with endometrial cancer (cases) from Australia and the UK and 5,190 controls from the Wellcome Trust Case Control Consortium. We compared genotype frequencies in cases and controls for 519,655 SNPs. Forty seven SNPs that showed evidence of association with endometrial cancer in stage 1 were genotyped in 3,957 additional cases and 6,886 controls. We identified an endometrial cancer susceptibility locus close to HNF1B at 17q12 (rs4430796, P = 7.1 × 10-10) that is also associated with risk of prostate cancer and is inversely associated with risk of type 2 diabetes. © 2011 Nature America, Inc. All rights reserved.
Published: 2011

38. Clonality assessment and clonal ordering of individual neoplastic crypts shows polyclonality of colorectal adenomas

Author: O. C. C. Will, Manuel Rodriguez–Justo, Marco Novelli, Nicholas A. Wright, Jo-Anne Chin Aleong, Ian Tomlinson, Maggie Gorman, Simon J. Leedham, Dahmane Oukrif, Enric Domingo, Trevor A. Graham, Janusz Jankowski, Stuart McDonald, Susan K. Clark, Christina Thirlwell, and Rosemary Jeffrey
Subjects: Adenoma, Pathology, medicine.medical_specialty, Genes, APC, Hepatology, medicine.diagnostic_test, Adenomatous polyposis coli, Gastroenterology, Loss of Heterozygosity, Biology, medicine.disease, Somatic evolution in cancer, Familial adenomatous polyposis, Loss of heterozygosity, Germline mutation, Attenuated familial adenomatous polyposis, Mutation, Cancer research, medicine, biology.protein, Humans, Colorectal Neoplasms, In Situ Hybridization, Fluorescence, Fluorescence in situ hybridization
Abstract: BACKGROUND and AIMS: According to the somatic mutation theory, monoclonal colorectal lesions arise from sequential mutations in the progeny of a single stem cell. However, studies in a sex chromosome mixoploid mosaic (XO/XY) patient indicated that colorectal adenomas were polyclonal. We assessed adenoma clonality on an individual crypt basis and completed a genetic dependency analysis in carcinomas-in-adenomas to assess mutation order and timing. METHODS: Polyp samples were analyzed from the XO/XY individual, patients with familial adenomatous polyposis and attenuated familial adenomatous polyposis, patients with small sporadic adenomas, and patients with sporadic carcinoma-in-adenomas. Clonality was analyzed using X/Y chromosome fluorescence in situ hybridization, analysis of 5q loss of heterozygosity in XO/XY tissue, and sequencing of adenomatous polyposis coli. Individual crypts and different phenotypic areas of carcinoma-in-adenoma lesions were analyzed for mutations in adenomatous polyposis coli, p53, and K-RAS; loss of heterozygosity at 5q, 17p, and 18q; and aneuploidy. Phylogenetic trees were constructed. RESULTS: All familial adenomatous polyposis-associated adenomas and some sporadic lesions had polyclonal genetic defects. Some independent clones appeared to be maintained in advanced adenomas. No clear obligate order of genetic events was established. Top-down growth of dysplastic tissue into neighboring crypts was a possible mechanism of clonal competition. CONCLUSIONS: Human colorectal microadenomas are polyclonal and may arise from a combination of host genetic features, mucosal exposures, and active crypt interactions. Analyses of tumor phylogenies show that most lesions undergo intermittent genetic homogenization, but heterotypic mutation patterns indicate that independent clonal evolution can occur throughout adenoma development. Based on observations of clonal ordering the requirement and timing of genetic events during neoplastic progression may be more variable than previously thought.
Published: 2009

39. Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk

Author: Zoe Kemp, Axel Walther, Steven J. Lubbe, Ian Tomlinson, Alan M. Pittman, Lynn Martin, Luis G. Carvajal-Carmona, Richard S. Houlston, Andrew Rowan, Albert Tenesa, Sarah L. Spain, Susan M. Farrington, Kate Sullivan, Huw Thomas, Julian Peto, David J. Kerr, Emily L. Webb, Ian Chandler, Karl Heinimann, Enric Domingo, Emma Jaeger, Malcolm G. Dunlop, Ella Barclay, Jean-Baptiste Cazier, Steven Penegar, Harry Campbell, Maggie Gorman, Richard Gray, Peter Broderick, Wendy Wood, Kimberley Howarth, Elli Papaemmanuil, Jayaram Vijayakrishnan, and Mobshra Qureshi
Subjects: Adenoma, Genetics, Chromosomes, Human, Pair 15, education.field_of_study, Colorectal cancer, Population, Chromosome, Cancer, Genome-wide association study, Locus (genetics), Single-nucleotide polymorphism, Biology, medicine.disease, Polymorphism, Single Nucleotide, Chromosome 15, Cell Line, Tumor, Jews, medicine, Humans, Genetic Predisposition to Disease, Colorectal Neoplasms, education, Cells, Cultured
Abstract: We mapped a high-penetrance gene (CRAC1; also known as HMPS) associated with colorectal cancer (CRC) in the Ashkenazi population to a 0.6-Mb region on chromosome 15 containing SCG5 (also known as SGNE1), GREM1 and FMN1. We hypothesized that the CRAC1 locus harbored low-penetrance variants that increased CRC risk in the general population. In a large series of colorectal cancer cases and controls, SNPs near GREM1 and SCG5 were strongly associated with increased CRC risk (for rs4779584, P = 4.44 x 10(-14)).
Published: 2008

40. A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21

Author: Sarah Fielding, Richard Gray, Wendy Wood, Elaine C. Johnstone, David J. Kerr, Kimberley Howarth, Ruth Wild, Richard A. Hubner, Emma Jaeger, Luis G. Carvajal-Carmona, Ian Chandler, Ian Tomlinson, Ella Barclay, Steven J. Lubbe, Andrew Rowan, Wendy Atkin, Sarah L. Spain, Gabrielle S. Sellick, Julian Peto, Oliver M. Sieber, Richard F A Logan, Zoe Kemp, Lynn Martin, Jean-Baptiste Cazier, Kenneth Muir, Richard S. Houlston, Huw Thomas, Emily L. Webb, Steven Penegar, Andrew Silver, Maggie Gorman, and Peter Broderick
Subjects: Genetics, Male, Genotype, Colorectal cancer, Single-nucleotide polymorphism, Colorectal adenoma, Odds ratio, Biology, Middle Aged, medicine.disease, Polymorphism, Single Nucleotide, Polymorphism (computer science), medicine, SNP, Humans, Female, Genetic Predisposition to Disease, Allele, Colorectal Neoplasms, Aged, Chromosomes, Human, Pair 8
Abstract: Much of the variation in inherited risk of colorectal cancer (CRC) is probably due to combinations of common low risk variants. We conducted a genome- wide association study of 550,000 tag SNPs in 930 familial colorectal tumor cases and 960 controls. The most strongly associated SNP (P = 1.72 x 10(-7), allelic test) was rs6983267 at 8q24.21. To validate this finding, we genotyped rs6983267 in three additional CRC case-control series (4,361 affected individuals and 3,752 controls; 1,901 affected individuals and 1,079 controls; 1,072 affected individuals and 415 controls) and replicated the association, providing P = 1.27 x 10(-14) (allelic test) overall, with odds ratios (ORs) of 1.27 (95% confidence interval (c.i.): 1.16-1.39) and 1.47 (95% c.i.: 1.34-1.62) for heterozygotes and rare homozygotes, respectively. Analyses based on 1,477 individuals with colorectal adenoma and 2,136 controls suggest that susceptibility to CRC is mediated through development of adenomas (OR = 1.21, 95% c.i.: 1.10-1.34; P = 6.89 x 10(-5)). These data show that common, low-penetrance susceptibility alleles predispose to colorectal neoplasia.
Published: 2007

41. Molecular classification and genetic pathways in hyperplastic polyposis syndrome

Author: Ella Barclay, Brian P. Saunders, J. Paterson, Andrew Silver, Luis G. Carvajal-Carmona, Marco Novelli, Thomas Guenther, R. K. S. Phillips, Kimberley Howarth, Maggie Gorman, Huw Thomas, Lynn Martin, Guadalupe Polanco-Echeverry, Alan Donaldson, Ian Tomlinson, Ian M. Frayling, Wendy Atkin, Emmanouil Volikos, Angela M. Jones, and M. Lockett
Subjects: Adult, Male, Proto-Oncogene Proteins B-raf, medicine.medical_specialty, Adolescent, Colorectal cancer, Loss of Heterozygosity, medicine.disease_cause, Gastroenterology, Pathology and Forensic Medicine, Loss of heterozygosity, Proto-Oncogene Proteins p21(ras), Intestinal mucosa, Internal medicine, Proto-Oncogene Proteins, Medicine, Humans, Genetic Predisposition to Disease, Intestinal Mucosa, Child, neoplasms, Aged, Mutation, Hyperplasia, business.industry, Intestinal Polyposis, Microsatellite instability, Anatomical pathology, Middle Aged, medicine.disease, digestive system diseases, Neoplasm Proteins, Cell Transformation, Neoplastic, Phenotype, Hyperplastic Polyp, Cancer research, ras Proteins, Female, business, Carcinogenesis, Colorectal Neoplasms
Abstract: Hyperplastic Polyposis (HPPS) is a poorly characterized syndrome that increases colorectal cancer (CRC) risk. We aimed to provide a molecular classification of HPPS. We obtained 282 tumours from 32 putative HPPS patients with >or= 10 hyperplastic polyps (HPs); some patients also had adenomas and CRCs. We found no good evidence of microsatellite instability (MSI) in our samples. The epithelium of HPs was monoclonal. Somatic BRAF mutations occurred in two-thirds of our patients' HPs, and KRAS2 mutations in 10%; both mutations were more common in younger cases. The respective mutation frequencies in a set of 'sporadic' HPs were 18% and 10%. Importantly, the putative HPPS patients generally fell into two readily defined groups, one set whose polyps had BRAF mutations, and another set whose polyps had KRAS2 mutations. The most plausible explanation for this observation is that there exist different forms of inherited predisposition to HPPS, and that these determine whether polyps follow a BRAF or KRAS2 pathway. Most adenomas and CRCs from our putative HPPS patients had 'classical' morphology and few of these lesions had BRAF or KRAS2 mutations. These findings suggest that tumourigenesis in HPPS does not necessarily follow the 'serrated' pathway. Although current definitions of HPPS are sub-optimal, we suggest that diagnosis could benefit from molecular analysis. Specifically, testing BRAF and KRAS2 mutations, and perhaps MSI, in multiple polyps could help to distinguish HPPS from sporadic HPs. We propose a specific model which would have diagnosed five more of our cases as HPPS compared with the WHO clinical criteria.
Published: 2007

42. Genetic overlap between endometriosis and endometrial cancer: evidence from cross‐disease genetic correlation and GWAS meta‐analyses

Author: Diether Lambrechts, Dale R. Nyholt, Matthias Rübner, Graham G. Giles, Katie A. Ashton, Camilla Krakstad, Catherine S. Healey, Alexander Hein, Miriam Mints, Anthony J. Swerdlow, Tony Proietto, Matthias Dürst, Jenny Chang-Claude, Jeroen Depreeuw, Shahana Ahmed, Joe Dennis, Elizabeth G. Holliday, Anjali K. Henders, Angela Cox, Arif B. Ekici, Julian Peto, Peter A. Fasching, Stuart MacGregor, Barbara Burwinkel, Mark McEvoy, Grant W. Montgomery, Henrica M.J. Werner, Frédéric Amant, Annika Lindblom, Stacey J. Winham, Manjeet K. Bolla, Thilo Dörk, Rodney J. Scott, Peter Hillemanns, Hermann Brenner, Julie M. Cunningham, Timothy H.T. Cheng, Ellen L. Goode, Geoffrey Otton, Andrew P. Morris, Emma Tham, Fergus J. Couch, Erling A. Hoivik, Ingo B. Runnebaum, Krina T. Zondervan, Vessela N. Kristensen, Jonathan Tyrer, Mitul Shah, Matthias W. Beckmann, Kyriaki Michailidou, John Attia, Paul D.P. Pharoah, Sean C. Dowdy, Penelope M. Webb, Douglas F. Easton, Per Hall, Adriaan Vanderstichele, Daniela Annibali, Lynn Martin, Tracy A. O'Mara, Ian Tomlinson, Amanda B. Spurdle, Deborah J. Thompson, Qin Wang, Maggie Gorman, Angela Jones, Hiltrud Brauch, Scott D. Gordon, Kamila Czene, John L. Hopper, Alfons Meindl, Nicholas G. Martin, Jodie N. Painter, Alison M. Dunning, Jone Trovik, Shirley Hodson, CCA - Cancer biology and immunology, Obstetrics and Gynaecology, ARD - Amsterdam Reproduction and Development, Painter, Jodie N [0000-0002-4992-2458], Fasching, Peter A [0000-0003-4885-8471], Dörk, Thilo [0000-0002-9458-0282], Lambrechts, Diether [0000-0002-2402-4029], Goode, Ellen L [0000-0002-9094-8326], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Oncology, endometriosis, STAT3 Transcription Factor, Cancer Research, medicine.medical_specialty, Concordance, Endometriosis, Genome-wide association study, Disease, Cross-disease analysis, Genetic correlation, Polymorphism, Single Nucleotide, 03 medical and health sciences, Endometrium, Internal medicine, Medicine, SNP, Humans, Radiology, Nuclear Medicine and imaging, Genetic Predisposition to Disease, Original Research, Cancer Biology, genome‐wide association study, business.industry, Endometrial cancer, Cross‐disease analysis, Australia, Receptor-Like Protein Tyrosine Phosphatases, Class 2, medicine.disease, genetic correlation, 3. Good health, Endometrial Neoplasms, 030104 developmental biology, endometrial cancer, Female, business, Ovarian cancer, Genome-Wide Association Study
Abstract: Epidemiological, biological, and molecular data suggest links between endometriosis and endometrial cancer, with recent epidemiological studies providing evidence for an association between a previous diagnosis of endometriosis and risk of endometrial cancer. We used genetic data as an alternative approach to investigate shared biological etiology of these two diseases. Genetic correlation analysis of summary level statistics from genomewide association studies (GWAS) using LD Score regression revealed moderate but significant genetic correlation (r = 0.23, P = 9.3 × 10 ), and SNP effect concordance analysis provided evidence for significant SNP pleiotropy (P = 6.0 × 10 ) and concordance in effect direction (P = 2.0 × 10 ) between the two diseases. Cross-disease GWAS meta-analysis highlighted 13 distinct loci associated at P ≤ 10 with both endometriosis and endometrial cancer, with one locus (SNP rs2475335) located within PTPRD associated at a genomewide significant level (P = 4.9 × 10 , OR = 1.11, 95% CI = 1.07-1.15). PTPRD acts in the STAT3 pathway, which has been implicated in both endometriosis and endometrial cancer. This study demonstrates the value of cross-disease genetic analysis to support epidemiological observations and to identify biological pathways of relevance to multiple diseases. ispartof: Cancer Medicine vol:7 issue:5 pages:1978-1987 ispartof: location:United States status: published
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