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1. 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

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

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