Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1

Timothy H.T. Cheng; Deborah Thompson; Jodie Painter; Tracy Omara; Maggie Gorman; Lynn Martin; Claire Palles; Angela Jones; Daniel D. Buchanan; Aung Ko Win; John Hopper; Mark Jenkins; Noralane M. Lindor; Polly A. Newcomb; Steve Gallinger; David Conti; Fred Schumacher; Graham Casey; Graham G. Giles; Paul Pharoah; Julian Peto; Angela Cox; Anthony Swerdlow; Fergus Couch; Julie M. Cunningham; Ellen L. Goode; Stacey J. Winham; Diether Lambrechts; Peter Fasching; Barbara Burwinkel; Hermann Brenner; Hiltrud Brauch; Jenny Chang-Claude; Helga B. Salvesen; Vessela Kristensen; Hatef Darabi; Jingmei Li; Tao Liu; Annika Lindblom; Per Hall; Magdalena Echeverry De Polanco; Monica Sans; Angel Carracedo; Sergi Castellvi-Bel; Augusto Rojas-Martinez; Samuel Aguiar Jnr; Manuel R. Teixeira; Alison M. Dunning; Joe Dennis; Geoffrey Otton; Tony Proietto; Elizabeth Holliday; John Attia; Katie Ashton; Rodney J. Scott; Mark McEvoy; Sean C. Dowdy; Brooke L. Fridley; Henrica M.J. Werner; Jone Trovik; Tormund S. Njolstad; Emma Tham; Miriam Mints; Ingo Runnebaum; Peter Hillemanns; Thilo Dörk; Frederic Amant; Stefanie Schrauwen; Alexander Hein; Matthias W. Beckmann; Arif Ekici; Kamila Czene; Alfons Meindl; Manjeet K. Bolla; Kyriaki Michailidou; Jonathan P. Tyrer; Qin Wang; Shahana Ahmed; Catherine S. Healey; Mitul Shah; Daniela Annibali; Jeroen Depreeuw; Nada A. Al-Tassan; Rebecca Harris; Brian F. Meyer; Nicola Whiffin; Fay J. Hosking; Ben Kinnersley; Susan M. Farrington; Maria Timofeeva; Albert Tenesa; Harry Campbell; Robert W. Haile; Shirley Hodgson; Luis Carvajal-Carmona; Jeremy P. Cheadle; Douglas Easton; Malcolm Dunlop; Richard Houlston; Amanda Spurdle; Ian Tomlinson

doi:10.1038/srep17369

Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1

Timothy H.T. Cheng, Deborah Thompson, Jodie Painter, Tracy Omara, Maggie Gorman, Lynn Martin, Claire Palles, Angela Jones, Daniel D. Buchanan, Aung Ko Win, John Hopper, Mark Jenkins, Noralane M. Lindor, Polly A. Newcomb, Steve Gallinger, David Conti, Fred Schumacher, Graham Casey, Graham G. Giles, Paul PharoahJulian Peto, Angela Cox, Anthony Swerdlow, Fergus Couch, Julie M. Cunningham, Ellen L. Goode, Stacey J. Winham, Diether Lambrechts, Peter Fasching, Barbara Burwinkel, Hermann Brenner, Hiltrud Brauch, Jenny Chang-Claude, Helga B. Salvesen, Vessela Kristensen, Hatef Darabi, Jingmei Li, Tao Liu, Annika Lindblom, Per Hall, Magdalena Echeverry De Polanco, Monica Sans, Angel Carracedo, Sergi Castellvi-Bel, Augusto Rojas-Martinez, Samuel Aguiar Jnr, Manuel R. Teixeira, Alison M. Dunning, Joe Dennis, Geoffrey Otton, Tony Proietto, Elizabeth Holliday, John Attia, Katie Ashton, Rodney J. Scott, Mark McEvoy, Sean C. Dowdy, Brooke L. Fridley, Henrica M.J. Werner, Jone Trovik, Tormund S. Njolstad, Emma Tham, Miriam Mints, Ingo Runnebaum, Peter Hillemanns, Thilo Dörk, Frederic Amant, Stefanie Schrauwen, Alexander Hein, Matthias W. Beckmann, Arif Ekici, Kamila Czene, Alfons Meindl, Manjeet K. Bolla, Kyriaki Michailidou, Jonathan P. Tyrer, Qin Wang, Shahana Ahmed, Catherine S. Healey, Mitul Shah, Daniela Annibali, Jeroen Depreeuw, Nada A. Al-Tassan, Rebecca Harris, Brian F. Meyer, Nicola Whiffin, Fay J. Hosking, Ben Kinnersley, Susan M. Farrington, Maria Timofeeva, Albert Tenesa, Harry Campbell, Robert W. Haile, Shirley Hodgson, Luis Carvajal-Carmona, Jeremy P. Cheadle, Douglas Easton, Malcolm Dunlop, Richard Houlston, Amanda Spurdle, Ian Tomlinson

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Abstract

High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10^-9) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10^-8), with the alleles showing opposite effects on the risks of the two cancers.

Original language	English (US)
Article number	17369
Journal	Scientific reports
Volume	5
DOIs	https://doi.org/10.1038/srep17369
State	Published - Dec 1 2015

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Cheng, T. H. T., Thompson, D., Painter, J., Omara, T., Gorman, M., Martin, L., Palles, C., Jones, A., Buchanan, D. D., Ko Win, A., Hopper, J., Jenkins, M., Lindor, N. M., Newcomb, P. A., Gallinger, S., Conti, D., Schumacher, F., Casey, G., Giles, G. G., ... Tomlinson, I. (2015). Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1. Scientific reports, 5, [17369]. https://doi.org/10.1038/srep17369

Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1. / Cheng, Timothy H.T.; Thompson, Deborah; Painter, Jodie; Omara, Tracy; Gorman, Maggie; Martin, Lynn; Palles, Claire; Jones, Angela; Buchanan, Daniel D.; Ko Win, Aung; Hopper, John; Jenkins, Mark; Lindor, Noralane M.; Newcomb, Polly A.; Gallinger, Steve; Conti, David; Schumacher, Fred; Casey, Graham; Giles, Graham G.; Pharoah, Paul; Peto, Julian; Cox, Angela; Swerdlow, Anthony; Couch, Fergus ; Cunningham, Julie M.; Goode, Ellen L.; Winham, Stacey J.; Lambrechts, Diether; Fasching, Peter; Burwinkel, Barbara; Brenner, Hermann; Brauch, Hiltrud; Chang-Claude, Jenny; Salvesen, Helga B.; Kristensen, Vessela; Darabi, Hatef; Li, Jingmei; Liu, Tao; Lindblom, Annika; Hall, Per; De Polanco, Magdalena Echeverry; Sans, Monica; Carracedo, Angel; Castellvi-Bel, Sergi; Rojas-Martinez, Augusto; Aguiar Jnr, Samuel; Teixeira, Manuel R.; Dunning, Alison M.; Dennis, Joe; Otton, Geoffrey; Proietto, Tony; Holliday, Elizabeth; Attia, John; Ashton, Katie; Scott, Rodney J.; McEvoy, Mark; Dowdy, Sean C.; Fridley, Brooke L.; Werner, Henrica M.J.; Trovik, Jone; Njolstad, Tormund S.; Tham, Emma; Mints, Miriam; Runnebaum, Ingo; Hillemanns, Peter; Dörk, Thilo; Amant, Frederic; Schrauwen, Stefanie; Hein, Alexander; Beckmann, Matthias W.; Ekici, Arif; Czene, Kamila; Meindl, Alfons; Bolla, Manjeet K.; Michailidou, Kyriaki; Tyrer, Jonathan P.; Wang, Qin; Ahmed, Shahana; Healey, Catherine S.; Shah, Mitul; Annibali, Daniela; Depreeuw, Jeroen; Al-Tassan, Nada A.; Harris, Rebecca; Meyer, Brian F.; Whiffin, Nicola; Hosking, Fay J.; Kinnersley, Ben; Farrington, Susan M.; Timofeeva, Maria; Tenesa, Albert; Campbell, Harry; Haile, Robert W.; Hodgson, Shirley; Carvajal-Carmona, Luis; Cheadle, Jeremy P.; Easton, Douglas; Dunlop, Malcolm; Houlston, Richard; Spurdle, Amanda; Tomlinson, Ian.

In: Scientific reports, Vol. 5, 17369, 01.12.2015.

Research output: Contribution to journal › Article › peer-review

Cheng, THT, Thompson, D, Painter, J, Omara, T, Gorman, M, Martin, L, Palles, C, Jones, A, Buchanan, DD, Ko Win, A, Hopper, J, Jenkins, M, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Giles, GG, Pharoah, P, Peto, J, Cox, A, Swerdlow, A, Couch, F , Cunningham, JM , Goode, EL , Winham, SJ, Lambrechts, D, Fasching, P, Burwinkel, B, Brenner, H, Brauch, H, Chang-Claude, J, Salvesen, HB, Kristensen, V, Darabi, H, Li, J, Liu, T, Lindblom, A, Hall, P, De Polanco, ME, Sans, M, Carracedo, A, Castellvi-Bel, S, Rojas-Martinez, A, Aguiar Jnr, S, Teixeira, MR, Dunning, AM, Dennis, J, Otton, G, Proietto, T, Holliday, E, Attia, J, Ashton, K, Scott, RJ, McEvoy, M, Dowdy, SC, Fridley, BL, Werner, HMJ, Trovik, J, Njolstad, TS, Tham, E, Mints, M, Runnebaum, I, Hillemanns, P, Dörk, T, Amant, F, Schrauwen, S, Hein, A, Beckmann, MW, Ekici, A, Czene, K, Meindl, A, Bolla, MK, Michailidou, K, Tyrer, JP, Wang, Q, Ahmed, S, Healey, CS, Shah, M, Annibali, D, Depreeuw, J, Al-Tassan, NA, Harris, R, Meyer, BF, Whiffin, N, Hosking, FJ, Kinnersley, B, Farrington, SM, Timofeeva, M, Tenesa, A, Campbell, H, Haile, RW, Hodgson, S, Carvajal-Carmona, L, Cheadle, JP, Easton, D, Dunlop, M, Houlston, R, Spurdle, A & Tomlinson, I 2015, 'Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1', Scientific reports, vol. 5, 17369. https://doi.org/10.1038/srep17369

Cheng, Timothy H.T. ; Thompson, Deborah ; Painter, Jodie ; Omara, Tracy ; Gorman, Maggie ; Martin, Lynn ; Palles, Claire ; Jones, Angela ; Buchanan, Daniel D. ; Ko Win, Aung ; Hopper, John ; Jenkins, Mark ; Lindor, Noralane M. ; Newcomb, Polly A. ; Gallinger, Steve ; Conti, David ; Schumacher, Fred ; Casey, Graham ; Giles, Graham G. ; Pharoah, Paul ; Peto, Julian ; Cox, Angela ; Swerdlow, Anthony ; Couch, Fergus ; Cunningham, Julie M. ; Goode, Ellen L. ; Winham, Stacey J. ; Lambrechts, Diether ; Fasching, Peter ; Burwinkel, Barbara ; Brenner, Hermann ; Brauch, Hiltrud ; Chang-Claude, Jenny ; Salvesen, Helga B. ; Kristensen, Vessela ; Darabi, Hatef ; Li, Jingmei ; Liu, Tao ; Lindblom, Annika ; Hall, Per ; De Polanco, Magdalena Echeverry ; Sans, Monica ; Carracedo, Angel ; Castellvi-Bel, Sergi ; Rojas-Martinez, Augusto ; Aguiar Jnr, Samuel ; Teixeira, Manuel R. ; Dunning, Alison M. ; Dennis, Joe ; Otton, Geoffrey ; Proietto, Tony ; Holliday, Elizabeth ; Attia, John ; Ashton, Katie ; Scott, Rodney J. ; McEvoy, Mark ; Dowdy, Sean C. ; Fridley, Brooke L. ; Werner, Henrica M.J. ; Trovik, Jone ; Njolstad, Tormund S. ; Tham, Emma ; Mints, Miriam ; Runnebaum, Ingo ; Hillemanns, Peter ; Dörk, Thilo ; Amant, Frederic ; Schrauwen, Stefanie ; Hein, Alexander ; Beckmann, Matthias W. ; Ekici, Arif ; Czene, Kamila ; Meindl, Alfons ; Bolla, Manjeet K. ; Michailidou, Kyriaki ; Tyrer, Jonathan P. ; Wang, Qin ; Ahmed, Shahana ; Healey, Catherine S. ; Shah, Mitul ; Annibali, Daniela ; Depreeuw, Jeroen ; Al-Tassan, Nada A. ; Harris, Rebecca ; Meyer, Brian F. ; Whiffin, Nicola ; Hosking, Fay J. ; Kinnersley, Ben ; Farrington, Susan M. ; Timofeeva, Maria ; Tenesa, Albert ; Campbell, Harry ; Haile, Robert W. ; Hodgson, Shirley ; Carvajal-Carmona, Luis ; Cheadle, Jeremy P. ; Easton, Douglas ; Dunlop, Malcolm ; Houlston, Richard ; Spurdle, Amanda ; Tomlinson, Ian. / Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1. In: Scientific reports. 2015 ; Vol. 5.

@article{2149e239d3574fde95e71ce08dbae912,

title = "Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1",

abstract = "High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10-9) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10-8), with the alleles showing opposite effects on the risks of the two cancers.",

author = "Cheng, {Timothy H.T.} and Deborah Thompson and Jodie Painter and Tracy Omara and Maggie Gorman and Lynn Martin and Claire Palles and Angela Jones and Buchanan, {Daniel D.} and {Ko Win}, Aung and John Hopper and Mark Jenkins and Lindor, {Noralane M.} and Newcomb, {Polly A.} and Steve Gallinger and David Conti and Fred Schumacher and Graham Casey and Giles, {Graham G.} and Paul Pharoah and Julian Peto and Angela Cox and Anthony Swerdlow and Fergus Couch and Cunningham, {Julie M.} and Goode, {Ellen L.} and Winham, {Stacey J.} and Diether Lambrechts and Peter Fasching and Barbara Burwinkel and Hermann Brenner and Hiltrud Brauch and Jenny Chang-Claude and Salvesen, {Helga B.} and Vessela Kristensen and Hatef Darabi and Jingmei Li and Tao Liu and Annika Lindblom and Per Hall and {De Polanco}, {Magdalena Echeverry} and Monica Sans and Angel Carracedo and Sergi Castellvi-Bel and Augusto Rojas-Martinez and {Aguiar Jnr}, Samuel and Teixeira, {Manuel R.} and Dunning, {Alison M.} and Joe Dennis and Geoffrey Otton and Tony Proietto and Elizabeth Holliday and John Attia and Katie Ashton and Scott, {Rodney J.} and Mark McEvoy and Dowdy, {Sean C.} and Fridley, {Brooke L.} and Werner, {Henrica M.J.} and Jone Trovik and Njolstad, {Tormund S.} and Emma Tham and Miriam Mints and Ingo Runnebaum and Peter Hillemanns and Thilo D{\"o}rk and Frederic Amant and Stefanie Schrauwen and Alexander Hein and Beckmann, {Matthias W.} and Arif Ekici and Kamila Czene and Alfons Meindl and Bolla, {Manjeet K.} and Kyriaki Michailidou and Tyrer, {Jonathan P.} and Qin Wang and Shahana Ahmed and Healey, {Catherine S.} and Mitul Shah and Daniela Annibali and Jeroen Depreeuw and Al-Tassan, {Nada A.} and Rebecca Harris and Meyer, {Brian F.} and Nicola Whiffin and Hosking, {Fay J.} and Ben Kinnersley and Farrington, {Susan M.} and Maria Timofeeva and Albert Tenesa and Harry Campbell and Haile, {Robert W.} and Shirley Hodgson and Luis Carvajal-Carmona and Cheadle, {Jeremy P.} and Douglas Easton and Malcolm Dunlop and Richard Houlston and Amanda Spurdle and Ian Tomlinson",

note = "Funding Information: We are grateful for funding to the Oxford NIHR Comprehensive Biomedical Research Centre. Core funding to the Wellcome Trust Centre for Human Genetics was provided by the Wellcome Trust (090532/Z/09/Z). The European colorectal cancer data were supported by COST Action BM1206. We thank Breakthrough Breast Cancer and the Institute of Cancer Research for support and funding of the Breakthrough Generations Study, and the study participants, study staff, and the doctors, nurses and other health care providers and health information sources who have contributed to the study. We acknowledge NHS funding to the Royal Marsden/ICR NIHR Biomedical Research Centre. The Colon CFR was supported by grant UM1 CA167551 from the National Cancer Institute and through cooperative agreements with the following CCFR centres: Australasian Colorectal Cancer Family Registry, Mayo Clinic Cooperative Family Registry for Colon Cancer Studies, Ontario Familial Colorectal Cancer Registry, Seattle Colorectal Cancer Family Registry, USC Consortium Colorectal Cancer Family Registry. The Colon CFR GWAS was supported by funding from the National Cancer Institute, National Institutes of Health (U01 CA122839 and R01 CA143237 to Graham Casey). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the Colon Cancer Family Registry (CCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the CCFR. Jeremy P. Cheadle was funded by the Bobby Moore Fund from Cancer Research UK, Tenovus, the Kidani Trust, Cancer Research Wales and the National Institute for Social Care and Health Research Cancer Genetics Biomedical Research Unit. Nada A. Al-Tassan and Brian F. Meyer were funded and supported by KFSHRC. Luis Carvajal-Carmona receives founding from The V Foundation for Cancer Research.The authors would also like to acknowledge The Australian Ovarian Cancer Study (AOCS) group. A full list of the participants and their affiliations appears in the suppplementary information file that is appended to this article.",

year = "2015",

month = dec,

day = "1",

doi = "10.1038/srep17369",

language = "English (US)",

volume = "5",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1

AU - Cheng, Timothy H.T.

AU - Thompson, Deborah

AU - Painter, Jodie

AU - Omara, Tracy

AU - Gorman, Maggie

AU - Martin, Lynn

AU - Palles, Claire

AU - Jones, Angela

AU - Buchanan, Daniel D.

AU - Ko Win, Aung

AU - Hopper, John

AU - Jenkins, Mark

AU - Lindor, Noralane M.

AU - Newcomb, Polly A.

AU - Gallinger, Steve

AU - Conti, David

AU - Schumacher, Fred

AU - Casey, Graham

AU - Giles, Graham G.

AU - Pharoah, Paul

AU - Peto, Julian

AU - Cox, Angela

AU - Swerdlow, Anthony

AU - Couch, Fergus

AU - Cunningham, Julie M.

AU - Goode, Ellen L.

AU - Winham, Stacey J.

AU - Lambrechts, Diether

AU - Fasching, Peter

AU - Burwinkel, Barbara

AU - Brenner, Hermann

AU - Brauch, Hiltrud

AU - Chang-Claude, Jenny

AU - Salvesen, Helga B.

AU - Kristensen, Vessela

AU - Darabi, Hatef

AU - Li, Jingmei

AU - Liu, Tao

AU - Lindblom, Annika

AU - Hall, Per

AU - De Polanco, Magdalena Echeverry

AU - Sans, Monica

AU - Carracedo, Angel

AU - Castellvi-Bel, Sergi

AU - Rojas-Martinez, Augusto

AU - Aguiar Jnr, Samuel

AU - Teixeira, Manuel R.

AU - Dunning, Alison M.

AU - Dennis, Joe

AU - Otton, Geoffrey

AU - Proietto, Tony

AU - Holliday, Elizabeth

AU - Attia, John

AU - Ashton, Katie

AU - Scott, Rodney J.

AU - McEvoy, Mark

AU - Dowdy, Sean C.

AU - Fridley, Brooke L.

AU - Werner, Henrica M.J.

AU - Trovik, Jone

AU - Njolstad, Tormund S.

AU - Tham, Emma

AU - Mints, Miriam

AU - Runnebaum, Ingo

AU - Hillemanns, Peter

AU - Dörk, Thilo

AU - Amant, Frederic

AU - Schrauwen, Stefanie

AU - Hein, Alexander

AU - Beckmann, Matthias W.

AU - Ekici, Arif

AU - Czene, Kamila

AU - Meindl, Alfons

AU - Bolla, Manjeet K.

AU - Michailidou, Kyriaki

AU - Tyrer, Jonathan P.

AU - Wang, Qin

AU - Ahmed, Shahana

AU - Healey, Catherine S.

AU - Shah, Mitul

AU - Annibali, Daniela

AU - Depreeuw, Jeroen

AU - Al-Tassan, Nada A.

AU - Harris, Rebecca

AU - Meyer, Brian F.

AU - Whiffin, Nicola

AU - Hosking, Fay J.

AU - Kinnersley, Ben

AU - Farrington, Susan M.

AU - Timofeeva, Maria

AU - Tenesa, Albert

AU - Campbell, Harry

AU - Haile, Robert W.

AU - Hodgson, Shirley

AU - Carvajal-Carmona, Luis

AU - Cheadle, Jeremy P.

AU - Easton, Douglas

AU - Dunlop, Malcolm

AU - Houlston, Richard

AU - Spurdle, Amanda

AU - Tomlinson, Ian

N1 - Funding Information: We are grateful for funding to the Oxford NIHR Comprehensive Biomedical Research Centre. Core funding to the Wellcome Trust Centre for Human Genetics was provided by the Wellcome Trust (090532/Z/09/Z). The European colorectal cancer data were supported by COST Action BM1206. We thank Breakthrough Breast Cancer and the Institute of Cancer Research for support and funding of the Breakthrough Generations Study, and the study participants, study staff, and the doctors, nurses and other health care providers and health information sources who have contributed to the study. We acknowledge NHS funding to the Royal Marsden/ICR NIHR Biomedical Research Centre. The Colon CFR was supported by grant UM1 CA167551 from the National Cancer Institute and through cooperative agreements with the following CCFR centres: Australasian Colorectal Cancer Family Registry, Mayo Clinic Cooperative Family Registry for Colon Cancer Studies, Ontario Familial Colorectal Cancer Registry, Seattle Colorectal Cancer Family Registry, USC Consortium Colorectal Cancer Family Registry. The Colon CFR GWAS was supported by funding from the National Cancer Institute, National Institutes of Health (U01 CA122839 and R01 CA143237 to Graham Casey). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the Colon Cancer Family Registry (CCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the CCFR. Jeremy P. Cheadle was funded by the Bobby Moore Fund from Cancer Research UK, Tenovus, the Kidani Trust, Cancer Research Wales and the National Institute for Social Care and Health Research Cancer Genetics Biomedical Research Unit. Nada A. Al-Tassan and Brian F. Meyer were funded and supported by KFSHRC. Luis Carvajal-Carmona receives founding from The V Foundation for Cancer Research.The authors would also like to acknowledge The Australian Ovarian Cancer Study (AOCS) group. A full list of the participants and their affiliations appears in the suppplementary information file that is appended to this article.

PY - 2015/12/1

Y1 - 2015/12/1

N2 - High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10-9) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10-8), with the alleles showing opposite effects on the risks of the two cancers.

AB - High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10-9) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10-8), with the alleles showing opposite effects on the risks of the two cancers.

UR - http://www.scopus.com/inward/record.url?scp=84949294759&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84949294759&partnerID=8YFLogxK

U2 - 10.1038/srep17369

DO - 10.1038/srep17369

M3 - Article

C2 - 26621817

AN - SCOPUS:84949294759

VL - 5

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 17369

ER -

Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1

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