Genetic Predisposition to In Situ and Invasive Lobular Carcinoma of the Breast

Elinor Sawyer; Rebecca Roylance; Christos Petridis; Mark N. Brook; Salpie Nowinski; Efterpi Papouli; Olivia Fletcher; Sarah Pinder; Andrew Hanby; Kelly Kohut; Patricia Gorman; Michele Caneppele; Julian Peto; Isabel Dos Santos Silva; Nichola Johnson; Ruth Swann; Miriam Dwek; Katherine-anne Perkins; Cheryl Gillett; Richard Houlston; Gillian Ross; Paolo De Ieso; Melissa C. Southey; John L. Hopper; Elena Provenzano; Carmel Apicella; Jelle Wesseling; Sten Cornelissen; Renske Keeman; Peter A. Fasching; Sebastian M. Jud; Arif B. Ekici; Matthias W. Beckmann; Michael J. Kerin; Federick Marme; Andreas Schneeweiss; Christof Sohn; Barbara Burwinkel; Pascal Gu??nel; Therese Truong; Pierre Laurent-puig; Pierre Kerbrat; Stig E. Bojesen; B??rge G. Nordestgaard; Sune F. Nielsen; Henrik Flyger; Roger L. Milne; Jose Ignacio Arias Perez; Primitiva Men??ndez; Javier Benitez; Hermann Brenner; Aida Karina Dieffenbach; Volker Arndt; Christa Stegmaier; Alfons Meindl; Peter Lichtner; Rita K. Schmutzler; Magdalena Lochmann; Hiltrud Brauch; Hans-peter Fischer; Yon-dschun Ko; Heli Nevanlinna; Taru A. Muranen; Kristiina Aittom??ki; Carl Blomqvist; Natalia V. Bogdanova; Thilo D??rk; Annika Lindblom; Sara Margolin; Arto Mannermaa; Vesa Kataja; Veli-matti Kosma; Jaana M. Hartikainen; Georgia Chenevix-trench; Kconfab Investigators; Diether Lambrechts; Caroline Weltens; Erik Van Limbergen; Sigrid Hatse; Jenny Chang-claude; Anja Rudolph; Petra Seibold; Dieter Flesch-janys; Paolo Radice; Paolo Peterlongo; Bernardo Bonanni; Sara Volorio; Graham G. Giles; Gianluca Severi; Laura Baglietto; Catriona A. Mclean; Christopher A. Haiman; Brian E. Henderson; Fredrick Schumacher; Loic Le Marchand; Jacques Simard; Mark S. Goldberg; France Labr??che; Martine Dumont; Vessela Kristensen; Robert Winqvist; Katri Pylk??s; Arja Jukkola-vuorinen; Saila Kauppila; Irene L. Andrulis; Julia A. Knight; Gord Glendon; Anna Marie Mulligan; Peter Devillee; Rob A. E. M. Tollenaar; Caroline M. Seynaeve; Mieke Kriege; Jonine Figueroa; Stephen J. Chanock; Mark E. Sherman; Maartje J. Hooning; Antoinette Hollestelle; Ans M. W. Van Den Ouweland; Carolien H. M. Van Deurzen; Jingmei Li; Kamila Czene; Keith Humphreys; Angela Cox; Simon S. Cross; Malcolm W. R. Reed; Mitul Shah; Anna Jakubowska; Jan Lubinski; Katarzyna Jaworska-bieniek; Katarzyna Durda; Anthony Swerdlow; Alan Ashworth; Nicholas Orr; Minouk Schoemaker; Fergus J. Couch; Emily Hallberg; Anna Gonz??lez-neira; Guillermo Pita; M. Rosario Alonso; Daniel C. Tessier; Daniel Vincent; Francois Bacot; Manjeet K. Bolla; Qin Wang; Joe Dennis; Kyriaki Michailidou; Alison M. Dunning; Per Hall; Doug Easton; Paul Pharoah; Marjanka K. Schmidt; Ian Tomlinson; Montserrat Garcia-closas; Greg Gibson

doi:10.1371/journal.pgen.1004285

Genetic Predisposition to In Situ and Invasive Lobular Carcinoma of the Breast

Elinor Sawyer, Rebecca Roylance, Christos Petridis, Mark N. Brook, Salpie Nowinski, Efterpi Papouli, Olivia Fletcher, Sarah Pinder, Andrew Hanby, Kelly Kohut, Patricia Gorman, Michele Caneppele, Julian Peto, Isabel Dos Santos Silva, Nichola Johnson, Ruth Swann, Miriam Dwek, Katherine-anne Perkins, Cheryl Gillett, Richard HoulstonGillian Ross, Paolo De Ieso, Melissa C. Southey, John L. Hopper, Elena Provenzano, Carmel Apicella, Jelle Wesseling, Sten Cornelissen, Renske Keeman, Peter A. Fasching, Sebastian M. Jud, Arif B. Ekici, Matthias W. Beckmann, Michael J. Kerin, Federick Marme, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Pascal Gu??nel, Therese Truong, Pierre Laurent-puig, Pierre Kerbrat, Stig E. Bojesen, B??rge G. Nordestgaard, Sune F. Nielsen, Henrik Flyger, Roger L. Milne, Jose Ignacio Arias Perez, Primitiva Men??ndez, Javier Benitez, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Alfons Meindl, Peter Lichtner, Rita K. Schmutzler, Magdalena Lochmann, Hiltrud Brauch, Hans-peter Fischer, Yon-dschun Ko, Heli Nevanlinna, Taru A. Muranen, Kristiina Aittom??ki, Carl Blomqvist, Natalia V. Bogdanova, Thilo D??rk, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-matti Kosma, Jaana M. Hartikainen, Georgia Chenevix-trench, Kconfab Investigators, Diether Lambrechts, Caroline Weltens, Erik Van Limbergen, Sigrid Hatse, Jenny Chang-claude, Anja Rudolph, Petra Seibold, Dieter Flesch-janys, Paolo Radice, Paolo Peterlongo, Bernardo Bonanni, Sara Volorio, Graham G. Giles, Gianluca Severi, Laura Baglietto, Catriona A. Mclean, Christopher A. Haiman, Brian E. Henderson, Fredrick Schumacher, Loic Le Marchand, Jacques Simard, Mark S. Goldberg, France Labr??che, Martine Dumont, Vessela Kristensen, Robert Winqvist, Katri Pylk??s, Arja Jukkola-vuorinen, Saila Kauppila, Irene L. Andrulis, Julia A. Knight, Gord Glendon, Anna Marie Mulligan, Peter Devillee, Rob A. E. M. Tollenaar, Caroline M. Seynaeve, Mieke Kriege, Jonine Figueroa, Stephen J. Chanock, Mark E. Sherman, Maartje J. Hooning, Antoinette Hollestelle, Ans M. W. Van Den Ouweland, Carolien H. M. Van Deurzen, Jingmei Li, Kamila Czene, Keith Humphreys, Angela Cox, Simon S. Cross, Malcolm W. R. Reed, Mitul Shah, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska-bieniek, Katarzyna Durda, Anthony Swerdlow, Alan Ashworth, Nicholas Orr, Minouk Schoemaker, Fergus J. Couch, Emily Hallberg, Anna Gonz??lez-neira, Guillermo Pita, M. Rosario Alonso, Daniel C. Tessier, Daniel Vincent, Francois Bacot, Manjeet K. Bolla, Qin Wang, Joe Dennis, Kyriaki Michailidou, Alison M. Dunning, Per Hall, Doug Easton, Paul Pharoah, Marjanka K. Schmidt, Ian Tomlinson, Montserrat Garcia-closas, Greg Gibson (Editor)

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Abstract

Invasive lobular breast cancer (ILC) accounts for 10–15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09–1.18), P = 6.0×10−10; P-het for ILC vs IDC ER+ tumors = 1.8×10−4). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P<0.05. Two SNPs showed significantly stronger associations for ILC than LCIS (rs2981579/10q26/FGFR2, P-het = 0.04 and rs889312/5q11/MAP3K1, P-het = 0.03); and two showed stronger associations for LCIS than ILC (rs6678914/1q32/LGR6, P-het = 0.001 and rs1752911/6q14, P-het = 0.04). In addition, seven of the 75 known loci showed significant differences between ER+ tumors with IDC and ILC histology, three of these showing stronger associations for ILC (rs11249433/1p11, rs2981579/10q26/FGFR2 and rs10995190/10q21/ZNF365) and four associated only with IDC (5p12/rs10941679; rs2588809/14q24/RAD51L1, rs6472903/8q21 and rs1550623/2q31/CDCA7). In conclusion, we have identified one novel lobular breast cancer specific predisposition polymorphism at 7q34, and shown for the first time that common breast cancer polymorphisms predispose to LCIS. We have shown that many of the ER+ breast cancer predisposition loci also predispose to ILC, although there is some heterogeneity between ER+ lobular and ER+ IDC tumors. These data provide evidence for overlapping, but distinct etiological pathways within ER+ breast cancer between morphological subtypes.

Original language	English
Article number	e1004285
Number of pages	14
Journal	PL o S Genetics
Volume	10
Issue number	4
Early online date	17 Apr 2014
DOIs	https://doi.org/10.1371/journal.pgen.1004285
Publication status	Published - 17 Apr 2014

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Genetic Predisposition to In Situ_SAWYER_Publishedonline17April2014_GOLD VoR (CC BY)Final published version, 596 KBLicence: CC BY

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Sawyer, E., Roylance, R., Petridis, C., Brook, M. N., Nowinski, S., Papouli, E., Fletcher, O., Pinder, S., Hanby, A., Kohut, K., Gorman, P., Caneppele, M., Peto, J., Dos Santos Silva, I., Johnson, N., Swann, R., Dwek, M., Perkins, K., Gillett, C., ... Gibson, G. (Ed.) (2014). Genetic Predisposition to In Situ and Invasive Lobular Carcinoma of the Breast. PL o S Genetics, 10(4), Article e1004285. https://doi.org/10.1371/journal.pgen.1004285

@article{c45219eda389445eba8e65f5f1fc3b7a,

title = "Genetic Predisposition to In Situ and Invasive Lobular Carcinoma of the Breast",

abstract = "Invasive lobular breast cancer (ILC) accounts for 10–15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09–1.18), P = 6.0×10−10; P-het for ILC vs IDC ER+ tumors = 1.8×10−4). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P<0.05. Two SNPs showed significantly stronger associations for ILC than LCIS (rs2981579/10q26/FGFR2, P-het = 0.04 and rs889312/5q11/MAP3K1, P-het = 0.03); and two showed stronger associations for LCIS than ILC (rs6678914/1q32/LGR6, P-het = 0.001 and rs1752911/6q14, P-het = 0.04). In addition, seven of the 75 known loci showed significant differences between ER+ tumors with IDC and ILC histology, three of these showing stronger associations for ILC (rs11249433/1p11, rs2981579/10q26/FGFR2 and rs10995190/10q21/ZNF365) and four associated only with IDC (5p12/rs10941679; rs2588809/14q24/RAD51L1, rs6472903/8q21 and rs1550623/2q31/CDCA7). In conclusion, we have identified one novel lobular breast cancer specific predisposition polymorphism at 7q34, and shown for the first time that common breast cancer polymorphisms predispose to LCIS. We have shown that many of the ER+ breast cancer predisposition loci also predispose to ILC, although there is some heterogeneity between ER+ lobular and ER+ IDC tumors. These data provide evidence for overlapping, but distinct etiological pathways within ER+ breast cancer between morphological subtypes.",

author = "Elinor Sawyer and Rebecca Roylance and Christos Petridis and Brook, {Mark N.} and Salpie Nowinski and Efterpi Papouli and Olivia Fletcher and Sarah Pinder and Andrew Hanby and Kelly Kohut and Patricia Gorman and Michele Caneppele and Julian Peto and {Dos Santos Silva}, Isabel and Nichola Johnson and Ruth Swann and Miriam Dwek and Katherine-anne Perkins and Cheryl Gillett and Richard Houlston and Gillian Ross and {De Ieso}, Paolo and Southey, {Melissa C.} and Hopper, {John L.} and Elena Provenzano and Carmel Apicella and Jelle Wesseling and Sten Cornelissen and Renske Keeman and Fasching, {Peter A.} and Jud, {Sebastian M.} and Ekici, {Arif B.} and Beckmann, {Matthias W.} and Kerin, {Michael J.} and Federick Marme and Andreas Schneeweiss and Christof Sohn and Barbara Burwinkel and Pascal Gu??nel and Therese Truong and Pierre Laurent-puig and Pierre Kerbrat and Bojesen, {Stig E.} and Nordestgaard, {B??rge G.} and Nielsen, {Sune F.} and Henrik Flyger and Milne, {Roger L.} and Perez, {Jose Ignacio Arias} and Primitiva Men??ndez and Javier Benitez and Hermann Brenner and Dieffenbach, {Aida Karina} and Volker Arndt and Christa Stegmaier and Alfons Meindl and Peter Lichtner and Schmutzler, {Rita K.} and Magdalena Lochmann and Hiltrud Brauch and Hans-peter Fischer and Yon-dschun Ko and Heli Nevanlinna and Muranen, {Taru A.} and Kristiina Aittom??ki and Carl Blomqvist and Bogdanova, {Natalia V.} and Thilo D??rk and Annika Lindblom and Sara Margolin and Arto Mannermaa and Vesa Kataja and Veli-matti Kosma and Hartikainen, {Jaana M.} and Georgia Chenevix-trench and Kconfab Investigators and Diether Lambrechts and Caroline Weltens and {Van Limbergen}, Erik and Sigrid Hatse and Jenny Chang-claude and Anja Rudolph and Petra Seibold and Dieter Flesch-janys and Paolo Radice and Paolo Peterlongo and Bernardo Bonanni and Sara Volorio and Giles, {Graham G.} and Gianluca Severi and Laura Baglietto and Mclean, {Catriona A.} and Haiman, {Christopher A.} and Henderson, {Brian E.} and Fredrick Schumacher and {Le Marchand}, Loic and Jacques Simard and Goldberg, {Mark S.} and France Labr??che and Martine Dumont and Vessela Kristensen and Robert Winqvist and Katri Pylk??s and Arja Jukkola-vuorinen and Saila Kauppila and Andrulis, {Irene L.} and Knight, {Julia A.} and Gord Glendon and Mulligan, {Anna Marie} and Peter Devillee and Tollenaar, {Rob A. E. M.} and Seynaeve, {Caroline M.} and Mieke Kriege and Jonine Figueroa and Chanock, {Stephen J.} and Sherman, {Mark E.} and Hooning, {Maartje J.} and Antoinette Hollestelle and {Van Den Ouweland}, {Ans M. W.} and {Van Deurzen}, {Carolien H. M.} and Jingmei Li and Kamila Czene and Keith Humphreys and Angela Cox and Cross, {Simon S.} and Reed, {Malcolm W. R.} and Mitul Shah and Anna Jakubowska and Jan Lubinski and Katarzyna Jaworska-bieniek and Katarzyna Durda and Anthony Swerdlow and Alan Ashworth and Nicholas Orr and Minouk Schoemaker and Couch, {Fergus J.} and Emily Hallberg and Anna Gonz??lez-neira and Guillermo Pita and Alonso, {M. Rosario} and Tessier, {Daniel C.} and Daniel Vincent and Francois Bacot and Bolla, {Manjeet K.} and Qin Wang and Joe Dennis and Kyriaki Michailidou and Dunning, {Alison M.} and Per Hall and Doug Easton and Paul Pharoah and Schmidt, {Marjanka K.} and Ian Tomlinson and Montserrat Garcia-closas and Greg Gibson",

year = "2014",

month = apr,

day = "17",

doi = "10.1371/journal.pgen.1004285",

language = "English",

volume = "10",

journal = "PL o S Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "4",

}

Sawyer, E, Roylance, R, Petridis, C, Brook, MN, Nowinski, S, Papouli, E, Fletcher, O, Pinder, S, Hanby, A, Kohut, K, Gorman, P, Caneppele, M, Peto, J, Dos Santos Silva, I, Johnson, N, Swann, R, Dwek, M, Perkins, K, Gillett, C, Houlston, R, Ross, G, De Ieso, P, Southey, MC, Hopper, JL, Provenzano, E, Apicella, C, Wesseling, J, Cornelissen, S, Keeman, R, Fasching, PA, Jud, SM, Ekici, AB, Beckmann, MW, Kerin, MJ, Marme, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Gu??nel, P, Truong, T, Laurent-puig, P, Kerbrat, P, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Milne, RL, Perez, JIA, Men??ndez, P, Benitez, J, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Meindl, A, Lichtner, P, Schmutzler, RK, Lochmann, M, Brauch, H, Fischer, H, Ko, Y, Nevanlinna, H, Muranen, TA, Aittom??ki, K, Blomqvist, C, Bogdanova, NV, D??rk, T, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, V, Hartikainen, JM, Chenevix-trench, G, Investigators, K, Lambrechts, D, Weltens, C, Van Limbergen, E, Hatse, S, Chang-claude, J, Rudolph, A, Seibold, P, Flesch-janys, D, Radice, P, Peterlongo, P, Bonanni, B, Volorio, S, Giles, GG, Severi, G, Baglietto, L, Mclean, CA, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Simard, J, Goldberg, MS, Labr??che, F, Dumont, M, Kristensen, V, Winqvist, R, Pylk??s, K, Jukkola-vuorinen, A, Kauppila, S, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Devillee, P, Tollenaar, RAEM, Seynaeve, CM, Kriege, M, Figueroa, J, Chanock, SJ, Sherman, ME, Hooning, MJ, Hollestelle, A, Van Den Ouweland, AMW, Van Deurzen, CHM, Li, J, Czene, K, Humphreys, K, Cox, A, Cross, SS, Reed, MWR, Shah, M, Jakubowska, A, Lubinski, J, Jaworska-bieniek, K, Durda, K, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, M, Couch, FJ, Hallberg, E, Gonz??lez-neira, A, Pita, G, Alonso, MR, Tessier, DC, Vincent, D, Bacot, F, Bolla, MK, Wang, Q, Dennis, J, Michailidou, K, Dunning, AM, Hall, P, Easton, D, Pharoah, P, Schmidt, MK, Tomlinson, I, Garcia-closas, M & Gibson, G (ed.) 2014, 'Genetic Predisposition to In Situ and Invasive Lobular Carcinoma of the Breast', PL o S Genetics, vol. 10, no. 4, e1004285. https://doi.org/10.1371/journal.pgen.1004285

TY - JOUR

T1 - Genetic Predisposition to In Situ and Invasive Lobular Carcinoma of the Breast

AU - Sawyer, Elinor

AU - Roylance, Rebecca

AU - Petridis, Christos

AU - Brook, Mark N.

AU - Nowinski, Salpie

AU - Papouli, Efterpi

AU - Fletcher, Olivia

AU - Pinder, Sarah

AU - Hanby, Andrew

AU - Kohut, Kelly

AU - Gorman, Patricia

AU - Caneppele, Michele

AU - Peto, Julian

AU - Dos Santos Silva, Isabel

AU - Johnson, Nichola

AU - Swann, Ruth

AU - Dwek, Miriam

AU - Perkins, Katherine-anne

AU - Gillett, Cheryl

AU - Houlston, Richard

AU - Ross, Gillian

AU - De Ieso, Paolo

AU - Southey, Melissa C.

AU - Hopper, John L.

AU - Provenzano, Elena

AU - Apicella, Carmel

AU - Wesseling, Jelle

AU - Cornelissen, Sten

AU - Keeman, Renske

AU - Fasching, Peter A.

AU - Jud, Sebastian M.

AU - Ekici, Arif B.

AU - Beckmann, Matthias W.

AU - Kerin, Michael J.

AU - Marme, Federick

AU - Schneeweiss, Andreas

AU - Sohn, Christof

AU - Burwinkel, Barbara

AU - Gu??nel, Pascal

AU - Truong, Therese

AU - Laurent-puig, Pierre

AU - Kerbrat, Pierre

AU - Bojesen, Stig E.

AU - Nordestgaard, B??rge G.

AU - Nielsen, Sune F.

AU - Flyger, Henrik

AU - Milne, Roger L.

AU - Perez, Jose Ignacio Arias

AU - Men??ndez, Primitiva

AU - Benitez, Javier

AU - Brenner, Hermann

AU - Dieffenbach, Aida Karina

AU - Arndt, Volker

AU - Stegmaier, Christa

AU - Meindl, Alfons

AU - Lichtner, Peter

AU - Schmutzler, Rita K.

AU - Lochmann, Magdalena

AU - Brauch, Hiltrud

AU - Fischer, Hans-peter

AU - Ko, Yon-dschun

AU - Nevanlinna, Heli

AU - Muranen, Taru A.

AU - Aittom??ki, Kristiina

AU - Blomqvist, Carl

AU - Bogdanova, Natalia V.

AU - D??rk, Thilo

AU - Lindblom, Annika

AU - Margolin, Sara

AU - Mannermaa, Arto

AU - Kataja, Vesa

AU - Kosma, Veli-matti

AU - Hartikainen, Jaana M.

AU - Chenevix-trench, Georgia

AU - Investigators, Kconfab

AU - Lambrechts, Diether

AU - Weltens, Caroline

AU - Van Limbergen, Erik

AU - Hatse, Sigrid

AU - Chang-claude, Jenny

AU - Rudolph, Anja

AU - Seibold, Petra

AU - Flesch-janys, Dieter

AU - Radice, Paolo

AU - Peterlongo, Paolo

AU - Bonanni, Bernardo

AU - Volorio, Sara

AU - Giles, Graham G.

AU - Severi, Gianluca

AU - Baglietto, Laura

AU - Mclean, Catriona A.

AU - Haiman, Christopher A.

AU - Henderson, Brian E.

AU - Schumacher, Fredrick

AU - Le Marchand, Loic

AU - Simard, Jacques

AU - Goldberg, Mark S.

AU - Labr??che, France

AU - Dumont, Martine

AU - Kristensen, Vessela

AU - Winqvist, Robert

AU - Pylk??s, Katri

AU - Jukkola-vuorinen, Arja

AU - Kauppila, Saila

AU - Andrulis, Irene L.

AU - Knight, Julia A.

AU - Glendon, Gord

AU - Mulligan, Anna Marie

AU - Devillee, Peter

AU - Tollenaar, Rob A. E. M.

AU - Seynaeve, Caroline M.

AU - Kriege, Mieke

AU - Figueroa, Jonine

AU - Chanock, Stephen J.

AU - Sherman, Mark E.

AU - Hooning, Maartje J.

AU - Hollestelle, Antoinette

AU - Van Den Ouweland, Ans M. W.

AU - Van Deurzen, Carolien H. M.

AU - Li, Jingmei

AU - Czene, Kamila

AU - Humphreys, Keith

AU - Cox, Angela

AU - Cross, Simon S.

AU - Reed, Malcolm W. R.

AU - Shah, Mitul

AU - Jakubowska, Anna

AU - Lubinski, Jan

AU - Jaworska-bieniek, Katarzyna

AU - Durda, Katarzyna

AU - Swerdlow, Anthony

AU - Ashworth, Alan

AU - Orr, Nicholas

AU - Schoemaker, Minouk

AU - Couch, Fergus J.

AU - Hallberg, Emily

AU - Gonz??lez-neira, Anna

AU - Pita, Guillermo

AU - Alonso, M. Rosario

AU - Tessier, Daniel C.

AU - Vincent, Daniel

AU - Bacot, Francois

AU - Bolla, Manjeet K.

AU - Wang, Qin

AU - Dennis, Joe

AU - Michailidou, Kyriaki

AU - Dunning, Alison M.

AU - Hall, Per

AU - Easton, Doug

AU - Pharoah, Paul

AU - Schmidt, Marjanka K.

AU - Tomlinson, Ian

AU - Garcia-closas, Montserrat

A2 - Gibson, Greg

PY - 2014/4/17

Y1 - 2014/4/17

N2 - Invasive lobular breast cancer (ILC) accounts for 10–15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09–1.18), P = 6.0×10−10; P-het for ILC vs IDC ER+ tumors = 1.8×10−4). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P<0.05. Two SNPs showed significantly stronger associations for ILC than LCIS (rs2981579/10q26/FGFR2, P-het = 0.04 and rs889312/5q11/MAP3K1, P-het = 0.03); and two showed stronger associations for LCIS than ILC (rs6678914/1q32/LGR6, P-het = 0.001 and rs1752911/6q14, P-het = 0.04). In addition, seven of the 75 known loci showed significant differences between ER+ tumors with IDC and ILC histology, three of these showing stronger associations for ILC (rs11249433/1p11, rs2981579/10q26/FGFR2 and rs10995190/10q21/ZNF365) and four associated only with IDC (5p12/rs10941679; rs2588809/14q24/RAD51L1, rs6472903/8q21 and rs1550623/2q31/CDCA7). In conclusion, we have identified one novel lobular breast cancer specific predisposition polymorphism at 7q34, and shown for the first time that common breast cancer polymorphisms predispose to LCIS. We have shown that many of the ER+ breast cancer predisposition loci also predispose to ILC, although there is some heterogeneity between ER+ lobular and ER+ IDC tumors. These data provide evidence for overlapping, but distinct etiological pathways within ER+ breast cancer between morphological subtypes.

AB - Invasive lobular breast cancer (ILC) accounts for 10–15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09–1.18), P = 6.0×10−10; P-het for ILC vs IDC ER+ tumors = 1.8×10−4). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P<0.05. Two SNPs showed significantly stronger associations for ILC than LCIS (rs2981579/10q26/FGFR2, P-het = 0.04 and rs889312/5q11/MAP3K1, P-het = 0.03); and two showed stronger associations for LCIS than ILC (rs6678914/1q32/LGR6, P-het = 0.001 and rs1752911/6q14, P-het = 0.04). In addition, seven of the 75 known loci showed significant differences between ER+ tumors with IDC and ILC histology, three of these showing stronger associations for ILC (rs11249433/1p11, rs2981579/10q26/FGFR2 and rs10995190/10q21/ZNF365) and four associated only with IDC (5p12/rs10941679; rs2588809/14q24/RAD51L1, rs6472903/8q21 and rs1550623/2q31/CDCA7). In conclusion, we have identified one novel lobular breast cancer specific predisposition polymorphism at 7q34, and shown for the first time that common breast cancer polymorphisms predispose to LCIS. We have shown that many of the ER+ breast cancer predisposition loci also predispose to ILC, although there is some heterogeneity between ER+ lobular and ER+ IDC tumors. These data provide evidence for overlapping, but distinct etiological pathways within ER+ breast cancer between morphological subtypes.

U2 - 10.1371/journal.pgen.1004285

DO - 10.1371/journal.pgen.1004285

M3 - Article

SN - 1553-7390

VL - 10

JO - PL o S Genetics

JF - PL o S Genetics

IS - 4

M1 - e1004285

ER -

Genetic Predisposition to In Situ and Invasive Lobular Carcinoma of the Breast

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