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 Guénel; Therese Truong; Pierre Laurent-Puig; Pierre Kerbrat; Stig E. Bojesen; Børge G. Nordestgaard; Sune F. Nielsen; Henrik Flyger; Roger L. Milne; Jose Ignacio Arias Perez; Primitiva Menéndez; Nicholas Orr; GENICA Network; KConFab Investigators

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 Guénel, Therese Truong, Pierre Laurent-Puig, Pierre Kerbrat, Stig E. Bojesen, Børge G. Nordestgaard, Sune F. Nielsen, Henrik Flyger, Roger L. Milne, Jose Ignacio Arias Perez, Primitiva Menéndez, Nicholas Orr, GENICA Network, KConFab Investigators

^*Corresponding author for this work

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

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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
Journal	PLoS Genetics
Volume	10
Issue number	4
DOIs	https://doi.org/10.1371/journal.pgen.1004285
Publication status	Published - 17 Apr 2014
Externally published	Yes

ASJC Scopus subject areas

Ecology, Evolution, Behavior and Systematics
Molecular Biology
Genetics
Genetics(clinical)
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Genetic Predisposition to In Situ and Invasive Lobular Carcinoma of the Breast
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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. A., Gillett, C., ... KConFab Investigators (2014). Genetic Predisposition to In Situ and Invasive Lobular Carcinoma of the Breast. PLoS Genetics, 10(4), Article e1004285. https://doi.org/10.1371/journal.pgen.1004285

@article{a90374fb1c8143228880b5eacedc2a3f,

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 Perkins, \{Katherine Anne\} 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{\'e}nel and Therese Truong and Pierre Laurent-Puig and Pierre Kerbrat and Bojesen, \{Stig E.\} and Nordestgaard, \{B{\o}rge G.\} and Nielsen, \{Sune F.\} and Henrik Flyger and Milne, \{Roger L.\} and Perez, \{Jose Ignacio Arias\} and Primitiva Men{\'e}ndez and Nicholas Orr and \{GENICA Network\} and \{KConFab Investigators\}",

year = "2014",

month = apr,

day = "17",

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

language = "English",

volume = "10",

journal = "PLoS 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, KA, 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, Guénel, P, Truong, T, Laurent-Puig, P, Kerbrat, P, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Milne, RL, Perez, JIA, Menéndez, P, Orr, N, GENICA Network & KConFab Investigators 2014, 'Genetic Predisposition to In Situ and Invasive Lobular Carcinoma of the Breast', PLoS 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 - Guénel, Pascal

AU - Truong, Therese

AU - Laurent-Puig, Pierre

AU - Kerbrat, Pierre

AU - Bojesen, Stig E.

AU - Nordestgaard, Børge G.

AU - Nielsen, Sune F.

AU - Flyger, Henrik

AU - Milne, Roger L.

AU - Perez, Jose Ignacio Arias

AU - Menéndez, Primitiva

AU - Orr, Nicholas

AU - GENICA Network

AU - KConFab Investigators

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

AN - SCOPUS:84901352347

SN - 1553-7390

VL - 10

JO - PLoS Genetics

JF - PLoS Genetics

IS - 4

M1 - e1004285

ER -

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

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