Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer

Giovanni Ciriello, Michael L. Gatza, Andrew H. Beck, Matthew D. Wilkerson, Suhn K. Rhie, Alessandro Pastore, Hailei Zhang, Michael McLellan, Christina Yau, Cyriac Kandoth, Reanne Bowlby, Hui Shen, Sikander Hayat, Robert Fieldhouse, Susan C. Lester, Gary M.K. Tse, Rachel E. Factor, Laura C. Collins, Kimberly H. Allison, Yunn Yi ChenKristin Jensen, Nicole B. Johnson, Steffi Oesterreich, Gordon Mills, Andrew D. Cherniack, Gordon Robertson, Christopher Benz, Chris Sander, Peter W. Laird, Katherine A. Hoadley, Tari A. King, Rehan Akbani, J. Todd Auman, Miruna Balasundaram, Saianand Balu, Thomas Barr, Stephen Benz, Mario Berrios, Rameen Beroukhim, Tom Bodenheimer, Lori Boice, Moiz S. Bootwalla, Jay Bowen, Denise Brooks, Lynda Chin, Juok Cho, Sudha Chudamani, Tanja Davidsen, John A. Demchok, Jennifer B. Dennison, Li Ding, Ina Felau, Martin L. Ferguson, Scott Frazer, Stacey B. Gabriel, Jian Jiong Gao, Julie M. Gastier-Foster, Nils Gehlenborg, Mark Gerken, Gad Getz, William J. Gibson, D. Neil Hayes, David I. Heiman, Andrea Holbrook, Robert A. Holt, Alan P. Hoyle, Hai Hu, Mei Huang, Carolyn M. Hutter, E. Shelley Hwang, Stuart R. Jefferys, Steven J.M. Jones, Zhenlin Ju, Jaegil Kim, Phillip H. Lai, Michael S. Lawrence, Kristen M. Leraas, Tara M. Lichtenberg, Pei Lin, Shiyun Ling, Jia Liu, Wenbin Liu, Laxmi Lolla, Yiling Lu, Yussanne Ma, Dennis T. Maglinte, Elaine Mardis, Jeffrey Marks, Marco A. Marra, Cynthia McAllister, Shaowu Meng, Matthew Meyerson, Richard A. Moore, Lisle E. Mose, Andrew J. Mungall, Bradley A. Murray, Rashi Naresh, Michael S. Noble, Olufunmilayo Olopade, Joel S. Parker, Todd Pihl, Gordon Saksena, Steven E. Schumacher, Kenna R.Mills Shaw, Nilsa C. Ramirez, W. Kimryn Rathmell, Jeffrey Roach, A. Gordon Robertson, Jacqueline E. Schein, Nikolaus Schultz, Margi Sheth, Yan Shi, Juliann Shih, Carl Simon Shelley, Craig Shriver, Janae V. Simons, Heidi J. Sofia, Matthew G. Soloway, Carrie Sougnez, Charlie Sun, Roy Tarnuzzer, Daniel G. Tiezzi, David J. Van Den Berg, Doug Voet, Yunhu Wan, Zhining Wang, John N. Weinstein, Daniel J. Weisenberger, Richard Wilson, Lisa Wise, MacIej Wiznerowicz, Junyuan Wu, Ye Wu, Liming Yang, Travis I. Zack, Jean C. Zenklusen, Jiashan Zhang, Erik Zmuda, Charles M. Perou

Research output: Contribution to journalArticle

602 Citations (Scopus)

Abstract

Invasive lobular carcinoma (ILC) is the second most prevalent histologic subtype of invasive breast cancer. Here, we comprehensively profiled 817 breast tumors, including 127 ILC, 490 ductal (IDC), and 88 mixed IDC/ILC. Besides E-cadherin loss, the best known ILC genetic hallmark, we identified mutations targeting PTEN, TBX3, and FOXA1 as ILC enriched features. PTEN loss associated with increased AKT phosphorylation, which was highest in ILC among all breast cancer subtypes. Spatially clustered FOXA1 mutations correlated with increased FOXA1 expression and activity. Conversely, GATA3 mutations and high expression characterized luminal A IDC, suggesting differential modulation of ER activity in ILC and IDC. Proliferation and immune-related signatures determined three ILC transcriptional subtypes associated with survival differences. Mixed IDC/ILC cases were molecularly classified as ILC-like and IDC-like revealing no true hybrid features. This multidimensional molecular atlas sheds new light on the genetic bases of ILC and provides potential clinical options.

Original languageEnglish (US)
Pages (from-to)506-519
Number of pages14
JournalCell
Volume163
Issue number2
DOIs
StatePublished - Oct 8 2015
Externally publishedYes

Fingerprint

Lobular Carcinoma
Breast Neoplasms
Phosphorylation
Cadherins
Tumors
Modulation
Mutation
Atlases

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Ciriello, G., Gatza, M. L., Beck, A. H., Wilkerson, M. D., Rhie, S. K., Pastore, A., ... Perou, C. M. (2015). Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer. Cell, 163(2), 506-519. https://doi.org/10.1016/j.cell.2015.09.033

Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer. / Ciriello, Giovanni; Gatza, Michael L.; Beck, Andrew H.; Wilkerson, Matthew D.; Rhie, Suhn K.; Pastore, Alessandro; Zhang, Hailei; McLellan, Michael; Yau, Christina; Kandoth, Cyriac; Bowlby, Reanne; Shen, Hui; Hayat, Sikander; Fieldhouse, Robert; Lester, Susan C.; Tse, Gary M.K.; Factor, Rachel E.; Collins, Laura C.; Allison, Kimberly H.; Chen, Yunn Yi; Jensen, Kristin; Johnson, Nicole B.; Oesterreich, Steffi; Mills, Gordon; Cherniack, Andrew D.; Robertson, Gordon; Benz, Christopher; Sander, Chris; Laird, Peter W.; Hoadley, Katherine A.; King, Tari A.; Akbani, Rehan; Auman, J. Todd; Balasundaram, Miruna; Balu, Saianand; Barr, Thomas; Benz, Stephen; Berrios, Mario; Beroukhim, Rameen; Bodenheimer, Tom; Boice, Lori; Bootwalla, Moiz S.; Bowen, Jay; Brooks, Denise; Chin, Lynda; Cho, Juok; Chudamani, Sudha; Davidsen, Tanja; Demchok, John A.; Dennison, Jennifer B.; Ding, Li; Felau, Ina; Ferguson, Martin L.; Frazer, Scott; Gabriel, Stacey B.; Gao, Jian Jiong; Gastier-Foster, Julie M.; Gehlenborg, Nils; Gerken, Mark; Getz, Gad; Gibson, William J.; Hayes, D. Neil; Heiman, David I.; Holbrook, Andrea; Holt, Robert A.; Hoyle, Alan P.; Hu, Hai; Huang, Mei; Hutter, Carolyn M.; Hwang, E. Shelley; Jefferys, Stuart R.; Jones, Steven J.M.; Ju, Zhenlin; Kim, Jaegil; Lai, Phillip H.; Lawrence, Michael S.; Leraas, Kristen M.; Lichtenberg, Tara M.; Lin, Pei; Ling, Shiyun; Liu, Jia; Liu, Wenbin; Lolla, Laxmi; Lu, Yiling; Ma, Yussanne; Maglinte, Dennis T.; Mardis, Elaine; Marks, Jeffrey; Marra, Marco A.; McAllister, Cynthia; Meng, Shaowu; Meyerson, Matthew; Moore, Richard A.; Mose, Lisle E.; Mungall, Andrew J.; Murray, Bradley A.; Naresh, Rashi; Noble, Michael S.; Olopade, Olufunmilayo; Parker, Joel S.; Pihl, Todd; Saksena, Gordon; Schumacher, Steven E.; Shaw, Kenna R.Mills; Ramirez, Nilsa C.; Rathmell, W. Kimryn; Roach, Jeffrey; Robertson, A. Gordon; Schein, Jacqueline E.; Schultz, Nikolaus; Sheth, Margi; Shi, Yan; Shih, Juliann; Shelley, Carl Simon; Shriver, Craig; Simons, Janae V.; Sofia, Heidi J.; Soloway, Matthew G.; Sougnez, Carrie; Sun, Charlie; Tarnuzzer, Roy; Tiezzi, Daniel G.; Van Den Berg, David J.; Voet, Doug; Wan, Yunhu; Wang, Zhining; Weinstein, John N.; Weisenberger, Daniel J.; Wilson, Richard; Wise, Lisa; Wiznerowicz, MacIej; Wu, Junyuan; Wu, Ye; Yang, Liming; Zack, Travis I.; Zenklusen, Jean C.; Zhang, Jiashan; Zmuda, Erik; Perou, Charles M.

In: Cell, Vol. 163, No. 2, 08.10.2015, p. 506-519.

Research output: Contribution to journalArticle

Ciriello, G, Gatza, ML, Beck, AH, Wilkerson, MD, Rhie, SK, Pastore, A, Zhang, H, McLellan, M, Yau, C, Kandoth, C, Bowlby, R, Shen, H, Hayat, S, Fieldhouse, R, Lester, SC, Tse, GMK, Factor, RE, Collins, LC, Allison, KH, Chen, YY, Jensen, K, Johnson, NB, Oesterreich, S, Mills, G, Cherniack, AD, Robertson, G, Benz, C, Sander, C, Laird, PW, Hoadley, KA, King, TA, Akbani, R, Auman, JT, Balasundaram, M, Balu, S, Barr, T, Benz, S, Berrios, M, Beroukhim, R, Bodenheimer, T, Boice, L, Bootwalla, MS, Bowen, J, Brooks, D, Chin, L, Cho, J, Chudamani, S, Davidsen, T, Demchok, JA, Dennison, JB, Ding, L, Felau, I, Ferguson, ML, Frazer, S, Gabriel, SB, Gao, JJ, Gastier-Foster, JM, Gehlenborg, N, Gerken, M, Getz, G, Gibson, WJ, Hayes, DN, Heiman, DI, Holbrook, A, Holt, RA, Hoyle, AP, Hu, H, Huang, M, Hutter, CM, Hwang, ES, Jefferys, SR, Jones, SJM, Ju, Z, Kim, J, Lai, PH, Lawrence, MS, Leraas, KM, Lichtenberg, TM, Lin, P, Ling, S, Liu, J, Liu, W, Lolla, L, Lu, Y, Ma, Y, Maglinte, DT, Mardis, E, Marks, J, Marra, MA, McAllister, C, Meng, S, Meyerson, M, Moore, RA, Mose, LE, Mungall, AJ, Murray, BA, Naresh, R, Noble, MS, Olopade, O, Parker, JS, Pihl, T, Saksena, G, Schumacher, SE, Shaw, KRM, Ramirez, NC, Rathmell, WK, Roach, J, Robertson, AG, Schein, JE, Schultz, N, Sheth, M, Shi, Y, Shih, J, Shelley, CS, Shriver, C, Simons, JV, Sofia, HJ, Soloway, MG, Sougnez, C, Sun, C, Tarnuzzer, R, Tiezzi, DG, Van Den Berg, DJ, Voet, D, Wan, Y, Wang, Z, Weinstein, JN, Weisenberger, DJ, Wilson, R, Wise, L, Wiznerowicz, M, Wu, J, Wu, Y, Yang, L, Zack, TI, Zenklusen, JC, Zhang, J, Zmuda, E & Perou, CM 2015, 'Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer', Cell, vol. 163, no. 2, pp. 506-519. https://doi.org/10.1016/j.cell.2015.09.033
Ciriello G, Gatza ML, Beck AH, Wilkerson MD, Rhie SK, Pastore A et al. Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer. Cell. 2015 Oct 8;163(2):506-519. https://doi.org/10.1016/j.cell.2015.09.033
Ciriello, Giovanni ; Gatza, Michael L. ; Beck, Andrew H. ; Wilkerson, Matthew D. ; Rhie, Suhn K. ; Pastore, Alessandro ; Zhang, Hailei ; McLellan, Michael ; Yau, Christina ; Kandoth, Cyriac ; Bowlby, Reanne ; Shen, Hui ; Hayat, Sikander ; Fieldhouse, Robert ; Lester, Susan C. ; Tse, Gary M.K. ; Factor, Rachel E. ; Collins, Laura C. ; Allison, Kimberly H. ; Chen, Yunn Yi ; Jensen, Kristin ; Johnson, Nicole B. ; Oesterreich, Steffi ; Mills, Gordon ; Cherniack, Andrew D. ; Robertson, Gordon ; Benz, Christopher ; Sander, Chris ; Laird, Peter W. ; Hoadley, Katherine A. ; King, Tari A. ; Akbani, Rehan ; Auman, J. Todd ; Balasundaram, Miruna ; Balu, Saianand ; Barr, Thomas ; Benz, Stephen ; Berrios, Mario ; Beroukhim, Rameen ; Bodenheimer, Tom ; Boice, Lori ; Bootwalla, Moiz S. ; Bowen, Jay ; Brooks, Denise ; Chin, Lynda ; Cho, Juok ; Chudamani, Sudha ; Davidsen, Tanja ; Demchok, John A. ; Dennison, Jennifer B. ; Ding, Li ; Felau, Ina ; Ferguson, Martin L. ; Frazer, Scott ; Gabriel, Stacey B. ; Gao, Jian Jiong ; Gastier-Foster, Julie M. ; Gehlenborg, Nils ; Gerken, Mark ; Getz, Gad ; Gibson, William J. ; Hayes, D. Neil ; Heiman, David I. ; Holbrook, Andrea ; Holt, Robert A. ; Hoyle, Alan P. ; Hu, Hai ; Huang, Mei ; Hutter, Carolyn M. ; Hwang, E. Shelley ; Jefferys, Stuart R. ; Jones, Steven J.M. ; Ju, Zhenlin ; Kim, Jaegil ; Lai, Phillip H. ; Lawrence, Michael S. ; Leraas, Kristen M. ; Lichtenberg, Tara M. ; Lin, Pei ; Ling, Shiyun ; Liu, Jia ; Liu, Wenbin ; Lolla, Laxmi ; Lu, Yiling ; Ma, Yussanne ; Maglinte, Dennis T. ; Mardis, Elaine ; Marks, Jeffrey ; Marra, Marco A. ; McAllister, Cynthia ; Meng, Shaowu ; Meyerson, Matthew ; Moore, Richard A. ; Mose, Lisle E. ; Mungall, Andrew J. ; Murray, Bradley A. ; Naresh, Rashi ; Noble, Michael S. ; Olopade, Olufunmilayo ; Parker, Joel S. ; Pihl, Todd ; Saksena, Gordon ; Schumacher, Steven E. ; Shaw, Kenna R.Mills ; Ramirez, Nilsa C. ; Rathmell, W. Kimryn ; Roach, Jeffrey ; Robertson, A. Gordon ; Schein, Jacqueline E. ; Schultz, Nikolaus ; Sheth, Margi ; Shi, Yan ; Shih, Juliann ; Shelley, Carl Simon ; Shriver, Craig ; Simons, Janae V. ; Sofia, Heidi J. ; Soloway, Matthew G. ; Sougnez, Carrie ; Sun, Charlie ; Tarnuzzer, Roy ; Tiezzi, Daniel G. ; Van Den Berg, David J. ; Voet, Doug ; Wan, Yunhu ; Wang, Zhining ; Weinstein, John N. ; Weisenberger, Daniel J. ; Wilson, Richard ; Wise, Lisa ; Wiznerowicz, MacIej ; Wu, Junyuan ; Wu, Ye ; Yang, Liming ; Zack, Travis I. ; Zenklusen, Jean C. ; Zhang, Jiashan ; Zmuda, Erik ; Perou, Charles M. / Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer. In: Cell. 2015 ; Vol. 163, No. 2. pp. 506-519.
@article{11d53961b3274a36a16b708b74488dde,
title = "Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer",
abstract = "Invasive lobular carcinoma (ILC) is the second most prevalent histologic subtype of invasive breast cancer. Here, we comprehensively profiled 817 breast tumors, including 127 ILC, 490 ductal (IDC), and 88 mixed IDC/ILC. Besides E-cadherin loss, the best known ILC genetic hallmark, we identified mutations targeting PTEN, TBX3, and FOXA1 as ILC enriched features. PTEN loss associated with increased AKT phosphorylation, which was highest in ILC among all breast cancer subtypes. Spatially clustered FOXA1 mutations correlated with increased FOXA1 expression and activity. Conversely, GATA3 mutations and high expression characterized luminal A IDC, suggesting differential modulation of ER activity in ILC and IDC. Proliferation and immune-related signatures determined three ILC transcriptional subtypes associated with survival differences. Mixed IDC/ILC cases were molecularly classified as ILC-like and IDC-like revealing no true hybrid features. This multidimensional molecular atlas sheds new light on the genetic bases of ILC and provides potential clinical options.",
author = "Giovanni Ciriello and Gatza, {Michael L.} and Beck, {Andrew H.} and Wilkerson, {Matthew D.} and Rhie, {Suhn K.} and Alessandro Pastore and Hailei Zhang and Michael McLellan and Christina Yau and Cyriac Kandoth and Reanne Bowlby and Hui Shen and Sikander Hayat and Robert Fieldhouse and Lester, {Susan C.} and Tse, {Gary M.K.} and Factor, {Rachel E.} and Collins, {Laura C.} and Allison, {Kimberly H.} and Chen, {Yunn Yi} and Kristin Jensen and Johnson, {Nicole B.} and Steffi Oesterreich and Gordon Mills and Cherniack, {Andrew D.} and Gordon Robertson and Christopher Benz and Chris Sander and Laird, {Peter W.} and Hoadley, {Katherine A.} and King, {Tari A.} and Rehan Akbani and Auman, {J. Todd} and Miruna Balasundaram and Saianand Balu and Thomas Barr and Stephen Benz and Mario Berrios and Rameen Beroukhim and Tom Bodenheimer and Lori Boice and Bootwalla, {Moiz S.} and Jay Bowen and Denise Brooks and Lynda Chin and Juok Cho and Sudha Chudamani and Tanja Davidsen and Demchok, {John A.} and Dennison, {Jennifer B.} and Li Ding and Ina Felau and Ferguson, {Martin L.} and Scott Frazer and Gabriel, {Stacey B.} and Gao, {Jian Jiong} and Gastier-Foster, {Julie M.} and Nils Gehlenborg and Mark Gerken and Gad Getz and Gibson, {William J.} and Hayes, {D. Neil} and Heiman, {David I.} and Andrea Holbrook and Holt, {Robert A.} and Hoyle, {Alan P.} and Hai Hu and Mei Huang and Hutter, {Carolyn M.} and Hwang, {E. Shelley} and Jefferys, {Stuart R.} and Jones, {Steven J.M.} and Zhenlin Ju and Jaegil Kim and Lai, {Phillip H.} and Lawrence, {Michael S.} and Leraas, {Kristen M.} and Lichtenberg, {Tara M.} and Pei Lin and Shiyun Ling and Jia Liu and Wenbin Liu and Laxmi Lolla and Yiling Lu and Yussanne Ma and Maglinte, {Dennis T.} and Elaine Mardis and Jeffrey Marks and Marra, {Marco A.} and Cynthia McAllister and Shaowu Meng and Matthew Meyerson and Moore, {Richard A.} and Mose, {Lisle E.} and Mungall, {Andrew J.} and Murray, {Bradley A.} and Rashi Naresh and Noble, {Michael S.} and Olufunmilayo Olopade and Parker, {Joel S.} and Todd Pihl and Gordon Saksena and Schumacher, {Steven E.} and Shaw, {Kenna R.Mills} and Ramirez, {Nilsa C.} and Rathmell, {W. Kimryn} and Jeffrey Roach and Robertson, {A. Gordon} and Schein, {Jacqueline E.} and Nikolaus Schultz and Margi Sheth and Yan Shi and Juliann Shih and Shelley, {Carl Simon} and Craig Shriver and Simons, {Janae V.} and Sofia, {Heidi J.} and Soloway, {Matthew G.} and Carrie Sougnez and Charlie Sun and Roy Tarnuzzer and Tiezzi, {Daniel G.} and {Van Den Berg}, {David J.} and Doug Voet and Yunhu Wan and Zhining Wang and Weinstein, {John N.} and Weisenberger, {Daniel J.} and Richard Wilson and Lisa Wise and MacIej Wiznerowicz and Junyuan Wu and Ye Wu and Liming Yang and Zack, {Travis I.} and Zenklusen, {Jean C.} and Jiashan Zhang and Erik Zmuda and Perou, {Charles M.}",
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T1 - Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer

AU - Ciriello, Giovanni

AU - Gatza, Michael L.

AU - Beck, Andrew H.

AU - Wilkerson, Matthew D.

AU - Rhie, Suhn K.

AU - Pastore, Alessandro

AU - Zhang, Hailei

AU - McLellan, Michael

AU - Yau, Christina

AU - Kandoth, Cyriac

AU - Bowlby, Reanne

AU - Shen, Hui

AU - Hayat, Sikander

AU - Fieldhouse, Robert

AU - Lester, Susan C.

AU - Tse, Gary M.K.

AU - Factor, Rachel E.

AU - Collins, Laura C.

AU - Allison, Kimberly H.

AU - Chen, Yunn Yi

AU - Jensen, Kristin

AU - Johnson, Nicole B.

AU - Oesterreich, Steffi

AU - Mills, Gordon

AU - Cherniack, Andrew D.

AU - Robertson, Gordon

AU - Benz, Christopher

AU - Sander, Chris

AU - Laird, Peter W.

AU - Hoadley, Katherine A.

AU - King, Tari A.

AU - Akbani, Rehan

AU - Auman, J. Todd

AU - Balasundaram, Miruna

AU - Balu, Saianand

AU - Barr, Thomas

AU - Benz, Stephen

AU - Berrios, Mario

AU - Beroukhim, Rameen

AU - Bodenheimer, Tom

AU - Boice, Lori

AU - Bootwalla, Moiz S.

AU - Bowen, Jay

AU - Brooks, Denise

AU - Chin, Lynda

AU - Cho, Juok

AU - Chudamani, Sudha

AU - Davidsen, Tanja

AU - Demchok, John A.

AU - Dennison, Jennifer B.

AU - Ding, Li

AU - Felau, Ina

AU - Ferguson, Martin L.

AU - Frazer, Scott

AU - Gabriel, Stacey B.

AU - Gao, Jian Jiong

AU - Gastier-Foster, Julie M.

AU - Gehlenborg, Nils

AU - Gerken, Mark

AU - Getz, Gad

AU - Gibson, William J.

AU - Hayes, D. Neil

AU - Heiman, David I.

AU - Holbrook, Andrea

AU - Holt, Robert A.

AU - Hoyle, Alan P.

AU - Hu, Hai

AU - Huang, Mei

AU - Hutter, Carolyn M.

AU - Hwang, E. Shelley

AU - Jefferys, Stuart R.

AU - Jones, Steven J.M.

AU - Ju, Zhenlin

AU - Kim, Jaegil

AU - Lai, Phillip H.

AU - Lawrence, Michael S.

AU - Leraas, Kristen M.

AU - Lichtenberg, Tara M.

AU - Lin, Pei

AU - Ling, Shiyun

AU - Liu, Jia

AU - Liu, Wenbin

AU - Lolla, Laxmi

AU - Lu, Yiling

AU - Ma, Yussanne

AU - Maglinte, Dennis T.

AU - Mardis, Elaine

AU - Marks, Jeffrey

AU - Marra, Marco A.

AU - McAllister, Cynthia

AU - Meng, Shaowu

AU - Meyerson, Matthew

AU - Moore, Richard A.

AU - Mose, Lisle E.

AU - Mungall, Andrew J.

AU - Murray, Bradley A.

AU - Naresh, Rashi

AU - Noble, Michael S.

AU - Olopade, Olufunmilayo

AU - Parker, Joel S.

AU - Pihl, Todd

AU - Saksena, Gordon

AU - Schumacher, Steven E.

AU - Shaw, Kenna R.Mills

AU - Ramirez, Nilsa C.

AU - Rathmell, W. Kimryn

AU - Roach, Jeffrey

AU - Robertson, A. Gordon

AU - Schein, Jacqueline E.

AU - Schultz, Nikolaus

AU - Sheth, Margi

AU - Shi, Yan

AU - Shih, Juliann

AU - Shelley, Carl Simon

AU - Shriver, Craig

AU - Simons, Janae V.

AU - Sofia, Heidi J.

AU - Soloway, Matthew G.

AU - Sougnez, Carrie

AU - Sun, Charlie

AU - Tarnuzzer, Roy

AU - Tiezzi, Daniel G.

AU - Van Den Berg, David J.

AU - Voet, Doug

AU - Wan, Yunhu

AU - Wang, Zhining

AU - Weinstein, John N.

AU - Weisenberger, Daniel J.

AU - Wilson, Richard

AU - Wise, Lisa

AU - Wiznerowicz, MacIej

AU - Wu, Junyuan

AU - Wu, Ye

AU - Yang, Liming

AU - Zack, Travis I.

AU - Zenklusen, Jean C.

AU - Zhang, Jiashan

AU - Zmuda, Erik

AU - Perou, Charles M.

PY - 2015/10/8

Y1 - 2015/10/8

N2 - Invasive lobular carcinoma (ILC) is the second most prevalent histologic subtype of invasive breast cancer. Here, we comprehensively profiled 817 breast tumors, including 127 ILC, 490 ductal (IDC), and 88 mixed IDC/ILC. Besides E-cadherin loss, the best known ILC genetic hallmark, we identified mutations targeting PTEN, TBX3, and FOXA1 as ILC enriched features. PTEN loss associated with increased AKT phosphorylation, which was highest in ILC among all breast cancer subtypes. Spatially clustered FOXA1 mutations correlated with increased FOXA1 expression and activity. Conversely, GATA3 mutations and high expression characterized luminal A IDC, suggesting differential modulation of ER activity in ILC and IDC. Proliferation and immune-related signatures determined three ILC transcriptional subtypes associated with survival differences. Mixed IDC/ILC cases were molecularly classified as ILC-like and IDC-like revealing no true hybrid features. This multidimensional molecular atlas sheds new light on the genetic bases of ILC and provides potential clinical options.

AB - Invasive lobular carcinoma (ILC) is the second most prevalent histologic subtype of invasive breast cancer. Here, we comprehensively profiled 817 breast tumors, including 127 ILC, 490 ductal (IDC), and 88 mixed IDC/ILC. Besides E-cadherin loss, the best known ILC genetic hallmark, we identified mutations targeting PTEN, TBX3, and FOXA1 as ILC enriched features. PTEN loss associated with increased AKT phosphorylation, which was highest in ILC among all breast cancer subtypes. Spatially clustered FOXA1 mutations correlated with increased FOXA1 expression and activity. Conversely, GATA3 mutations and high expression characterized luminal A IDC, suggesting differential modulation of ER activity in ILC and IDC. Proliferation and immune-related signatures determined three ILC transcriptional subtypes associated with survival differences. Mixed IDC/ILC cases were molecularly classified as ILC-like and IDC-like revealing no true hybrid features. This multidimensional molecular atlas sheds new light on the genetic bases of ILC and provides potential clinical options.

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