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 language | English (US) |
|---|---|
| Pages (from-to) | 506-519 |
| Number of pages | 14 |
| Journal | Cell |
| Volume | 163 |
| Issue number | 2 |
| DOIs | |
| State | Published - Oct 8 2015 |
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
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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 B.; 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 journal › Article › peer-review
}
TY - JOUR
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 B.
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.
N1 - Funding Information: We wish to thank the many members of the TCGA Network, including the Tissue Source Sites, and patients, whom contributed samples to this study. This study was supported by funds from the TCGA Project (U24-CA143848), the NCI Breast SPORE program grant P50-CA58223-09A1, and the Breast Cancer Research Foundation. G.C. is supported by the Gabriella Giorgi-Cavaglieri Foundation, M.L.G. is supported by the National Cancer Institute of the US NIH award number K99-CA166228, A.H.B. is supported by National Library of Medicine of the NIH under Award Number K22LM011931, and A.P. is supported by Mildred-Scheel Postdoctoral Research Fellowship of the Deutsche Krebshilfe e.V. (No. 111354). C.M.P is an equity stock holder, and Board of Director Member, of BioClassifier. C.M.P is also listed an inventor on patent applications on the Breast PAM50 assay. A.D.C. receives research funding from Bayer AG.
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.
UR - http://www.scopus.com/inward/record.url?scp=84943613527&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84943613527&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2015.09.033
DO - 10.1016/j.cell.2015.09.033
M3 - Article
C2 - 26451490
AN - SCOPUS:84943613527
VL - 163
SP - 506
EP - 519
JO - Cell
JF - Cell
SN - 0092-8674
IS - 2
ER -