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 Chen; Kristin Jensen; Nicole B Johnson; Steffi Oesterreich; Gordon B Mills; Andrew D Cherniack; Gordon Robertson; Christopher Benz; Chris Sander; Peter W Laird; Katherine A Hoadley; Tari A King; TCGA Research Network; Charles M Perou

doi:10.1016/j.cell.2015.09.033

Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer

Cell. 2015 Oct 8;163(2):506-19. doi: 10.1016/j.cell.2015.09.033.

Authors

Giovanni Ciriello¹, Michael L Gatza², Andrew H Beck³, Matthew D Wilkerson⁴, Suhn K Rhie⁵, Alessandro Pastore⁶, Hailei Zhang⁷, Michael McLellan⁸, Christina Yau⁹, Cyriac Kandoth¹⁰, Reanne Bowlby¹¹, Hui Shen¹², Sikander Hayat⁶, Robert Fieldhouse⁶, Susan C Lester³, Gary M K Tse¹³, Rachel E Factor¹⁴, Laura C Collins³, Kimberly H Allison¹⁵, Yunn-Yi Chen¹⁶, Kristin Jensen¹⁷, Nicole B Johnson³, Steffi Oesterreich¹⁸, Gordon B Mills¹⁹, Andrew D Cherniack⁷, Gordon Robertson¹¹, Christopher Benz⁹, Chris Sander⁶, Peter W Laird¹², Katherine A Hoadley²⁰, Tari A King²¹; TCGA Research Network; Charles M Perou²²

Collaborators

TCGA Research Network:
Rehan Akbani, J Todd Auman, Miruna Balasundaram, Saianand Balu, Thomas Barr, Andrew Beck, Christopher Benz, Stephen Benz, Mario Berrios, Rameen Beroukhim, Tom Bodenheimer, Lori Boice, Moiz S Bootwalla, Jay Bowen, Reanne Bowlby, Denise Brooks, Andrew D Cherniack, Lynda Chin, Juok Cho, Sudha Chudamani, Giovanni Ciriello, Tanja Davidsen, John A Demchok, Jennifer B Dennison, Li Ding, Ina Felau, Martin L Ferguson, Scott Frazer, Stacey B Gabriel, JianJiong Gao, Julie M Gastier-Foster, Michael L Gatza, Nils Gehlenborg, Mark Gerken, Gad Getz, William J Gibson, D Neil Hayes, David I Heiman, Katherine A Hoadley, 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, Peter W Laird, 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, Michael McLellan, Shaowu Meng, Matthew Meyerson, Gordon B Mills, Richard A Moore, Lisle E Mose, Andrew J Mungall, Bradley A Murray, Rashi Naresh, Michael S Noble, Steffi Oesterreich, Olufunmilayo Olopade, Joel S Parker, Charles M Perou, Todd Pihl, Gordon Saksena, Steven E Schumacher, Kenna R Mills Shaw, Nilsa C Ramirez, W Kimryn Rathmell, Suhn K Rhie, Jeffrey Roach, A Gordon Robertson, Gordon Saksena, Chris Sander, Jacqueline E Schein, Nikolaus Schultz, Hui Shen, 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, Matthew D Wilkerson, Richard Wilson, Lisa Wise, Maciej Wiznerowicz, Junyuan Wu, Ye Wu, Liming Yang, Christina Yau, Travis I Zack, Jean C Zenklusen, Hailei Zhang, Jiashan Zhang, Erik Zmuda

Affiliations

¹ Department of Medical Genetics, University of Lausanne (UNIL), 1011 Lausanne, Switzerland; Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
² Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
³ Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.
⁴ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
⁵ Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033, USA.
⁶ Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
⁷ The Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
⁸ The Genome Institute, Washington University School of Medicine, MO, 63108, USA.
⁹ Buck Institute For Research on Aging, Novato, CA, 94945, USA.
¹⁰ Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
¹¹ Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, V5Z4S6, Canada.
¹² Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI, 49503, USA.
¹³ Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong.
¹⁴ Department of Pathology, School of Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
¹⁵ Department of Pathology, School of Medicine, Stanford University Medical Center, Stanford University, Stanford, CA, USA.
¹⁶ Department of Pathology and Laboratory Medicine, University of California, San Francisco, CA, 94143, USA.
¹⁷ Department of Pathology, School of Medicine, Stanford University Medical Center, Stanford University, Stanford, CA, USA; VA Palo Alto Healthcare System, Palo Alto, 94304, CA, USA.
¹⁸ Department of Pharmacology and Chemical Biology, Women's Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15232, USA.
¹⁹ MD Anderson Cancer Center, The University of Texas, Houston, TX, 77230, USA.
²⁰ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
²¹ Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
²² Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. Electronic address: cperou@med.unc.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antigens, CD
Breast Neoplasms / genetics*
Breast Neoplasms / metabolism
Breast Neoplasms / pathology*
Cadherins / chemistry
Cadherins / genetics
Cadherins / metabolism
Carcinoma, Ductal, Breast / genetics
Carcinoma, Ductal, Breast / pathology
Carcinoma, Lobular / genetics*
Carcinoma, Lobular / metabolism
Carcinoma, Lobular / pathology*
Female
Hepatocyte Nuclear Factor 3-alpha / chemistry
Hepatocyte Nuclear Factor 3-alpha / genetics
Hepatocyte Nuclear Factor 3-alpha / metabolism
Humans
Models, Molecular
Mutation
Oligonucleotide Array Sequence Analysis
Oncogene Protein v-akt / metabolism
Transcriptome

Substances

Antigens, CD
CDH1 protein, human
Cadherins
FOXA1 protein, human
Hepatocyte Nuclear Factor 3-alpha
Oncogene Protein v-akt

Abstract

Publication types

MeSH terms

Substances

Grants and funding