title: Gene expression profiling of lobular carcinoma in situ reveals candidate precursor genes for invasion.
abstract: OBJECTIVE
  Lobular carcinoma in situ (LCIS) is both a risk indicator and non-obligate precursor of invasive lobular carcinoma (ILC). We sought to characterize the transcriptomic features of LCIS and ILC, with a focus on the identification of intrinsic molecular subtypes of LCIS and the changes involved in the progression from normal breast epithelium to LCIS and ILC.
  
  
  METHODS
  Fresh-frozen classic LCIS, classic ILC, and normal breast epithelium (N) from women undergoing prophylactic or therapeutic mastectomy were prospectively collected, laser-capture microdissected, and subjected to gene expression profiling using Affymetrix HG-U133A 2.0 microarrays.
  
  
  RESULTS
  Unsupervised hierarchical clustering of 40 LCIS samples identified 2 clusters of LCIS distinguished by 6431 probe sets (p < 0.001). Genes identifying the clusters included proliferation genes and other genes related to cancer canonical pathways such as TGF beta signaling, p53 signaling, actin cytoskeleton, apoptosis and Wnt-Signaling pathway. A supervised analysis to identify differentially expressed genes (p < 0.001) between normal epithelium, LCIS, and ILC, using 23 patient-matched triplets of N, LCIS, and ILC, identified 169 candidate precursor genes, which likely play a role in LCIS progression, including PIK3R1, GOLM1, and GPR137B. These potential precursor genes map significantly more frequently to 1q and 16q, regions frequently targeted by gene copy number alterations in LCIS and ILC.
  
  
  CONCLUSIONS
  Here we demonstrate that classic LCIS is a heterogeneous disease at the transcriptomic level and identify potential precursor genes in lobular carcinogenesis. Understanding the molecular heterogeneity of LCIS and the potential role of these potential precursor genes may help personalize the therapy of patients with LCIS.
authors.affiliation: Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 300 E. 66th St., New York, NY, 10065, USA; Department of Pathology, A.C. Camargo Cancer Center, Sao Paulo, Brazil.
authors.forename: Victor P
authors.initials: VP
authors.lastname: Andrade
authors.affiliation: Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 300 E. 66th St., New York, NY, 10065, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Morrogh
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Li-Xuan
authors.initials: LX
authors.lastname: Qin
authors.affiliation: Sloan-Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Narciso
authors.initials: N
authors.lastname: Olvera
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Dilip
authors.initials: D
authors.lastname: Giri
authors.affiliation: Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 300 E. 66th St., New York, NY, 10065, USA.
authors.forename: Shirin
authors.initials: S
authors.lastname: Muhsen
authors.affiliation: Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 300 E. 66th St., New York, NY, 10065, USA.
authors.forename: Rita A
authors.initials: RA
authors.lastname: Sakr
authors.affiliation: Sloan-Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Michail
authors.initials: M
authors.lastname: Schizas
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Charlotte K Y
authors.initials: CK
authors.lastname: Ng
authors.affiliation: Sloan-Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Crispinita D
authors.initials: CD
authors.lastname: Arroyo
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Edi
authors.initials: E
authors.lastname: Brogi
authors.affiliation: Genomics Core, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Agnes
authors.initials: A
authors.lastname: Viale
authors.affiliation: Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 300 E. 66th St., New York, NY, 10065, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Morrow
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.affiliation: Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 300 E. 66th St., New York, NY, 10065, USA. Electronic address: kingt@mskcc.org.
authors.forename: Tari A
authors.initials: TA
authors.lastname: King
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002278:Carcinoma in Situ / Q000235:genetics* / Q000473:pathology; D018275:Carcinoma, Lobular / Q000235:genetics* / Q000473:pathology; D002877:Chromosomes, Human / Q000235:genetics; D016000:Cluster Analysis; D056915:DNA Copy Number Variations / Q000235:genetics; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics; D004848:Epithelium / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D056726:Genetic Association Studies; D018740:Genetic Heterogeneity; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics*; D012984:Software
keywords: Breast cancer; Gene expression; Lobular carcinoma in situ; Precursor; Risk factor