title: Targeted capture massively parallel sequencing analysis of LCIS and invasive lobular cancer: Repertoire of somatic genetic alterations and clonal relationships.
abstract: OBJECTIVE
  Lobular carcinoma in situ (LCIS) has been proposed as a non-obligate precursor of invasive lobular carcinoma (ILC). Here we sought to define the repertoire of somatic genetic alterations in pure LCIS and in synchronous LCIS and ILC using targeted massively parallel sequencing.
  
  
  METHODS
  DNA samples extracted from microdissected LCIS, ILC and matched normal breast tissue or peripheral blood from 30 patients were subjected to massively parallel sequencing targeting all exons of 273 genes, including the genes most frequently mutated in breast cancer and DNA repair-related genes. Single nucleotide variants and insertions and deletions were identified using state-of-the-art bioinformatics approaches.
  
  
  RESULTS
  The constellation of somatic mutations found in LCIS (n = 34) and ILC (n = 21) were similar, with the most frequently mutated genes being CDH1 (56% and 66%, respectively), PIK3CA (41% and 52%, respectively) and CBFB (12% and 19%, respectively). Among 19 LCIS and ILC synchronous pairs, 14 (74%) had at least one identical mutation in common, including identical PIK3CA and CDH1 mutations. Paired analysis of independent foci of LCIS from 3 breasts revealed at least one common mutation in each of the 3 pairs (CDH1, PIK3CA, CBFB and PKHD1L1).
  
  
  CONCLUSIONS
  LCIS and ILC have a similar repertoire of somatic mutations, with PIK3CA and CDH1 being the most frequently mutated genes. The presence of identical mutations between LCIS-LCIS and LCIS-ILC pairs demonstrates that LCIS is a clonal neoplastic lesion, and provides additional evidence that at least some LCIS are non-obligate precursors of ILC.
authors.affiliation: Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors.forename: Rita A
authors.initials: RA
authors.lastname: Sakr
authors.affiliation: Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors.forename: Michail
authors.initials: M
authors.lastname: Schizas
authors.affiliation: Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors.forename: Jose V Scarpa
authors.initials: JV
authors.lastname: Carniello
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors.forename: Charlotte K Y
authors.initials: CK
authors.lastname: Ng
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Piscuoglio
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors.forename: Dilip
authors.initials: D
authors.lastname: Giri
authors.affiliation: Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors.forename: Victor P
authors.initials: VP
authors.lastname: Andrade
authors.affiliation: Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors.forename: Marina
authors.initials: M
authors.lastname: De Brot
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Lim
authors.affiliation: Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors.forename: Russell
authors.initials: R
authors.lastname: Towers
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors.forename: Britta
authors.initials: B
authors.lastname: Weigelt
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, United States. Electronic address: reisfilj@mskcc.org.
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.affiliation: Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States. Electronic address: tking7@partners.org.
authors.forename: Tari A
authors.initials: TA
authors.lastname: King
mesh_terms: D015703:Antigens, CD; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D015820:Cadherins / Q000235:genetics*; D002278:Carcinoma in Situ / Q000235:genetics* / Q000473:pathology; D018275:Carcinoma, Lobular / Q000235:genetics* / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D015331:Cohort Studies; D050658:Core Binding Factor beta Subunit / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D058534:Class I Phosphatidylinositol 3-Kinases; D050658:Core Binding Factor beta Subunit; D019869:Phosphatidylinositol 3-Kinases; D011956:Receptors, Cell Surface; C493692:CBFB protein, human; C513384:CDH1 protein, human; C478647:PKHD1L1 protein, human; C484760:PIK3CA protein, human
keywords: Clonality; Invasive lobular carcinoma; Lobular carcinoma in situ; Massively parallel sequencing; Somatic genetic alterations