title: Increased SOX2 gene copy number is associated with FGFR1 and PIK3CA gene gain in non-small cell lung cancer and predicts improved survival in early stage disease.
abstract: BACKGROUND
  We aimed to investigate prevalence and prognostic role of SOX2, PIK3CA, FGFR1 and BRF2 gene gain in patients with surgically resected non-small cell lung cancer (NSCLC).
  
  
  METHODS
  SOX2, PIK3CA, FGFR1 and BRF2 gene copy number was assessed by fluorescence in situ hybridization (FISH) in arrayed tissue cores from 447 resected NSCLCs.
  
  
  RESULTS
  Increased gene copy number (FISH+) for SOX2, PIK3CA, FGFR1 and BRF2 was observed in 23.6%, 29.2%, 16.6% and 14.9% of cases, respectively. FISH+ status for each gene was significantly associated with smoking history, squamous cell carcinoma (SCC) histology, and increased copy number of the other studied genes. Multivariate analysis of overall survival indicated increased SOX2 gene copy number (P = 0.008), stage I-II (P<0.001), and adenocarcinoma or SCC histology (P = 0.016) as independent, favorable prognostic factors. A statistically significant interaction was observed between stage and SOX2 gene status (P = 0.021), indicating that the prognostic impact of SOX2 gene gain differs across stages and is limited to patients with stage I-II disease (HR 0.44, 95% CI: 0.25-0.77; P = 0.004, adjusted for histology).
  
  
  CONCLUSIONS
  Increased SOX2 gene copy number is an independent and favorable prognostic factor in surgically resected, early stage NSCLC, regardless of histology. SOX2, PIK3CA, FGFR1 and BRF2 gene gains are likely to occur concurrently, with potentially relevant implications for the development of new therapeutic strategies.
authors.affiliation: Division of Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Toschi
authors.affiliation: Division of Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Finocchiaro
authors.affiliation: University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Teresa T
authors.initials: TT
authors.lastname: Nguyen
authors.affiliation: Forensic Biology/DNA, Denver Police Department Crime Laboratory, Denver, Colorado, United States of America.
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Skokan
authors.affiliation: Biostatistics Unit, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Giordano
authors.affiliation: Division of Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Gianoncelli
authors.affiliation: Division of Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Perrino
authors.affiliation: Division of Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Licia
authors.initials: L
authors.lastname: Siracusano
authors.affiliation: Division of Pathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; University of Milan, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Di Tommaso
authors.affiliation: Division of Thoracic Surgery, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Infante
authors.affiliation: Division of Thoracic Surgery, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Alloisio
authors.affiliation: Division of Pathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; University of Milan, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Roncalli
authors.affiliation: Department of Radiotherapy, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Scorsetti
authors.affiliation: Lowe Center for Thoracic Oncology and Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America.
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.affiliation: Division of Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.
authors.forename: Armando
authors.initials: A
authors.lastname: Santoro
authors.affiliation: University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D056915:DNA Copy Number Variations; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D008297:Male; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011379:Prognosis; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D055748:SOXB1 Transcription Factors / Q000235:genetics*; D016019:Survival Analysis
chemical_list: C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1
references.citation: Lung Cancer. 2013 Sep;81(3):462-467
references.pmid: 23806793
references.citation: PLoS One. 2010 Jan 29;5(1):e8960
references.pmid: 20126410
references.citation: Am J Surg Pathol. 2010 Aug;34(8):1193-8
references.pmid: 20631605
references.citation: J Thorac Oncol. 2013 Nov;8(11):1371-7
references.pmid: 24077455
references.citation: Science. 2002 May 31;296(5573):1655-7
references.pmid: 12040186
references.citation: Am J Clin Pathol. 2012 Nov;138(5):712-8
references.pmid: 23086772
references.citation: PLoS One. 2013 Aug 19;8(8):e71140
references.pmid: 23990933
references.citation: Nat Genet. 2009 Nov;41(11):1238-42
references.pmid: 19801978
references.citation: PLoS Med. 2010 Jul 27;7(7):e1000315
references.pmid: 20668658
references.citation: Mol Cancer. 2011 Apr 25;10:47
references.pmid: 21518452
references.citation: Mod Pathol. 2011 Jul;24(7):944-53
references.pmid: 21460799
references.citation: Trends Genet. 2000 Apr;16(4):182-7
references.pmid: 10729834
references.citation: Br J Cancer. 2011 Apr 26;104(9):1410-7
references.pmid: 21468047
references.citation: Nat Genet. 2012 Oct;44(10):1111-6
references.pmid: 22941189
references.citation: Mod Pathol. 2012 Nov;25(11):1473-80
references.pmid: 22684217
references.citation: Clin Cancer Res. 2012 Dec 15;18(24):6771-83
references.pmid: 23136191
references.citation: Cancer Res. 2008 Sep 1;68(17):6913-21
references.pmid: 18757405
references.citation: J Clin Oncol. 2013 Feb 20;31(6):731-7
references.pmid: 23182986
references.citation: J Thorac Oncol. 2012 Dec;7(12):1775-1780
references.pmid: 23154548
references.citation: Clin Cancer Res. 2012 May 1;18(9):2704-14
references.pmid: 22553375
references.citation: Clin Cancer Res. 2012 Dec 15;18(24):6658-67
references.pmid: 23082000
references.citation: PLoS One. 2011;6(6):e20351
references.pmid: 21666749
references.citation: Cytokine Growth Factor Rev. 2005 Apr;16(2):139-49
references.pmid: 15863030
references.citation: Lancet Oncol. 2012 Mar;13(3):239-46
references.pmid: 22285168
references.citation: PLoS One. 2013 Apr 19;8(4):e61427
references.pmid: 23620753
references.citation: J Clin Oncol. 2009 Apr 1;27(10):1667-74
references.pmid: 19255323
references.citation: N Engl J Med. 2010 Oct 28;363(18):1693-703
references.pmid: 20979469
references.citation: Sci Transl Med. 2010 Dec 15;2(62):62ra93
references.pmid: 21160078
references.citation: J Clin Oncol. 2011 Jul 20;29(21):2866-74
references.pmid: 21670455