PMID- 24736592 OWN - NLM STAT- MEDLINE DCOM- 20150529 LR - 20220330 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 9 IP - 4 DP - 2014 TI - 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. PG - e95303 LID - 10.1371/journal.pone.0095303 [doi] LID - e95303 AB - 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. FAU - Toschi, Luca AU - Toschi L AD - Division of Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. FAU - Finocchiaro, Giovanna AU - Finocchiaro G AD - Division of Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. FAU - Nguyen, Teresa T AU - Nguyen TT AD - University of Colorado School of Medicine, Aurora, Colorado, United States of America. FAU - Skokan, Margaret C AU - Skokan MC AD - Forensic Biology/DNA, Denver Police Department Crime Laboratory, Denver, Colorado, United States of America. FAU - Giordano, Laura AU - Giordano L AD - Biostatistics Unit, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. FAU - Gianoncelli, Letizia AU - Gianoncelli L AD - Division of Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. FAU - Perrino, Matteo AU - Perrino M AD - Division of Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. FAU - Siracusano, Licia AU - Siracusano L AD - Division of Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. FAU - Di Tommaso, Luca AU - Di Tommaso L AD - Division of Pathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; University of Milan, Milan, Italy. FAU - Infante, Maurizio AU - Infante M AD - Division of Thoracic Surgery, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. FAU - Alloisio, Marco AU - Alloisio M AD - Division of Thoracic Surgery, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. FAU - Roncalli, Massimo AU - Roncalli M AD - Division of Pathology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; University of Milan, Milan, Italy. FAU - Scorsetti, Marta AU - Scorsetti M AD - Department of Radiotherapy, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. FAU - Janne, Pasi A AU - Janne PA AD - Lowe Center for Thoracic Oncology and Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America. FAU - Santoro, Armando AU - Santoro A AD - Division of Oncology and Hematology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. FAU - Varella-Garcia, Marileila AU - Varella-Garcia M AD - University of Colorado School of Medicine, Aurora, Colorado, United States of America. LA - eng GR - P50 CA058187/CA/NCI NIH HHS/United States GR - P30CA046934/CA/NCI NIH HHS/United States GR - KL2 TR001080/TR/NCATS NIH HHS/United States GR - KL2 TR000156/TR/NCATS NIH HHS/United States GR - P30 CA046934/CA/NCI NIH HHS/United States GR - KL2TR000156/TR/NCATS NIH HHS/United States GR - P50CA058187/CA/NCI NIH HHS/United States GR - UL1 TR001082/TR/NCATS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20140415 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (SOX2 protein, human) RN - 0 (SOXB1 Transcription Factors) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases) RN - EC 2.7.1.137 (PIK3CA protein, human) RN - EC 2.7.10.1 (Receptor, Fibroblast Growth Factor, Type 1) SB - IM MH - Carcinoma, Non-Small-Cell Lung/*diagnosis/genetics/pathology MH - Class I Phosphatidylinositol 3-Kinases MH - *DNA Copy Number Variations MH - Female MH - Humans MH - Lung Neoplasms/*diagnosis/genetics/pathology MH - Male MH - Multivariate Analysis MH - Neoplasm Staging MH - Phosphatidylinositol 3-Kinases/*genetics MH - Prognosis MH - Receptor, Fibroblast Growth Factor, Type 1/*genetics MH - SOXB1 Transcription Factors/*genetics MH - Survival Analysis PMC - PMC3988173 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2014/04/17 06:00 MHDA- 2015/05/30 06:00 PMCR- 2014/04/15 CRDT- 2014/04/17 06:00 PHST- 2013/10/30 00:00 [received] PHST- 2014/03/26 00:00 [accepted] PHST- 2014/04/17 06:00 [entrez] PHST- 2014/04/17 06:00 [pubmed] PHST- 2015/05/30 06:00 [medline] PHST- 2014/04/15 00:00 [pmc-release] AID - PONE-D-13-44517 [pii] AID - 10.1371/journal.pone.0095303 [doi] PST - epublish SO - PLoS One. 2014 Apr 15;9(4):e95303. doi: 10.1371/journal.pone.0095303. eCollection 2014.