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SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas

Abstract

Lineage-survival oncogenes are activated by somatic DNA alterations in cancers arising from the cell lineages in which these genes play a role in normal development1,2. Here we show that a peak of genomic amplification on chromosome 3q26.33 found in squamous cell carcinomas (SCCs) of the lung and esophagus contains the transcription factor gene SOX2, which is mutated in hereditary human esophageal malformations3, is necessary for normal esophageal squamous development4, promotes differentiation and proliferation of basal tracheal cells5 and cooperates in induction of pluripotent stem cells6,7,8. SOX2 expression is required for proliferation and anchorage-independent growth of lung and esophageal cell lines, as shown by RNA interference experiments. Furthermore, ectopic expression of SOX2 here cooperated with FOXE1 or FGFR2 to transform immortalized tracheobronchial epithelial cells. SOX2-driven tumors show expression of markers of both squamous differentiation and pluripotency. These characteristics identify SOX2 as a lineage-survival oncogene in lung and esophageal SCC.

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Figure 1: Recurrent genomic amplifications of 3q target SOX2 in lung and esophageal squamous cell carcinomas.
Figure 2: SOX2 knockdown via RNAi reduces anchorage-independent growth and proliferation of SOX2-overexpressing cell lines.
Figure 3: SOX2 can transform FOXE1- or FGFR2 IIIb–expressing immortalized tracheobronchial epithelial cells.
Figure 4: SOX2 induces expression of markers of both pluripotency and squamous differentiation.

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Acknowledgements

We thank J. Francis, J. Cho, A. Schinzel, R. Firestein, I. Guney and J. Boehm for technical advice and discussions. A.J.B. is supported by the Harvard Clinical Investigator Training Program and American Society of Clinical Oncology. H.W. is supported by a Ruth L. Kirschstein NRSA T32 institutional training grant. R.G.V. is supported by the KWF Kankerbestrijding. The Morphology, Molecular Biology and Cell Culture Core of 5P01CA098101-05 (A.K.R.) provided tissue processing for this project. This work was supported by US Department of Defense VITAL grant (J.D.M, A.F.G.) and by National Cancer Institute grants K08CA134931 (A.J.B.), P50CA70907 (J.D.M, A.F.G.), R33CA128625 (W.C.H.), R01CA071606-12 (D.G.B.), P01CA098101-05 (A.K.R.) and R01CA109038 and P50CA90578 (M.M.). Funding for lung SCC SNP arrays was provided by Genentech, Inc. Funding was provided by the Sara Thomas Monopoli Lung Cancer Research Fund and the Seaman Corporation Fund for Lung Cancer Research.

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L.R.C., H.N., D.B.S., L.L., T.J.G., J.D.M., A.F.G., M.S.B., I.C., U.R. Jr., S.K.M., O.D., M.-S.T., K.K.W. and D.G.B. provided samples for analysis. S.P., P.W., C.J.L., V.S., T.W. and M.A.R. performed and analyzed FISH assays and performed immunohistochemistry analysis. C.H.M., R.G.V., P.T., I.G.-V., A.H.R., B.A.W., G.G., R.B., M.O., J.K., C.M., S.R. and A.R. performed bioinformatic analysis. A.J.B., H.W., S.Y., S.Y.K., L.W., P.D. and C.Q.Z. performed laboratory experiments. O.R.-R., A.D. and M.S.W. provided expression constructs and extensive technical expertise. R.A.S. and W.C.H. provided guidance regarding experimental design and data interpretation. A.J.B., H.W., A.K.R. and M.M. designed the study, analyzed data and prepared the manuscript. All authors discussed results and edited the manuscript.

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Correspondence to Matthew Meyerson.

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The authors Matthew Meyerson, William C Hahn and Ramesh A Shivdasani serve as consultants to Novartis.

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Bass, A., Watanabe, H., Mermel, C. et al. SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat Genet 41, 1238–1242 (2009). https://doi.org/10.1038/ng.465

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