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  • Oncogenomics
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Differential association of STK11 and TP53 with KRAS mutation-associated gene expression, proliferation and immune surveillance in lung adenocarcinoma

Oncogene volume 35, pages 3209–3216 (2016)Cite this article

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Abstract

While mutations in the KRAS oncogene are among the most prevalent in human cancer, there are few successful treatments to target these tumors. It is also likely that heterogeneity in KRAS-mutant tumor biology significantly contributes to the response to therapy. We hypothesized that the presence of commonly co-occurring mutations in STK11 and TP53 tumor suppressors may represent a significant source of heterogeneity in KRAS-mutant tumors. To address this, we utilized a large cohort of resected tumors from 442 lung adenocarcinoma patients with data including annotation of prevalent driver mutations (KRAS and EGFR) and tumor suppressor mutations (STK11 and TP53), microarray-based gene expression and clinical covariates, including overall survival (OS). Specifically, we determined impact of STK11 and TP53 mutations on a new KRAS mutation-associated gene expression signature as well as previously defined signatures of tumor cell proliferation and immune surveillance responses. Interestingly, STK11, but not TP53 mutations, were associated with highly elevated expression of KRAS mutation-associated genes. Mutations in TP53 and STK11 also impacted tumor biology regardless of KRAS status, with TP53 strongly associated with enhanced proliferation and STK11 with suppression of immune surveillance. These findings illustrate the remarkably distinct ways through which tumor suppressor mutations may contribute to heterogeneity in KRAS-mutant tumor biology. In addition, these studies point to novel associations between gene mutations and immune surveillance that could impact the response to immunotherapy.

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References

  1. Siegel R, Naishadham D, Jemal A . Cancer statistics, 2013. CA Cancer J Clin 2013; 63: 11–30.

    Article  PubMed  Google Scholar 

  2. Pao W, Girard N . New driver mutations in non-small-cell lung cancer. Lancet Oncol 2011; 12: 175–180.

    Article  CAS  PubMed  Google Scholar 

  3. Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 2008; 455: 1069–1075.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Weir BA, Woo MS, Getz G, Perner S, Ding L, Beroukhim R et al. Characterizing the cancer genome in lung adenocarcinoma. Nature 2007; 450: 893–898.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cox AD, Der CJ . Ras history: the saga continues. Small GTPases 2010; 1: 2–27.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Mitin N, Rossman KL, Der CJ . Signaling interplay in Ras superfamily function. Curr Biol 2005; 15: R563–R574.

    Article  CAS  PubMed  Google Scholar 

  7. Roberts PJ, Der CJ . Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 2007; 26: 3291–3310.

    Article  CAS  PubMed  Google Scholar 

  8. Bang D, Wilson W, Ryan M, Yeh JJ, Baldwin AS . GSK-3alpha promotes oncogenic KRAS function in pancreatic cancer via TAK1-TAB stabilization and regulation of noncanonical NF-kappaB. Cancer Discov 2013; 3: 690–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Baker NM, Yee Chow H, Chernoff J, Der CJ . Molecular pathways: targeting RAC-p21-activated serine-threonine kinase signaling in RAS-driven cancers. Clin Cancer Res 2014; 20: 4740–4746.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kim HS, Mendiratta S, Kim J, Pecot CV, Larsen JE, Zubovych I et al. Systematic identification of molecular subtype-selective vulnerabilities in non-small-cell lung cancer. Cell 2013; 155: 552–566.

    Article  CAS  PubMed  Google Scholar 

  11. Sos ML, Michel K, Zander T, Weiss J, Frommolt P, Peifer M et al. Predicting drug susceptibility of non-small cell lung cancers based on genetic lesions. J Clin Invest 2009; 119: 1727–1740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gibbons DL, Byers LA, Kurie JM . Smoking, p53 mutation, and lung cancer. Mol Cancer Res 2014; 12: 3–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Shackelford DB, Shaw RJ . The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer 2009; 9: 563–575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sanchez-Cespedes M, Parrella P, Esteller M, Nomoto S, Trink B, Engles JM et al. Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res 2002; 62: 3659–3662.

    CAS  PubMed  Google Scholar 

  15. Shah U, Sharpless NE, Hayes DN . LKB1 and lung cancer: more than the usual suspects. Cancer Res 2008; 68: 3562–3565.

    Article  CAS  PubMed  Google Scholar 

  16. Sanchez-Cespedes M . The role of LKB1 in lung cancer. Fam Cancer 2011; 10: 447–453.

    Article  CAS  PubMed  Google Scholar 

  17. Gao Y, Ge G, Ji H . LKB1 in lung cancerigenesis: a serine/threonine kinase as tumor suppressor. Protein Cell 2011; 2: 99–107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Matsumoto S, Iwakawa R, Takahashi K, Kohno T, Nakanishi Y, Matsuno Y et al. Prevalence and specificity of LKB1 genetic alterations in lung cancers. Oncogene 2007; 26: 5911–5918.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ji H, Ramsey MR, Hayes DN, Fan C, McNamara K, Kozlowski P et al. LKB1 modulates lung cancer differentiation and metastasis. Nature 2007; 448: 807–810.

    Article  CAS  PubMed  Google Scholar 

  20. O'Neill GM, Seo S, Serebriiskii IG, Lessin SR, Golemis EA . A new central scaffold for metastasis: parsing HEF1/Cas-L/NEDD9. Cancer Res 2007; 67: 8975–8979.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gao Y, Xiao Q, Ma H, Li L, Liu J, Feng Y et al. LKB1 inhibits lung cancer progression through lysyl oxidase and extracellular matrix remodeling. Proc Natl Acad Sci USA 2010; 107: 18892–18897.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bild AH, Yao G, Chang JT, Wang Q, Potti A, Chasse D et al. Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature 2006; 439: 353–357.

    Article  CAS  PubMed  Google Scholar 

  23. Singh A, Greninger P, Rhodes D, Koopman L, Violette S, Bardeesy N et al. A gene expression signature associated with ‘K-Ras addiction’ reveals regulators of EMT and tumor cell survival. Cancer Cell 2009; 15: 489–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Loboda A, Nebozhyn M, Klinghoffer R, Frazier J, Chastain M, Arthur W et al. A gene expression signature of RAS pathway dependence predicts response to PI3K and RAS pathway inhibitors and expands the population of RAS pathway activated tumors. BMC Med Genomics 2010; 3: 26.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Chen DT, Hsu YL, Fulp WJ, Coppola D, Haura EB, Yeatman TJ et al. Prognostic and predictive value of a malignancy-risk gene signature in early-stage non-small cell lung cancer. J Natl Cancer Inst 2011; 103: 1859–1870.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chen DT, Nasir A, Culhane A, Venkataramu C, Fulp W, Rubio R et al. Proliferative genes dominate malignancy-risk gene signature in histologically-normal breast tissue. Breast Cancer Res Treat 2010; 119: 335–346.

    Article  PubMed  Google Scholar 

  27. Dunn GP, Koebel CM, Schreiber RD . Interferons, immunity and cancer immunoediting. Nat Rev Immunol 2006; 6: 836–848.

    CAS  PubMed  Google Scholar 

  28. Schreiber RD, Old LJ, Smyth MJ . Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 2011; 331: 1565–1570.

    Article  CAS  PubMed  Google Scholar 

  29. Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ et al. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 2001; 410: 1107–1111.

    Article  CAS  PubMed  Google Scholar 

  30. Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 2003; 348: 203–213.

    Article  CAS  PubMed  Google Scholar 

  31. Fridman WH, Galon J, Pages F, Tartour E, Sautes-Fridman C, Kroemer G . Prognostic and predictive impact of intra- and peritumoral immune infiltrates. Cancer Res 2011; 71: 5601–5605.

    Article  CAS  PubMed  Google Scholar 

  32. Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 2005; 353: 2654–2666.

    Article  CAS  PubMed  Google Scholar 

  33. Yu H, Pardoll D, Jove R . STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 2009; 9: 798–809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yu H, Kortylewski M, Pardoll D . Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 2007; 7: 41–51.

    Article  CAS  PubMed  Google Scholar 

  35. Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ . Natural innate and adaptive immunity to cancer. Annu Rev Immunol 2011; 29: 235–271.

    Article  CAS  PubMed  Google Scholar 

  36. Ji RR, Chasalow SD, Wang L, Hamid O, Schmidt H, Cogswell J et al. An immune-active tumor microenvironment favors clinical response to ipilimumab. Cancer Immunol Immunother 2012; 61: 1019–1031.

    Article  CAS  PubMed  Google Scholar 

  37. Ulloa-Montoya F, Louahed J, Dizier B, Gruselle O, Spiessens B, Lehmann FF et al. Predictive gene signature in MAGE-A3 antigen-specific cancer immunotherapy. J Clin Oncol 2013; 31: 2388–2395.

    Article  CAS  PubMed  Google Scholar 

  38. Gajewski TF, Schreiber H, Fu YX . Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 2013; 14: 1014–1022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Fuertes MB, Woo SR, Burnett B, Fu YX, Gajewski TF . Type I interferon response and innate immune sensing of cancer. Trends Immunol 2013; 34: 67–73.

    Article  CAS  PubMed  Google Scholar 

  40. Gajewski TF, Schumacher T . Cancer immunotherapy. Curr Opin Immunol 2013; 25: 259–260.

    Article  CAS  PubMed  Google Scholar 

  41. Gajewski TF, Woo SR, Zha Y, Spaapen R, Zheng Y, Corrales L et al. Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment. Curr Opin Immunol 2013; 25: 268–276.

    Article  CAS  PubMed  Google Scholar 

  42. Hopewell EL, Zhao W, Fulp WJ, Bronk CC, Lopez AS, Massengill M et al. Lung tumor NF-kappaB signaling promotes T cell-mediated immune surveillance. J Clin Invest 2013; 123: 2509–2522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, Beare D et al. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res 2011; 39 (Database issue): D945–D950.

    Article  CAS  PubMed  Google Scholar 

  44. Meng D, Yuan M, Li X, Chen L, Yang J, Zhao X et al. Prognostic value of K-RAS mutations in patients with non-small cell lung cancer: a systematic review with meta-analysis. Lung Cancer 2013; 81: 1–10.

    Article  PubMed  Google Scholar 

  45. Kaufman JM, Amann JM, Park K, Arasada RR, Li H, Shyr Y et al. LKB1 Loss induces characteristic patterns of gene expression in human tumors associated with NRF2 activation and attenuation of PI3K-AKT. J Thorac Oncol 2014; 9: 794–804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Carretero J, Shimamura T, Rikova K, Jackson AL, Wilkerson MD, Borgman CL et al. Integrative genomic and proteomic analyses identify targets for Lkb1-deficient metastatic lung tumors. Cancer Cell 2010; 17: 547–559.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by a National Institutes of Health SPORE Grant (P50 CA119997). We would also like to thank Mr Andrew ‘Ross’ Myers, Anastasia Belock, Mercedes Rodriguez, Edward T Chwieseni, Marek Wloch, Hiba Gohar, and Moffitt’s Tissue Core facility, Moffitt’s Cancer Registry (Director: Karen A Coyne), Research Information Technology (IT) group, and the Data Management and Integration Technology (DMIT) group. Total Cancer Care® is enabled, in part, by the generous support of the DeBartolo Family, and we thank the many patients who provided data and tissue to the Total Cancer Care Consortium. Our study also received valuable assistance from the following Core Facilities at the Moffitt Cancer Center: Biostatistics and Cancer Informatics, Tissue, and Molecular Genomics. This work has been supported in part by a Cancer Center Support Grant (CCSG grant P30-CA76292) at the H. Lee Moffitt Cancer Center and Research Institute, a National Cancer Institute-designated Comprehensive Cancer Center.

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Authors and Affiliations

  1. Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    M B Schabath

  2. Department of Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    E A Welsh, J K Teer, A E Berglund & S A Eschrich

  3. Department of Biostatisics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    W J Fulp, L Chen, Z J Thompson & D-T Chen

  4. Cancer Biology Graduate Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    B E Engel & M Xie

  5. Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    B C Creelan, S J Antonia, J E Gray & E B Haura

  6. Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    W D Cress

  7. Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    A A Beg

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  1. M B Schabath
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Correspondence to M B Schabath or A A Beg.

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Schabath, M., Welsh, E., Fulp, W. et al. Differential association of STK11 and TP53 with KRAS mutation-associated gene expression, proliferation and immune surveillance in lung adenocarcinoma. Oncogene 35, 3209–3216 (2016). https://doi.org/10.1038/onc.2015.375

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