GATA binding protein 2 overexpression is associated with poor prognosis in KRAS mutant colorectal cancer.

Colorectal cancer (CRC) is one of the most lethal cancers worldwide. Mutations in KRAS occur with the frequency of 30-50% in CRC leading to decreased therapeutic response to anti-epidermal growth factor receptor (EGFR) agents. Recently GATA2 was proven to be essential in the survival of KRAS mutant non-small cell lung cancer (NSCLC) cells. However, the association between KRAS mutation and GATA2 expression in CRC remains largely unknown. In the present study, dideoxy sequencing and immunohistochemistry were used to determine KRAS mutation and GATA2 expression, respectively, in a cohort of 236 patients. Cox proportional hazard regression and Kaplan-Meier survival analysis were performed to study the association between KRAS mutation or GATA2 expression and clinical outcomes. Kaplan-Meier analysis revealed that KRAS mutant patients with high expression of GATA2 had significantly worse long-term clinical outcomes than those with low expression of GATA2 (P<0.001). Further analysis showed that patients with both KRAS mutation and high GATA2 expression experienced significantly more unfavorable 5-year outcomes than patients with wild- type KRAS and low GATA2 expression (P=0.001). Univariate and multivariate Cox proportional hazard regression demonstrated the GATA2 expression level was an independent risk factor for overall survival of CRC patients (HR 1.645; 95% CI 1.004-2.696; P=0.048). In conclusion, the results of this study demonstrated that high expression of GATA2 is correlated with worse survival outcomes in KRAS mutant CRC patients, suggesting that GATA2 may serve as a novel biomarker for the survival of CRC patients harboring KRAS mutation.

[1]  Xianzhu Yang,et al.  Cationic lipid-assisted polymeric nanoparticle mediated GATA2 siRNA delivery for synthetic lethal therapy of KRAS mutant non-small-cell lung carcinoma. , 2014, Molecular pharmaceutics.

[2]  Sabine Tejpar,et al.  KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer. , 2011, The Lancet. Oncology.

[3]  Rebecca L. Siegel Mph,et al.  Colorectal cancer statistics, 2014 , 2014 .

[4]  Y. Toiyama,et al.  The prognostic value of KRAS mutations in patients with colorectal cancer. , 2012, Oncology reports.

[5]  Kate Johnson,et al.  Advances in the management of colorectal cancer: from biology to treatment , 2014, International Journal of Colorectal Disease.

[6]  F.A.M. Bordonaba,et al.  Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer , 2009 .

[7]  G. Neale,et al.  Low-level GATA2 overexpression promotes myeloid progenitor self-renewal and blocks lymphoid differentiation in mice. , 2015, Experimental hematology.

[8]  A. Jemal,et al.  Cancer treatment and survivorship statistics, 2012 , 2012, CA: a cancer journal for clinicians.

[9]  V. Bigley,et al.  Haematopoietic and immune defects associated with GATA2 mutation , 2015, British journal of haematology.

[10]  Ben Readhead,et al.  A targetable GATA2-IGF2 axis confers aggressiveness in lethal prostate cancer. , 2015, Cancer cell.

[11]  Jung Eun Lee,et al.  Sex- and gender-specific disparities in colorectal cancer risk. , 2015, World journal of gastroenterology.

[12]  P. Delrio,et al.  Genetics, diagnosis and management of colorectal cancer (Review) , 2015, Oncology reports.

[13]  S. Holland,et al.  GATA2 deficiency , 2015, Current opinion in allergy and clinical immunology.

[14]  A. Cerone,et al.  Mathematical modeling of drug resistance due to KRAS mutation in colorectal cancer. , 2016, Journal of theoretical biology.

[15]  Masayuki Yamamoto,et al.  GATA2 is critical for the maintenance of cellular identity in differentiated mast cells derived from mouse bone marrow. , 2015, Blood.

[16]  C. Shou,et al.  Prognostic value of PRL‐3 overexpression in early stages of colonic cancer , 2009, Histopathology.

[17]  S. Qiu,et al.  Decreased Expression of GATA2 Promoted Proliferation, Migration and Invasion of HepG2 In Vitro and Correlated with Poor Prognosis of Hepatocellular Carcinoma , 2014, PloS one.

[18]  Julian Downward,et al.  The GATA2 Transcriptional Network Is Requisite for RAS Oncogene-Driven Non-Small Cell Lung Cancer , 2012, Cell.

[19]  K. Matsuo,et al.  Prognostic value of KRAS and BRAF mutations in curatively resected colorectal cancer. , 2015, World journal of gastroenterology.

[20]  M. Odero,et al.  The role of the GATA2 transcription factor in normal and malignant hematopoiesis. , 2012, Critical reviews in oncology/hematology.

[21]  Supriya Patel,et al.  Prognostic and Predictive Roles of KRAS Mutation in Colorectal Cancer , 2012, International journal of molecular sciences.

[22]  D. Carraro,et al.  Multiple mutations in the Kras gene in colorectal cancer: review of the literature with two case reports , 2011, International Journal of Colorectal Disease.

[23]  N. Zhang,et al.  Expression and prognostic significance of GATA-binding protein 2 in colorectal cancer , 2013, Medical Oncology.

[24]  A. Jemal,et al.  Colorectal cancer statistics, 2014 , 2014, CA: a cancer journal for clinicians.

[25]  A. Jemal,et al.  Cancer treatment and survivorship statistics, 2014 , 2014, CA: a cancer journal for clinicians.

[26]  Dongsheng Tu,et al.  K-ras mutations and benefit from cetuximab in advanced colorectal cancer. , 2008, The New England journal of medicine.

[27]  S. Orkin,et al.  Transcription factor GATA-2 is required for proliferation/survival of early hematopoietic cells and mast cell formation, but not for erythroid and myeloid terminal differentiation. , 1997, Blood.

[28]  J. Darnell Transcription factors as targets for cancer therapy , 2002, Nature Reviews Cancer.

[29]  K. Nephew,et al.  Three-tiered role of the pioneer factor GATA2 in promoting androgen-dependent gene expression in prostate cancer , 2014, Nucleic acids research.

[30]  C. Eng,et al.  GATA2 negatively regulates PTEN by preventing nuclear translocation of androgen receptor and by androgen-independent suppression of PTEN transcription in breast cancer. , 2012, Human molecular genetics.

[31]  D. Berger,et al.  GATA Factors in Gastrointestinal Malignancy , 2011, World Journal of Surgery.

[32]  L. Shen,et al.  Comparative analysis of dideoxy sequencing, the KRAS StripAssay and pyrosequencing for detection of KRAS mutation. , 2010, World journal of gastroenterology.

[33]  Arnulf Stenzl,et al.  Decreased mRNA expression of GATA1 and GATA2 is associated with tumor aggressiveness and poor outcome in clear cell renal cell carcinoma , 2015, Targeted Oncology.

[34]  S. Leng,et al.  GATA2 is Epigenetically Repressed in Human and Mouse Lung Tumors and Is Not Requisite for Survival of KRAS Mutant Lung Cancer , 2014, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[35]  A. Jemal,et al.  Cancer statistics, 2015 , 2015, CA: a cancer journal for clinicians.