RRM1 and PTEN as prognostic parameters for overall and disease-free survival in patients with non-small-cell lung cancer.

PURPOSE RRM1 has important functions in the determination of the malignant phenotype. It controls cell proliferation through deoxynucleotide production and metastatic propensity through PTEN induction. It is located in a region of loss of heterozygosity in non-small-cell lung cancer (NSCLC), which is a predictor of poor survival. We hypothesized that RRM1 expression would be a significant predictor of outcome in NSCLC. PATIENTS AND METHODS A retrospective data set of 49 patients and a prospective data set of 77 patients with resectable NSCLC were studied. RNA was extracted from tumor and normal lung tissue, and expression of the genes RRM1, PTEN, and RRM2 was determined by real-time quantitative polymerase chain reaction. RESULTS RRM1 expression was significantly correlated with PTEN and RRM2 expression in tumor tissue. RRM1 and PTEN expression in tumor tissue was highly predictive of overall (P =.011 and.018, respectively) and disease-free survival (P =.002 and.026, respectively). Patients with high levels of expression lived longer and had disease recurrence later than patients with low levels of RRM1 and PTEN. In a multivariate analysis, high RRM1 expression was predictive of long survival independent of tumor stage, performance status, and weight loss. CONCLUSION RRM1 is a biologically and clinically important determinant of malignant behavior in NSCLC. Knowing the level of expression of this gene adds significant information to management decisions independent of the currently used outcome predictors of tumor stage, performance status, and weight loss. Future clinical trials should stratify patients based on expression of this gene to avoid unwanted biases.

[1]  J. Wright,et al.  The R1 component of mammalian ribonucleotide reductase has malignancy-suppressing activity as demonstrated by gene transfer experiments. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[2]  I. Newsham,et al.  High-density marker analysis of 11p15.5 in non-small cell lung carcinomas reveals allelic deletion of one shared and one distinct region when compared to breast carcinomas. , 1996, Cancer research.

[3]  Hong Sun,et al.  TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. , 1997, Cancer research.

[4]  Y Z Xu,et al.  Inhibition of ribonucleotide reduction in CCRF-CEM cells by 2',2'-difluorodeoxycytidine. , 1990, Molecular pharmacology.

[5]  Iqbal Unnisa Ali,et al.  Reduction to homozygosity of genes on chromosome 11 in human breast neoplasia , 1987 .

[6]  W. K. Alfred Yung,et al.  Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers , 1997, Nature Genetics.

[7]  J. Guan,et al.  Stimulation of cell migration by overexpression of focal adhesion kinase and its association with Src and Fyn. , 1996, Journal of cell science.

[8]  Kenneth M. Yamada,et al.  Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. , 1998, Science.

[9]  G. Bepler,et al.  Transcripts in pretreatment biopsies from a three-arm randomized trial in metastatic non-small-cell lung cancer , 2003, Oncogene.

[10]  G. Bepler,et al.  RRM1-induced metastasis suppression through PTEN-regulated pathways , 2003, Oncogene.

[11]  Yusuke Nakamura,et al.  A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage , 2000, Nature.

[12]  M. Berger,et al.  Dysregulation of PTEN and protein kinase B is associated with glioma histology and patient survival. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[13]  Soma Das,et al.  Loss of PTEN expression is associated with metastatic disease in patients with endometrial carcinoma , 2002, Cancer.

[14]  M. Wigler,et al.  PTEN, a Putative Protein Tyrosine Phosphatase Gene Mutated in Human Brain, Breast, and Prostate Cancer , 1997, Science.

[15]  J. Ghiso Inhibition of FAK signaling activated by urokinase receptor induces dormancy in human carcinoma cells in vivo , 2002, Oncogene.

[16]  S. Elledge,et al.  Ribonucleotide reductase: regulation, regulation, regulation. , 1992, Trends in biochemical sciences.

[17]  M. Tachibana,et al.  Expression and prognostic significance of PTEN product protein in patients with esophageal squamous cell carcinoma , 2002, Cancer.

[18]  R. Brezinschek,et al.  Mutation analysis of the PTEN/MMAC1 gene in lung cancer , 1998, Oncogene.

[19]  Y. Engström,et al.  Cell cycle-dependent expression of mammalian ribonucleotide reductase. Differential regulation of the two subunits. , 1985, The Journal of biological chemistry.

[20]  Fang Tan,et al.  The expression of PAX6, PTEN, vascular endothelial growth factor, and epidermal growth factor receptor in gliomas: relationship to tumor grade and survival. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[21]  O. Halvorsen,et al.  Combined loss of PTEN and p27 expression is associated with tumor cell proliferation by Ki-67 and increased risk of recurrent disease in localized prostate cancer. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[22]  M. Hoopmann,et al.  Time to progression is dependent on the expression of the tumour suppressor PTEN in ovarian cancer patients , 2003, European journal of clinical investigation.

[23]  H. Lee,et al.  Tumour suppressor gene expression correlates with gastric cancer prognosis , 2003, The Journal of pathology.

[24]  A. Korshunov,et al.  Immunohistochemical Markers for Prognosis of Anaplastic Astrocytomas , 2002, Journal of Neuro-Oncology.

[25]  Li Mao,et al.  Lack of PTEN expression in non-small cell lung cancer could be related to promoter methylation. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[26]  D. Amadori,et al.  Loss of heterozygosity and K-ras gene mutations in gastric cancer , 1993, Human Genetics.

[27]  J. Willey,et al.  Differential DNA sequence deletions from chromosomes 3, 11, 13, and 17 in squamous-cell carcinoma, large-cell carcinoma, and adenocarcinoma of the human lung. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[28]  M. Imamura,et al.  Allelotype analysis of esophageal squamous cell carcinoma. , 1994, Cancer research.

[29]  G. Bepler,et al.  Three tumor-suppressor regions on chromosome 11p identified by high-resolution deletion mapping in human non-small-cell lung cancer. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[30]  H. Kuwano,et al.  FAK overexpression is correlated with tumour invasiveness and lymph node metastasis in oesophageal squamous cell carcinoma , 2003, British Journal of Cancer.

[31]  M. Mansukhani,et al.  Reduced expression of PTEN correlates with breast cancer progression. , 2002, Human pathology.

[32]  A. Gregor,et al.  Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  G. Bepler,et al.  Lung cancer and the human gene for ribonucleotide reductase subunit M1 (RRM1) , 1999, Mammalian Genome.

[34]  G. Bepler,et al.  Ribonucleotide Reductase Messenger RNA Expression and Survival in Gemcitabine/Cisplatin-Treated Advanced Non-Small Cell Lung Cancer Patients , 2004, Clinical Cancer Research.

[35]  G. Mann,et al.  Ribonucleotide reductase M1 subunit in cellular proliferation, quiescence, and differentiation. , 1988, Cancer research.

[36]  C. Turner,et al.  Tyrosine kinase activity, cytoskeletal organization, and motility in human vascular endothelial cells. , 1994, Molecular biology of the cell.

[37]  Kenneth M. Yamada,et al.  PTEN Interactions with Focal Adhesion Kinase and Suppression of the Extracellular Matrix-dependent Phosphatidylinositol 3-Kinase/Akt Cell Survival Pathway* , 1999, The Journal of Biological Chemistry.