Loss of RASSF1A Expression in Colorectal Cancer and Its Association with K-ras Status

Background. The RAS-association domain family 1 A (RASSF1A) is a classical member of RAS effectors regulating cell proliferation and apoptosis. Loss of RASSF1A expression may shift the balance towards a growth-promoting effect without the necessity of activating K-ras mutations. Its potential association with K-ras mutations in colorectal cancer (CRC) is unclear. Methods. RASSF1A expression was examined in normal mucosa, adenoma, and tumor tissues of colon and rectum, respectively. We examined the association of RASSF1A expression, mutations of K-ras, and EGFR status in 76 primary CRCs. The relationship between clinicopathological characteristics and RASSF1A expression was also analyzed. Results. RASSF1A expression level decreased progressively in normal mucosa, adenoma and, tumor tissues, and the loss of RASSF1A expression occurred more frequently in tumor tissues. Of 76 primary CRCs, loss of RASSF1A expression and/or K-ras mutations were detected in 77% cases. Loss of RASSF1A expression was more frequent in K-ras wild-type than in mutation cases (63% versus 32%, P = 0.011). Conclusions. Our study indicates that loss of RASSF1A may be involved in pathogenesis of CRC, its expression was found predominantly in K-ras wild-type CRCs, suggesting that it may be another way of affecting RAS signaling, in addition to K-ras mutations.

[1]  Rahul Bhagat,et al.  Aberrant promoter methylation of the RASSF1A and APC genes in epithelial ovarian carcinoma development , 2012, Cellular Oncology.

[2]  A. Kittai,et al.  Antiepidermal Growth Factor Receptor Monoclonal Antibodies: Applications in Colorectal Cancer , 2012, Chemotherapy research and practice.

[3]  M. Arends,et al.  RAS signalling in the colorectum in health and disease , 2012, Cell communication & adhesion.

[4]  Seon Ho Park,et al.  RASSF1A suppresses the activated K-Ras-induced oxidative DNA damage. , 2011, Biochemical and biophysical research communications.

[5]  T. Motoyama,et al.  Inverse correlation between EGFR mutation and FHIT, RASSF1A and RUNX3 methylation in lung adenocarcinoma: relation with smoking status. , 2011, Anticancer research.

[6]  Gang Wu,et al.  Methylation associated inactivation of RASSF1A and its synergistic effect with activated K-Ras in nasopharyngeal carcinoma , 2009, Journal of experimental & clinical cancer research : CR.

[7]  Shuji Ogino,et al.  CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer , 2008, Gut.

[8]  R. Lothe,et al.  RAS signaling in colorectal carcinomas through alteration of RAS, RAF, NF1, and/or RASSF1A. , 2008, Neoplasia.

[9]  Dong Sun Kim,et al.  Hypermethylation of the Ras association domain family 1A (RASSF1A) gene in gallbladder cancer. , 2007, Molecules and cells.

[10]  M. Lerman,et al.  Reduced expression of RASSF1A in esophageal and nasopharyngeal carcinomas significantly correlates with tumor stage. , 2007, Cancer letters.

[11]  H. Donninger,et al.  The RASSF1A tumor suppressor , 2007, Journal of Cell Science.

[12]  L. Hesson,et al.  The Role of RASSF1A Methylation in Cancer , 2007, Disease markers.

[13]  M. Roncalli,et al.  Genetic and epigenetic changes in primary metastatic and nonmetastatic colorectal cancer , 2006, British Journal of Cancer.

[14]  K. Hatakeyama,et al.  Chronic oral exposure to inorganic arsenate interferes with methylation status of p16INK4a and RASSF1A and induces lung cancer in A/J mice. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[15]  Miki Ohira,et al.  Aberrant methylation of RASGRF2 and RASSF1A in human non-small cell lung cancer. , 2006, Oncology reports.

[16]  R. Cohen,et al.  Targeting Signal Transduction Pathways in Colorectal Cancer—More Than Skin Deep , 2005 .

[17]  Jing-Yuan Fang,et al.  The MAPK signalling pathways and colorectal cancer. , 2005, The Lancet. Oncology.

[18]  G. Pfeifer,et al.  Methylation of the Tumor Suppressor Gene RASSF1A in Human Tumors , 2005, Biochemistry (Moscow).

[19]  W. Yeo,et al.  High frequency of promoter hypermethylation of RASSF1A in tumorous and non‐tumourous tissue of breast cancer , 2005, Pathology.

[20]  K. Hatakeyama,et al.  Aberrant expression of pRb and p16(INK4), alone or in combination, indicates poor outcome after resection in patients with colorectal carcinoma. , 2004, Human pathology.

[21]  Y. Shim,et al.  Relationship of Ras association domain family 1 methylation and K-ras mutation in primary non-small cell lung cancer. , 2003, Cancer research.

[22]  G. Pfeifer,et al.  Epigenetic inactivation of RAS association domain family protein 1 (RASSF1A) in malignant cutaneous melanoma. , 2003, Cancer research.

[23]  R. Labianca,et al.  Specific codon 13 K-ras mutations are predictive of clinical outcome in colorectal cancer patients, whereas codon 12 K-ras mutations are associated with mucinous histotype. , 2002, Annals of oncology : official journal of the European Society for Medical Oncology.

[24]  A. Protopopov,et al.  The RASSF1A tumor suppressor gene is inactivated in prostate tumors and suppresses growth of prostate carcinoma cells. , 2002, Cancer research.

[25]  S. Chi,et al.  Frequent epigenetic inactivation of RASSF1A in human bladder carcinoma. , 2001, Cancer research.

[26]  N. Goldstein,et al.  Epidermal growth factor receptor immunohistochemical reactivity in patients with American Joint Committee on Cancer Stage IV colon adenocarcinoma , 2001, Cancer.

[27]  J. Minna,et al.  Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression. , 2001, Journal of the National Cancer Institute.

[28]  A. Bell,et al.  Ras Uses the Novel Tumor Suppressor RASSF1 as an Effector to Mediate Apoptosis* , 2000, The Journal of Biological Chemistry.

[29]  M. Barbacid,et al.  Malignant activation of a K-ras oncogene in lung carcinoma but not in normal tissue of the same patient. , 1984, Science.

[30]  L. Hesson,et al.  The role of RASSF 1 A methylation in cancer , 2014 .

[31]  O. Olopade,et al.  RASSF1A polymorphism A133S is associated with early onset breast cancer in BRCA1/2 mutation carriers. , 2008, Cancer research.

[32]  J. Herman,et al.  RASSF1A methylation and K-ras and B-raf mutations and recurrent endometrial cancer. , 2007, Annals of oncology : official journal of the European Society for Medical Oncology.

[33]  J. Herman,et al.  RASSF 1 A methylation and Kras and B-raf mutations and recurrent endometrial cancer , 2007 .

[34]  A. Protopopov,et al.  The RASSF 1 A Tumor Suppressor Gene Is Inactivated in Prostate Tumors and Suppresses Growth of Prostate Carcinoma Cells 1 , 2002 .

[35]  M. Ohira,et al.  Aberrant methylation of RASGRF 2 and RASSF 1 A in human non-small cell lung cancer , 2022 .