High frequency somatic mutations in RASSF1A in nasopharyngeal carcinoma

Abstract

High frequency loss of 3p21.3 region is a common event in various kinds of tumors including nasopharyngeal carcinoma (NPC). RASSF1A has been identified as a putative tumor suppressor gene residing in this region. Chromosome alterations and epigenetic changes are commonly observed as mechanisms for inactivation of RASSF1A function. In this study, we applied the PCR-cloning-sequencing strategy to examine somatic mutations in RASSF1A in NPC tissues as compared with the sequences detected in the matched peripheral blood lymphocytes. Our results revealed a high incidence of RASSF1A mutation in primary tumor tissues of NPC. There are totally 35 mutations identified in 74% (17/23) of these NPC cases, including 30 transitions, three transversions and two deletions. Most of these mutations result in amino acid changes: three nonsense (stop codon) mutations, two-1 bp deletion (frameshift), 26 missense and the remaining four are synonymous (silent). No obvious 'hot-spot' mutations were observed in this study. A similarly high rate (74%) of promoter methylation of RASSF1A was also detected in the same group of NPC tissues, but no significant correlation between mutation and methylation was detected. Our results suggest various mechanisms involved in inactivation of RASSF1A function and indicate a critical role of RASSF1A in NPC development.

Evaluation of the 3p21.3 tumour-suppressor gene cluster

“…Most of these mutations are located in functional domains of RASSF1A. Recently, using a more sensitive methodology, a high incidence of RASSF1 mutations were found in primary NPC tumours (Pan et al, 2005). Interestingly, however, expression of RASSF1A, but not RASSF1C, is lost or downregulated in a variety of tumours.…”

Retracted: Promoter Methylation of theRASSF1AGene may Contribute to Colorectal Cancer Susceptibility: A Meta-Analysis of Cohort Studies

“…Ras-association domain family 1 isoform A (RASSF1A), encoded by the RASSF1 gene, is one of the most epigenetically silenced elements in human cancers and consists of a diacylglycerol -binding domain, a Ras-association domain, and an ATM kinase phosphorylation consensus motif (Pan et al, 2005;Amin & Banerjee, 2012). To the best of our knowledge, RASSF1A is functionally implicated in a variety of key biological processes, including cell cycle regulation, microtubule stabilization, and cellular adhesion and mortality, as well as apoptosis (Abouzeid et al, 2011).…”

Epigenetics of Nasopharyngeal Carcinoma

“…It has been shown that some genes are high frequently methylated in tumor tissue DNA obtained from NPC primary tumors, but not in normal tissues (Pan et al 2005;Sun et al 2007;Zhang et al 2007;Li, Shu, et al 2011). These genes are ideal candidate to serve as biomarkers for detection of NPC.…”