HISTOLOGY AND HISTOPATHOLOGY

Cellular and Molecular Biology

 

Review


The tumor suppressor RASSF1A in human carcinogenesis: an update

R. Dammann1, U. Schagdarsurengin1, C. Seidel1, M. Strunnikova1, M. Rastetter1, K. Baier1 and G.P. Pfeifer2

1AG Tumorgenetik der Medizinischen Fakultät, Martin-Luther-Universität Halle-Wittenberg, Germany and 2Department of Biology, Beckman Research Institute, City of Hope Cancer Center, Duarte, California, USA

Offprint requests to: Dr. Reinhard Dammann, Institut für Humangenetik und Medizinische Biologie, Martin-Luther-Universität Halle-Wittenberg, Magdeburger Straße 2, 06907 Halle/Saale, Germany. e-mail: reinhard.dammann@medizin.uni-halle.de


Summary. Loss of heterozygosity of the small arm of chromosome 3 is one of the most common alterations in human cancer. Most notably, a segment in 3p21.3 is frequently lost in lung cancer and several other carcinomas. We and others have identified a novel Ras effector at this segment, which was termed Ras Association Domain family 1 (RASSF1A) gene. RASSF1 consists of two main variants (RASSF1A and RASSF1C), which are transcribed from distinct CpG island promoters. Aberrant methylation of the RASSF1A promoter region is one of the most frequent epigenetic inactivation events detected in human cancer and leads to silencing of RASSF1A. Hypermethylation of RASSF1A was commonly observed in primary tumors including lung, breast, pancreas, kidney, liver, cervix, nasopharyngeal, prostate, thyroid and other cancers. Moreover, RASSF1A methylation was frequently detected in body fluids including blood, urine, nipple aspirates, sputum and bronchial alveolar lavages. Inactivation of RASSF1A was associated with an advanced tumor stage (e.g. bladder, brain, prostate, gastric tumors) and poor prognosis (e.g. lung, sarcoma and breast cancer). Detection of aberrant RASSF1A methylation may serve as a diagnostic and prognostic marker. The functional analyses of RASSF1A reveal an involvement in apoptotic signaling, microtubule stabilization and mitotic progression. The tumor suppressor RASSF1A may act as a negative Ras effector inhibiting cell growth and inducing cell death. Thus, RASSF1A may represent an epigenetically inactivated bona fide tumor suppressor in human carcinogenesis. Histol Histopathol 20, 645-663 (2005).

Key words: RASSF1A, Cancer, Methylation, Cell cycle, Apoptosis, Ras

DOI: 10.14670/HH-20.645