Review The tumor suppressor RASSF1A in human carcinogenesis: an update

Summary. Lossof heterozygosityof the small arm ofchromosome 3 is one of the most common alterations inhuman cancer. Most notably, a segment in 3p21.3 isfrequently lost in lung cancer and several othercarcinomas. We and others have identified a novel Raseffector at this segment, which was termed RasAssociation Domain family 1 (RASSF1A) gene.RASSF1 consists of two main variants (RASSF1A andRASSF1C), which are transcribed from distinct CpGisland promoters. Aberrant methylation of the RASSF1Apromoter region is one of the most frequent epigeneticinactivation events detected in human cancer and leadsto silencing of RASSF1A. Hypermethylation ofRASSF1A was commonly observed in primary tumorsincluding lung, breast, pancreas, kidney, liver, cervix,nasopharyngeal, prostate, thyroid and other cancers.Moreover, RASSF1A methylation was frequentlydetected in body fluids including blood, urine, nippleaspirates, sputum and bronchial alveolar lavages.Inactivation of RASSF1A was associated with anadvanced tumor stage (e.g. bladder, brain, prostate,gastric tumors) and poor prognosis (e.g. lung, sarcomaand breast cancer). Detection of aberrant RASSF1Amethylation may serve as a diagnostic and prognosticmarker. The functional analyses of RASSF1A reveal aninvolvement in apoptotic signaling, microtubulestabilization and mitotic progression. The tumorsuppressor RASSF1A may act as a negative Ras effectorinhibiting cell growth and inducing cell death. Thus,RASSF1A may represent an epigenetically inactivated