1. ¹Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
2. ²Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba 2608670, Japan
3. ³Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
4. ⁴Department of Thoracic Surgery, Karamanos Cancer Center, Detroit, MI 48201, USA
5. ⁵Department of Pathology, Cardinal Bernardin Cancer Center, Loyola University Chicago, Maywood, IL 60153, USA

Correspondence: AF Gazdar, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard Dallas, TX 75390-8593, USA. E-mail: adi.gazdar@utsouthwestern.edu

⁶These two authors contributed equally to this work

Received 5 July 2004; Revised 23 September 2004; Accepted 8 October 2004; Published online 13 December 2004.

Abstract

Malignant mesothelioma (MM) is associated with asbestos exposure and the presence of SV40 viral sequences. Recently, we reported that SV40 infection of human mesothelial cells (HM) causes aberrant methylation of the tumor suppressor gene (TSG) RASSF1A. We investigated methylation of 12 genes by methylation-specific PCR in 63 MMs, six MM cell lines, and two foci of SV40-infected HM. Methylation percentages of the tested genes ranged from 3 to 65%. The frequencies of HPP1, RASSF1A, Cyclin D2, and RRAD methylation, and the value of the methylation index, were significantly higher in SV40 sequence-positive MMs than in SV40-negative MMs. Methylation of TMS1 and HIC-1 was associated with shortened survival. SV40-infected HM showed progressive aberrant methylation of seven genes (RASSF1A, HPP1, DcR1, TMS1, CRBP1, HIC-1, and RRAD) during serial passage. Our results demonstrate a relationship between SV40 and methylation of multiple genes in MM, indicating that the virus plays a role in the pathogenesis of MM.