Aberrant methylation profile of human malignant mesotheliomas and its relationship to SV40 infection

Our plain-English summary of Aberrant methylation profile of human malignant mesotheliomas and its relationship to SV40 infection, by M. Suzuki, S. Toyooka, N. Shivapurkar, et al (Oncogene, 2005).

The study

• Authors: M. Suzuki, S. Toyooka, N. Shivapurkar, H. Shigematsu, K. Miyajima, T. Takahashi, V. Stastny, A.L. Zern, T. Fujisawa, H.I. Pass, M. Carbone, A.F. Gazdar
• Journal: Oncogene
• Published: 2005;24(7):1302-8
• Cited by: 58 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

In plain English

This laboratory study looked for methylation, a chemical change that can switch genes off, in 12 known or suspected tumor suppressor genes. It used 63 surgically removed malignant mesotheliomas, six mesothelioma cell lines, and human mesothelial cells infected with the virus SV40 in the laboratory. The article's abbreviation list defines MM as malignant pleural mesothelioma. It did not report patients' asbestos exposure. Uninfected mesothelial cell cultures showed no methylation of the tested genes. Of the 63 tumors, 59 (94%) had at least one methylated gene, and 31 (49%) contained SV40 sequences. Methylation of RRAD, HPP1, Cyclin D2 and RASSF1A was significantly more frequent in SV40-positive tumors. For example, RASSF1A was methylated in 15 of 31 SV40-positive versus 5 of 32 SV40-negative tumors. Among 50 patients with survival data, methylation of TMS1 or HIC-1 was linked to worse survival, while SV40 presence was not. In two infected cell cultures, six or seven genes became methylated after infection, mostly in later passages. The authors concluded that their data provide evidence that SV40 infection of mesothelial cells induces methylation of several tumor suppressor genes.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study of tumor tissue, cell lines and virus-infected cell cultures, testing methylation of known or suspected tumor suppressor genes by methylation-specific PCR and comparing it with the presence of SV40 sequences and with patient survival
• Who was studied: 63 resected primary malignant mesotheliomas (defined in the abbreviations as malignant pleural mesothelioma). Histology was available for 50 (39 epithelial, 11 sarcomatoid/mixed) and survival data for 50 patients. Also studied: six MM cell lines, four primary cultures of normal or reactive human mesothelial cells from cancer-free patients, and two foci of SV40-infected human mesothelial cells. Dates and location of patients not stated.
• Exposure: The exposure studied was SV40 virus: SV40 large T antigen (Tag) DNA sequences detected by PCR in tumors and cell lines, and laboratory SV40 infection of mesothelial cells. No asbestos exposure data were reported.
• Main results:
  • Four primary mesothelial cell cultures (not SV40-infected) showed no methylation of any of the 12 genes
  • 59 of 63 tumors (94%) had methylation of one or more genes
  • SV40 Tag sequences were found in 31 of 63 tumors (49%) and in four of six cell lines
  • SV40-positive tumors (n=31) versus SV40-negative tumors (n=32), Fisher's exact test: RRAD methylated in 22 (71%) vs 13 (41%), P = 0.02; HPP1 16 (52%) vs 6 (19%), P = 0.009; Cyclin D2 16 (52%) vs 6 (19%), P = 0.009; RASSF1A 15 (48%) vs 5 (16%), P = 0.007
  • TMS1 methylation was found only in SV40-positive tumors (4 of 31, 13%, vs 0 of 32), a difference the authors called of borderline significance (P = 0.05)
  • The methylation index (share of tested genes methylated) was higher in SV40-positive tumors than in SV40-negative tumors: 0.40 plus or minus 0.21 vs 0.24 plus or minus 0.15, P = 0.0007. In cell lines the difference was not statistically significant (P = 0.06).
  • The methylation index was higher in epithelial tumors than in sarcomatous/mixed tumors: 0.35 plus or minus 0.20 vs 0.19 plus or minus 0.15, P = 0.013
  • Among 50 patients with survival data (median follow-up 14.5 months), SV40 presence, histologic subtype and methylation index did not affect survival
  • Among the same 50 patients, those with TMS1 methylation (P = 0.01), HIC-1 methylation (P = 0.02), or methylation of either gene (P = 0.004) had significantly worse overall survival than patients without methylation
  • In two SV40-infected mesothelial cell foci, six (focus 4) or seven (focus 1) genes became methylated. Except for DcR1 in focus 1, methylation was absent in early passages (p6 to p12) and present in later passages (p51 to p60).
• The authors' conclusion: The authors concluded that their data provide evidence that SV40 infection of human mesothelial cells induces methylation of several tumor suppressor genes, and that SV40 plays a role in the development of mesothelioma

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, SV40, Asbestos Exposure, Mesothelial Cells, Tumor Suppressor Gene.

Related studies

• Progressive aberrant methylation of the RASSF1A gene in simian virus 40 infected human mesothelial cells — S. Toyooka, M. Carbone, et al. (2002)
• Evidence against a role for SV40 infection in human mesotheliomas and high risk of false-positive PCR results owing to presence of SV40 sequences in common laboratory plasmids — F. López-Ríos, P.B. Illei, et al. (2004)
• SV40 multiple tissue infection and asbestos exposure in a hyperendemic area for malignant mesothelioma — M. Comar, C. Rizzardi, et al. (2007)
• The role of SV40 in malignant mesothelioma and other human malignancies — M.A. Pershouse, S. Heivly, et al. (2006)
• Cellular and molecular parameters of mesothelioma — M.E. Ramos-Nino, J.R. Testa, et al. (2006)
• Simian virus 40 transformation, malignant mesothelioma and brain tumors — F. Qi, M. Carbone, et al. (2011)

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