Mesothelin (MSLN) promoter is hypomethylated in malignant mesothelioma, but its expression is not associated with methylation status of the promoter

Our plain-English summary of Mesothelin (MSLN) promoter is hypomethylated in malignant mesothelioma, but its expression is not associated with methylation status of the promoter, by K. Tan, K. Kajino, S. Momose, et al (Human Pathology, 2010).

The study

• Authors: K. Tan, K. Kajino, S. Momose, A. Masaoka, K. Sasahara, K. Shiomi, H. Izumi, M. Abe, N. Ohtsuji, T. Wang, O. Hino, H. Fujii
• Journal: Human Pathology
• Published: 2010;41(9):1330-8
• Cited by: 25 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Gene methylation leads to malignant progression in some tumors. The mechanism by which mesothelin is expressed in malignant mesothelioma (MM) is not well understood. MM is histologically divided into 3 subtypes, that is, the epithelioid, sarcomatoid, and biphasic types, and it was shown that mesothelin expression was restricted to the epithelioid type and the epithelioid component of the biphasic type of MM. However, its regulatory mechanism of expression has not been clarified. Here, we studied the expression of mesothelin by immunohistochemistry along with the methylation status of 20 CpG sites in the promoter of the mesothelin gene (MSLN) in 118 lung specimens, including 39 MM, 41 lung carcinoma, 26 nonneoplastic pulmonary lesions, and 12 normal lung tissue samples by the methylation-sensitive single nucleotide primer extension technique. We confirmed that mesothelin was expressed in the epithelioid type and epithelioid component of the biphasic type of MM but neither in the sarcomatoid type nor sarcomatous component of the biphasic type. Surprisingly, the MSLN promoter was significantly hypomethylated in the MM cases regardless of its subtype, compared with the other pulmonary lesions and normal lung tissue samples. These findings suggested that hypomethylation of the MSLN promoter may be specifically associated with the formation of MM, regardless of its expression status, and that the expression of mesothelin protein was lost in the sarcomatoid type by some unknown posttranscriptional regulatory mechanism. We also identified 4 CpG sites, among the 20 sites studied, to be more specifically hypomethylated in MM cases.

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In plain English

This laboratory study examined tissue from patients surgically treated between 1996 and 2008 at Juntendo University Hospital in Tokyo. The authors looked at mesothelin, a cell-surface protein, and at methylation (a chemical tag on DNA that can affect whether a gene is active) at 20 sites in the mesothelin gene's control region (promoter). They studied 118 specimens: 39 from pleural malignant mesothelioma, 41 from lung carcinoma, 26 from non-cancerous lung lesions and 12 of normal lung. All 24 epithelioid samples (including epithelioid parts of biphasic tumors) showed mesothelin; all 15 sarcomatoid samples (including sarcomatoid parts of biphasic tumors) did not. At four sites (S6, S11, S12 and S17), the promoter was significantly less methylated in mesothelioma than in the other groups. Epithelioid and sarcomatoid samples did not differ significantly at any site. Across all 118 specimens, lower methylation was significantly related to mesothelin being present, but this was not found within mesothelioma samples alone. The authors concluded that low methylation of this promoter was a characteristic feature of mesothelioma of either type. The study did not measure asbestos exposure.

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 human tissue specimens, using immunohistochemistry (protein staining) and DNA methylation analysis of the mesothelin gene promoter
• Who was studied: 118 specimens from patients surgically treated between 1996 and 2008 at Juntendo University Hospital, Tokyo: 39 pleural malignant mesothelioma, 41 lung carcinoma, 26 nonneoplastic lung lesions and 12 normal lung tissue samples
• Exposure: Asbestos exposure was not measured or reported for these patients. The study examined methylation at 20 CpG sites in the mesothelin gene (MSLN) promoter and mesothelin protein expression.
• Main results:
  • Mesothelioma samples: all 24 epithelioid samples (epithelioid mesothelioma and the epithelioid part of biphasic tumors) were positive for mesothelin
  • Mesothelioma samples: none of the 15 sarcomatoid samples (sarcomatoid mesothelioma and the sarcomatoid part of biphasic tumors) was positive for mesothelin
  • Lung carcinoma samples: mesothelin was found in 6 of 41 (15%)
  • Non-cancerous and normal lung samples: none of the 26 nonneoplastic lesions and none of the 12 normal lung samples was positive for mesothelin
  • At CpG sites S6, S11, S12 and S17, methylation was significantly lower in the mesothelioma group than in the other groups, whether 4 or 7 histologic groups were compared
  • Within mesothelioma, epithelioid and sarcomatoid types did not differ significantly in methylation at any of the 20 CpG sites
  • Across all 118 specimens, methylation level was significantly related to mesothelin expression. This relationship was not detected when only the mesothelioma specimens were analyzed.
  • Mesothelin messenger RNA tended to be higher in 6 epithelioid than in 4 sarcomatoid mesothelioma cases. The difference was not statistically significant.
• The authors' conclusion: The authors concluded that low methylation of the MSLN promoter was a characteristic feature of mesothelioma, whether epithelioid with high mesothelin expression or sarcomatoid with none. They suggested that some unidentified mechanism suppresses mesothelin expression in sarcomatoid mesothelioma.
• Limitations the authors state:
  • The messenger RNA comparison between epithelioid and sarcomatoid mesothelioma was based on a small number of samples with wide variation
  • The authors stated there is no direct evidence that low promoter methylation plays a role in how mesothelioma forms; this was speculation

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelin, Malignant Mesothelioma, Epithelioid, Sarcomatoid, Biphasic Mesothelioma, Immunohistochemistry, Carcinoma.

Related studies

• The relationship between tumor MSLN methylation and serum mesothelin (SMRP) in mesothelioma — H.H. Nelson, L.M. Almquist, et al. (2011)
• Exon deletion in the MSLN gene encoding MPF/mesothelin precursor protein during Laurasiatherian mammal evolution — D.S. Kim, Y. Hahn (2011)
• Promoter methylation of DAP-kinase: association with advanced stage in non-small cell lung cancer — D.H. Kim, H.H. Nelson, et al. (2001)
• Progressive aberrant methylation of the RASSF1A gene in simian virus 40 infected human mesothelial cells — S. Toyooka, M. Carbone, et al. (2002)
• Aberrant methylation of the CDKN2a/p16INK4a gene promoter region in preinvasive bronchial lesions: a prospective study in high-risk patients without invasive cancer — A. Lamy, R. Sesboüé, et al. (2002)
• DNA methylation status of REIC/Dkk-3 gene in human malignancies — T. Hayashi, H. Asano, et al. (2012)

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