Characterization of DNA hypermethylation in two cases of peritoneal mesothelioma

Our plain-English summary of Characterization of DNA hypermethylation in two cases of peritoneal mesothelioma, by R. Hama, Y. Watanabe, K. Shinada, et al (Tumour Biology, 2012).

The study

• Authors: R. Hama, Y. Watanabe, K. Shinada, Y. Yamada, Y. Ogata, Y. Yoshida, T. Tamura, T. Hiraishi, R. Oikawa, J. Sakurai, T. Maehata, H. Koizumi, F. Itoh
• Journal: Tumour Biology
• Published: 2012;33(6):2031-40
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma (MM) is a rare disease with a poor prognosis. Pleural mesothelioma, which is the most common type of MM, is considered to be caused by asbestos exposure and is increasing in incidence, with about 15,000 new cases diagnosed worldwide annually. On the other hand, peritoneal mesothelioma is a very rare type of MM; thus, its pathogenesis is even less understood than pleural mesothelioma. Recent research on the pathogenesis of malignant pleural mesothelioma has indicated that both epigenetic and genetic alterations contribute to tumorigenesis. Here, we hypothesize that peritoneal mesothelioma also has an epigenetic alteration in the same genes (Kazal-type serine peptidase inhibitor domain 1 (KAZALD1), transmembrane protein 30B (TMEM30B), and mitogen-activated protein kinase 13 (MAPK13)). Our goal is to identify DNA methylation of these three candidate genes in two peritoneal mesothelioma cases. Laser capture microdissection was used to separate diseased sections of formalin-fixed paraffin-embedded samples from one surgically resected tissue (epithelial type) and one autopsy tissue (sarcomatous type). Genomic DNA was subsequently extracted by the standard phenol chloroform method. The DNA was then treated with sodium bisulphite, and pyrosequencing analysis was used to quantitatively analyze the methylation of candidate genes reported to be hypermethylated in malignant pleural mesothelioma (KAZALD1, TMEM30B, and MAPK13). TMEM30B and MAPK13 were not methylated in either case. However, KAZALD1 was highly methylated in sarcomatoid-type peritoneal mesothelioma. We first report that the KAZALD1 gene was hypermethylated in sarcomatoid-type malignant peritoneal mesothelioma.

In plain English

This was a report on two patients with malignant peritoneal mesothelioma (mesothelioma of the abdominal lining) at St. Marianna University School of Medicine Hospital in Japan. Case A was a 43-year-old woman with a localized, epithelial-type tumor that was surgically removed. Case B was a 75-year-old man with diffuse, sarcomatoid-type disease who died and was autopsied. The authors reported that neither patient had a background suggesting asbestos exposure. In the tumor tissue they measured DNA methylation, a chemical change that can switch genes off, in three genes that earlier research had linked to pleural mesothelioma. Levels above 15% counted as methylated. TMEM30B was below that level in both cases. MAPK13 measured 2.7% in case A and gave no result in case B. KAZALD1 measured 9.0% in case A and 41.3% in case B. No mutations were found in the tested parts of the p53, KRAS and BRAF genes. The authors noted that only two cases were studied and that larger sets of samples are needed. They suspected that case B's disease developed through KAZALD1 methylation and might be correlated with chronic diverticulitis.

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: Report of two cases, with laboratory analysis of tumor tissue. The tests were DNA methylation of three genes previously linked to malignant pleural mesothelioma, gene mutation testing and immunostaining.
• Who was studied: Two patients with malignant peritoneal mesothelioma hospitalized at St. Marianna University School of Medicine Hospital, Kawasaki, Japan. The article describes the period as 2003 to 2012. Case A was a 43-year-old woman with localized, epithelial-type disease who survived after surgery. Case B was a 75-year-old man with diffuse, sarcomatoid-type disease who died and was autopsied.
• Exposure: Asbestos exposure was not the subject of the study. The authors reported that neither patient had a background suggesting asbestos exposure, and Table 1 lists asbestos exposure as negative for both.
• Main results:
  • A methylation level above 15% was considered methylation positive.
  • TMEM30B measured 1.0% in case A and 0.5% in case B. MAPK13 measured 2.7% in case A. In case B, MAPK13 could not be amplified, so the test gave no result. The authors nonetheless state that neither gene was methylated in either case.
  • KAZALD1 methylation was 9.0% in case A (epithelial type) and 41.3% in case B (sarcomatoid type). The authors described case B as highly methylated.
  • No p53, KRAS or BRAF mutations were found in either case in the gene regions that were tested.
  • For p53, mutation testing covered exons 2 to 11.
  • For KRAS, testing covered codons 12, 13 and 61. For BRAF, it covered only the V600E site.
  • Immunostaining for the KAZALD1 and MAPK13 proteins looked similar in both cases.
• The authors' conclusion: The authors suspected that case B developed peritoneal mesothelioma through KAZALD1 methylation, and that this might be correlated with chronic diverticulitis. They suggested that KAZALD1 hypermethylation in sarcomatoid-type peritoneal mesothelioma may provide clinically useful molecular, diagnostic and therapeutic markers.
• Limitations the authors state:
  • Only two cases were analyzed: one localized and one diffuse peritoneal mesothelioma.
  • The authors said the findings need to be confirmed in a large number of peritoneal mesothelioma samples.
  • No suitable antibody was available to stain for TMEM30B.

Topics

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

Medical terms in this study, explained in our Lexicon: Peritoneal Mesothelioma, Malignant Mesothelioma, Prognosis, Pleural Mesothelioma, Asbestos Exposure, Tumorigenesis, Autopsy, Sarcomatoid.

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