SFRP Tumour Suppressor Genes Are Potential Plasma-Based Epigenetic Biomarkers for Malignant Pleural Mesothelioma

Our plain-English summary of SFRP Tumour Suppressor Genes Are Potential Plasma-Based Epigenetic Biomarkers for Malignant Pleural Mesothelioma, by Y.Y. Cheng, E. Mok, S. Tan, et al (Disease Markers, 2017).

The study

• Authors: Y.Y. Cheng, E. Mok, S. Tan, C. Leygo, C. McLaughlin, A.M. George, G. Reid
• Journal: Disease Markers
• Published: 2017;2017:2536187
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is associated with asbestos exposure. Asbestos can induce chronic inflammation which in turn can lead to silencing of tumour suppressor genes. Wnt signaling pathway can be affected by chronic inflammation and is aberrantly activated in many cancers including colon and MPM. SFRP genes are antagonists of Wnt pathway, and SFRPs are potential tumour suppressors in colon, gastric, breast, ovarian, and lung cancers and mesothelioma. This study investigated the expression and DNA methylation of SFRP genes in MPM cells lines with and without demethylation treatment. Sixty-six patient FFPE samples were analysed and have showed methylation of SFRP2 (56%) and SFRP5 (70%) in MPM. SFRP2 and SFRP5 tumour-suppressive activity in eleven MPM lines was confirmed, and long-term asbestos exposure led to reduced expression of the SFRP1 and SFRP2 genes in the mesothelium (MeT-5A) via epigenetic alterations. Finally, DNA methylation of SFRPs is detectable in MPM patient plasma samples, with methylated SFRP2 and SFRP5 showing a tendency towards greater abundance in patients. These data suggested that SFRP genes have tumour-suppresive activity in MPM and that methylated DNA from SFRP gene promoters has the potential to serve as a biomarker for MPM patient plasma.

In plain English

This laboratory study examined SFRP genes, which can hold back tumour growth, in malignant pleural mesothelioma (MPM). In most mesothelioma cell lines, SFRP genes were less active than in non-cancer mesothelial cells (MeT-5A). A drug that removes DNA methylation, a chemical tag that can switch genes off, reactivated at least two SFRP genes in every mesothelioma line. When MeT-5A cells were grown with chrysotile asbestos for 3 months, SFRP1 and SFRP2 activity fell and their methylation rose from day 81. In 66 patients' tumour samples, SFRP5 was methylated in 70% (46 of 66). The article gives SFRP2 as 56% (40 of 66), but 40 of 66 is about 61%, and it does not say which is right. Methylation was not significantly linked to survival. Adding SFRP2 or SFRP5 slowed growth in all 11 mesothelioma cell lines. In plasma from 10 patients and 10 age-matched controls, methylated SFRP2 and SFRP5 separated patients from controls. The authors concluded that SFRP2 and SFRP5 act as tumour suppressors in MPM. They said the small sample means the blood test needs checking in a larger group.

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 using mesothelioma and mesothelial cell lines (including a 3-month in vitro asbestos exposure model), archived tumour samples, and plasma samples
• Who was studied: 11 MPM cell lines and the immortalised mesothelial cell line MeT-5A. Formalin-fixed paraffin-embedded (FFPE) tumour samples from 66 MPM patients, from a previously reported series, with ethics approval at Concord Repatriation General Hospital, Sydney. Plasma from 10 MPM patients and 10 age-matched controls. Dates were not given.
• Exposure: MeT-5A cells were grown for 3 months with or without chrysotile asbestos. The dose is given as 1 μg per cm3 in the methods and as 1 μg per cm2 in the results, and is described as low-level.
• Main results:
  • In most of the MPM cell lines, SFRP genes were downregulated compared with the non-cancer MeT-5A cell line
  • In MPM cell lines, treatment with the demethylating agent decitabine reactivated expression of at least two SFRP genes in every MPM cell line
  • In MeT-5A cells, SFRP1 and SFRP2 gene expression went down with prolonged chrysotile exposure
  • In asbestos-exposed MeT-5A cells, early methylation results did not differ significantly from controls. Later qMSP showed increased methylation of SFRP1 and SFRP2 from day 81, becoming highly methylated by day 108.
  • In the 66 MPM tumour samples, 70% (46 out of 66) had SFRP5 methylation. For SFRP2 the article prints 56% (40 out of 66), but 40 out of 66 is about 61%, and the article does not show which figure is correct.
  • Both SFRP2 and SFRP5 methylation were found in 44% (29 out of 66) of MPM tumour samples
  • Methylation of SFRP2 and SFRP5 was not detected in samples from healthy normal donors. The number of donors was not stated.
  • Cox regression of overall survival by methylation status gave p = 0.06 for SFRP2 and p = 0.56 for SFRP5. The authors described this as a lack of a significant correlation with survival.
  • In all 11 MPM cell lines, adding SFRP2 or SFRP5 separately suppressed cell growth compared with control transfections (p less than 0.05). They also inhibited colony formation.
  • In the non-cancer MeT-5A cell line, growth suppression was much less and not statistically significant (p = 0.07)
  • In plasma from 10 MPM patients and 10 age-matched controls, methylated SFRP2 and SFRP5 DNA showed a distinctive cut-off between patients and healthy controls. The figure legend describes this as significant (p less than 0.05).
  • Methylated SFRP1 and SFRP4 were also detected in plasma, but did not separate patients from controls
• The authors' conclusion: The authors concluded that SFRP2 and SFRP5 act as tumour suppressors in MPM and are silenced by DNA hypermethylation. They also concluded that detecting these genes in plasma shows potential for a noninvasive blood marker.
• Limitations the authors state:
  • Because the plasma sample was small, the authors said they could not conclude whether the finding can be used as a diagnostic marker for MPM
  • The authors said the plasma results need validation in a larger series of MPM patients and controls

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: Biomarker, Pleural Mesothelioma, Asbestos Exposure, Chronic Inflammation, Lung Cancer, Mesothelioma, Mesothelium.

Related studies

• Aberrant promoter methylation of WIF-1 and SFRP1, 2, 4 genes in mesothelioma — H. Kohno, V.J. Amatya, et al. (2010)
• A Succinate Ether Derivative of Tocotrienol Enhances Dickkopf-1 Gene Expression through Epigenetic Alterations in Malignant Mesothelioma Cells — A. Sato, H. Ueno, et al. (2018)
• A recombinant polypeptide of the megakaryocyte potentiating factor is a potential biomarker in plasma for the detection of mesothelioma — I. Raiko, H.P. Rihs, et al. (2017)
• Epigenetic down-regulation of integrin α7 increases migratory potential and confers poor prognosis in malignant pleural mesothelioma — V. Laszlo, M.A. Hoda, et al. (2015)
• Circulating epigenetic biomarkers in lung malignancies: From early diagnosis to therapy — M. Tomasetti, M. Amati, et al. (2017)
• Peripheral Blood DNA Methylation as Potential Biomarker of Malignant Pleural Mesothelioma in Asbestos-Exposed Subjects — S. Guarrera, C. Viberti, et al. (2019)

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