The value of SHOX2 methylation test in peripheral blood samples used for the differential diagnosis of lung cancer and other lung disorders

Our plain-English summary of The value of SHOX2 methylation test in peripheral blood samples used for the differential diagnosis of lung cancer and other lung disorders, by M. Konecny, J. Markus, I. Waczulikova, et al (Neoplasma, 2016).

The study

• Authors: M. Konecny, J. Markus, I. Waczulikova, L. Dolesova, R. Kozlova, V. Repiska, H. Novosadova, I. Majer
• Journal: Neoplasma
• Published: 2016;63(2):246-53
• Cited by: 41 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Methylation of the cytosine residues within the CpG dinucleotides plays an important role in the fundamental cellular processes, human diseases and even cancer. The DNA methylation represents a very stable sign and therefore may be used as a valuable marker for cancer screening. Epigenetic cancer biomarkers are independent of classical morphology and thus show extensive potential to overcome the limitations of cytology. Several epigenetic cancer markers have been reported to be detectable in body fluids such as bronchial aspirate, sputum, plasma and serum.Short stature homeobox gene 2 (SHOX2) encodes a homeo-domain transcription factor, which has been identified as a close homologue of the SHOX gene and both genes are involved in skeletogenesis and heart development. Methylation of SHOX2 gene has been shown to be present at high prevalence in carcinomas of lung, however may also be used to identify other tumour entities.In the presented study, we have compared suitability of two types of material associated with lung cancer for the detection of SHOX2 methylation. We have confirmed that methylation of SHOX2 gene represents reliable marker of lung malignancies. The parallel tests in the blood plasma revealed that it may represent a good alternative material for testing of the SHOX2 methylation, making the test available to patients who are unable to undergo bronchoscopy.

In plain English

This Slovak study tested whether SHOX2 gene methylation could help tell lung cancer apart from other lung disorders. The authors called it an observational case-control study; asbestos was not studied. They tested paired bronchial lavage (lung washing) and blood plasma samples from 69 bronchoscopy patients. Thirty-eight had malignant lung disease by cytology or histology. The other 31 formed a comparison group without lung cancer, which included lymphoma, mesothelioma and a non-lung cancer metastasis. Among valid results, lavage sensitivity was 83.78% (31 of 37; 95% CI 67.99 to 93.81) and specificity 84.62% (22 of 26; 65.13 to 95.65). Blood sensitivity was 64.52% (20 of 31; 45.37 to 80.77) and specificity 78.57% (22 of 28; 59.05 to 91.71). In 53 patients with valid results from both sample types, the tests agreed in 62.26%. Methylation was detected in the one mesothelioma sample (type not stated) and in 50% of the four lymphoma patients. The authors concluded lavage testing is the "gold standard" for this marker and that plasma may be a good alternative, especially when bronchoscopy is not possible. Quite a few tests were invalid because too little DNA was isolated.

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: Observational case-control study with data collected in a cross-sectional manner, evaluating a diagnostic test
• Who was studied: 69 patients (49 men, 20 women) undergoing bronchoscopy for suspected lung cancer or another lung disease at University Hospital in Bratislava, Slovakia. Samples were collected January to December 2014, with extra collection in January and February 2015. 38 were positive for malignant lung disease by cytology or histology. The other 31 were classed as negative for malignancy, but this group included 4 lymphomas, 1 mesothelioma and 1 cancer metastasis of non-lung origin.
• Exposure: No asbestos exposure was studied. The study measured SHOX2 gene methylation in paired bronchial lavage and peripheral blood plasma samples from each patient. Age, gender and smoking status were used in statistical models.
• Main results:
  • Among lung cancer patients, SHOX2 methylation was detected in 31 of 37 valid bronchial lavage samples and 20 of 31 valid blood samples.
  • Among patients without lung cancer, SHOX2 was unmethylated in 22 of 26 valid lavage samples and 22 of 28 valid blood samples.
  • Bronchial lavage test, compared with the final diagnosis: sensitivity 83.78% (67.99 to 93.81), specificity 84.62% (65.13 to 95.65).
  • Peripheral blood test, compared with the final diagnosis: sensitivity 64.52 (45.37 to 80.77), specificity 78.57 (59.05 to 91.71).
  • Among 53 patients with valid results from both sample types, lavage and blood results agreed in 62.26% (Kappa = 0.255; P = 0.029).
  • A model combining the lavage SHOX2 result with age, gender and smoking status, at a probability cut-off of 0.5 or more, gave sensitivity 89.19% and specificity 84.62%.
  • The corresponding model using the blood SHOX2 result gave sensitivity 80.65% and specificity 78.57%.
  • A patient was counted as positive if methylation was found in at least one sample type. On that basis, SHOX2 methylation was found in 100% of small cell lung cancers and 100% of squamous carcinomas, versus 67% of adenocarcinomas (P=0.0381).
  • In the group without lung cancer, SHOX2 methylation was detected in 50% of the 4 lymphoma patients. It was also detected in the single mesothelioma, pulmonary nodule and metastasis samples (one patient each; mesothelioma type not stated).
• The authors' conclusion: The authors concluded that SHOX2 methylation testing of bronchial lavage samples is the "gold standard" for lung cancer diagnosis using this marker. They said plasma may be a good alternative source of tumor DNA, especially for patients unable to undergo bronchoscopy.
• Limitations the authors state:
  • Quite a few tests gave invalid results because too little DNA was isolated.
  • The authors said these technical issues need to be resolved before the assay can be used in clinics.
  • The cancer and non-cancer groups differed in age distribution; the models were adjusted for age.

Topics

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

Medical terms in this study, explained in our Lexicon: Differential Diagnosis, Lung Cancer, Biomarker, Cytology, Aspirate, Sputum, Carcinoma, Bronchoscopy.

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• Peripheral Blood DNA Methylation as Potential Biomarker of Malignant Pleural Mesothelioma in Asbestos-Exposed Subjects — S. Guarrera, C. Viberti, et al. (2019)
• Methylation profile landscape in mesothelioma: possible implications in early detection, disease progression, and therapeutic options — X. Zhang, N. Tang, et al. (2015)
• Improved diagnosis and prognostication of patients with pleural malignant mesothelioma using biomarkers in pleural effusions and peripheral blood samples - a short report — N. Beije, J. Kraan, et al. (2017)
• Aberrant DNA methylation profile in pleural fluid for differential diagnosis of malignant pleural mesothelioma — M. Fujii, N. Fujimoto, et al. (2012)
• Asbestos-associated genome-wide DNA methylation changes in lung cancer — E. Kettunen, H. Hernandez-Vargas, et al. (2017)

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