Immune response profiling of malignant pleural mesothelioma for diagnostic and prognostic biomarkers

Our plain-English summary of Immune response profiling of malignant pleural mesothelioma for diagnostic and prognostic biomarkers, by J. Creaney, I.M. Dick, A.W. Musk, et al (Biomarkers, 2016).

The study

• Authors: J. Creaney, I.M. Dick, A.W. Musk, N.J. Olsen, B.W. Robinson
• Journal: Biomarkers
• Published: 2016;21(6):551-61
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The asbestos induced cancer malignant mesothelioma (MM) is difficult to diagnose and has a poor prognosis. MM is an immunological cancer, therefore autoantibodies may be suitable biomarkers and associated with prognosis. We used Protoarray(®) microarrays to determine immune responses to 8798 antigens in 10 MM and 10 asbestos exposed controls and developed diagnostic panels using 17 antigens from this. The AUC of these panels were independently tested in these 10 MM patients and controls and in a validation group of 36 controls and 35 MM patients using luminex assays; none of the antigens identified were validated. Immune responses to RAB38 were associated with a better prognosis.

In plain English

This Western Australian study searched blood for antibodies that might help diagnose malignant pleural mesothelioma or predict survival. The authors first tested stored serum from 10 men with mesothelioma and 10 asbestos-exposed men without detectable lung or pleural disease against 8,798 proteins. For 6,820 (78%) of the proteins, the median antibody response was higher in the mesothelioma group. The authors built 10 panels of 4 to 8 proteins that separated the groups with an AUC (a test-accuracy measure) above 0.8. They then tested 17 of these proteins with a second assay in 35 new mesothelioma patients and 36 controls with benign asbestos-related disease. None of the 17 showed a significantly higher response in mesothelioma, and no panel was diagnostically useful. In all mesothelioma patients combined, after adjustment, each one-log-unit (tenfold) increase in measured antibody response to one protein, RAB38, was associated with better survival (hazard ratio 0.30, 95% CI 0.10 to 0.88). The authors concluded they could not identify a useful diagnostic biomarker. They cited the small discovery sample and the differing control groups as possible reasons.

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: Biomarker discovery and validation study using stored (biobank) serum samples, with a discovery set, an independent validation set, and an extended set of mesothelioma cases for survival analysis
• Who was studied: The samples came from people seen at Sir Charles Gairdner Hospital, Western Australia, or followed up for asbestos exposure. The discovery set was 10 male malignant mesothelioma (MM) cases, mainly of epithelioid histology, and 10 asbestos-exposed controls with no X-ray-detectable lung or pleural disease. The validation set was 35 MM cases and 36 asbestos-exposed controls with benign asbestos-related disease. An extended set of 54 MM cases was used for survival analysis. Collection dates were not given.
• Exposure: All controls had asbestos exposure (fiber types not specified). The study measured serum antibody (immune) responses to 8,798 proteins on a protein microarray, then to selected proteins on Luminex bead assays. Soluble mesothelin was measured for comparison.
• Main results:
  • In the discovery set, the median immune response was higher in the 10 MM patients than in the 10 controls for 6,820 (78%) of the antigens. The response to 61 antigens was significantly two-fold greater in MM cases.
  • In the discovery set, eight of the 10 MM cases clustered separately from the controls, and one MM case grouped with the controls.
  • Ten predictive panels, using 4 to 8 antigens each (19 of 27 selected antigens in total), gave AUC above 0.8 for telling MM from controls in the discovery samples.
  • Re-tested on the Luminex platform in the same discovery samples, immune responses to 8 of the 17 antigens were significantly higher in MM cases than in controls.
  • In the validation samples (35 MM, 36 controls), none of the 17 antigens showed a significantly higher immune response in MM, and none of the 10 panels was diagnostically useful. Soluble mesothelin was significantly higher in MM cases than in controls.
  • Immune response to RAB38 was associated with survival in the combined discovery and validation MM cohort (HR 0.28, 95% CI 0.11 to 0.76, p = 0.012).
  • In all MM patients combined, after adjustment for age, histopathology, study cohort and chemotherapy, RAB38 immune response was associated with a more favourable prognosis (HR 0.30, 95% CI 0.10 to 0.88, p = 0.028).
  • The adjusted HR of 0.30 is per 1 log unit increase in the measured response. The Cox analysis used log10-transformed values, so one log unit is a tenfold increase.
  • The survival analyses were done on log10-transformed values.
  • In Kaplan–Meier analysis by tertiles, the association of RAB38 with survival was confined to the upper tertile of immune response.
• The authors' conclusion: The authors concluded that the study could not identify immune responses that could be developed into a useful biomarker for diagnosing MM. They noted that immune responses to antigens were more common in MM patients than in asbestos-exposed controls. They also said the RAB38 association with prognosis suggests RAB38 warrants further investigation as a treatment target for MM.
• Limitations the authors state:
  • Only a small number of samples were used in the discovery stage, because of resource constraints. The authors say this may have fundamentally contributed to the failure to replicate.
  • The validation controls had benign asbestos-related disease, whereas the discovery controls were healthy asbestos-exposed individuals. The authors say this may have contributed to the non-validation.
  • The MM cases used were heterogeneous, which may have contributed to the non-validation.
  • Candidate antigens were selected partly for a low signal in controls. Different selection criteria might have given a different result.
  • RAB38 was originally chosen as a diagnostic, not a prognostic, candidate. Its link with survival may stand in for responses to another unidentified antigen, or for a high overall immune response.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Biomarker, Malignant Mesothelioma, Prognosis.

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