Development of methods in protein analysis for the identification of candidate markers to facilitate the (early) diagnosis of asbestos-associated tumors of the lung and the pleura

Status:

completed 06/2015

Aims:

In Europe, lung cancer was the most common cause of death among all cancers in 2004. Some occupational exposures, like the exposure towards asbestos for example, are known to increase the relative risk for tumors of the lung or the pleura. For surveillance of workers formerly exposed to carcinogens, new screening methods to diagnose tumors at an early stage and to improve the chances for treatment are needed.

Activities/Methods:

Several candidate markers, potentially capable of the (early) diagnosis of tumors of the lung and pleura, have been successfully identified in the project. The first phase of the project from 2013-2015 focused on the discovery phase, in which biophotonical and proteome-analytical methods as well as epigenetic markers and the diagnosis of breathable air by ion mobility spectrometry technology were applied.

Approximately 850 subjects were included in the study. Pathology classified all specimens according to current clinical guidelines and provided the research platforms with them. In addition, microRNA profiles were investigated for the different tumor entities and control samples, which allowed for discrimination of different tumor subtypes.

Results:

Using ion-mobility-spectrometry, exhaled air of patients attending the Ruhrlandklinik in Essen with a suspected diagnosis of lung or pleural cancer was analyzed. The identified spectrometry patterns are currently analyzed.

Using FTIR-Imaging techniques, a spectral data bank for “spectral histopathology” was created, which was used to identify spectral biomarkers, allowing for an automated detection of lung tumors. We combined the spectral detection with laser microdissection of tissue slides and a subsequent identification of differentially expressed proteins to select a collective of mesothelioma samples, in which we differentiated two different histological subtypes (epithelioid vs. sarcomatoid). Applying this new workflow of spectroscopic characterization, laser microdissection and proteome analysis, new candidate markers were identified, which are capable of differentiating between the two aforementioned subtypes.

A promising translational application of these methods may be “just-in-time” or “on-site” diagnostics during surgery. Here, spectral histopathology may complement the classical pathological diagnostics and accelerate clinical diagnosis. This would allow implementing the “new” classification of pulmonary adenocarcinomas from 2012 regarding the assessment of the extent of surgery. Also, resection “in healthy tissue” could be confirmed intraoperatively, which could reduce the need of follow-up operations or subsequent treatment with irradiation or chemotherapy.

On the level of DNA-methylation, more than 800 marker candidates were identified by epigenetic tissue analysis. Moreover, the evidence of potential markers for lung cancer has successfully been confirmed in small biopsies as well as in salvia and blood samples.

The newly identified marker candidates allow for the composition of panels of epigenetic and protein markers with enhanced sensitivity. As soon as these multi marker panels are verified in non-invasive body fluids like blood or salvia and validated in prospective studies, simple and non-invasive marker tests would be available for secondary prevention. These panels may also be used in addition to radiological procedures such as low-dose high-resolution computer tomography (LD-HRCT), currently offered by the DGUV for past exposure examinations.

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