Peripheral blood DNA methylation as potential biomarker of Malignant Pleural Mesothelioma in asbestos-exposed subjects.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is an aggressive tumour strongly associated with asbestos exposure. Patients are usually diagnosed when current treatments have limited benefits, highlighting the need for non-invasive early diagnosis tests to monitor asbestos-exposed people.

METHODS: We used a genome-wide methylation array to identify, in asbestos-exposed subjects, novel blood DNA methylation markers of MPM in 163 MPM cases and 137 cancer-free controls (82/68 Training Set; replication in 81/69, Test Set) sampled from the same areas.

RESULTS: Evidence of differential methylation between MPM cases and controls was found (>800 CpG sites, Pfdr <0.05), mainly in immune system related genes. Considering the "top" differentially methylated signals, 7 single-CpGs and 5 genomic regions of coordinated methylation replicated with similar effect size in the Test Set (pfdr <0.05). The top hypomethylated single-CpG (cases vs controls effect size<-0.15, pfdr <0.05 in both Training and Test sets) was detected in FOXK1 (Forkhead-box K1) gene, an interactor of BAP1 which was found mutated in MPM tissue and as germline mutation in familial MPM. In the Test set, comparison of receiver operating characteristic (ROC) curves and the area under the curve (AUC) of two models, including/excluding methylation, showed a significant increase in case/control discrimination when considering DNA methylation together with asbestos exposure (AUC=0.81 vs AUC=0.89, DeLong's test p=0.0013).

CONCLUSIONS: We identified signatures of differential methylation in DNA from whole blood between asbestos exposed MPM cases and controls. Our results provide the rationale to further investigate, in prospective studies, the potential use of blood DNA methylation profiles for the identification of early changes related to MPM carcinogenic process.