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Congenital Pulmonary Malformations, or CPM, are anomalies in the development of the lung that occur during fetal development. They can be asymptomatic or lead to symptoms of variable severity since the first months of life. At the moment, there is no unanimous consensus on the surgical resection of the asymptomatic CPM cases: some clinicians advise against it, preferring a conservative approach, while others recommend it, to stimulate the compensatory growth of the rest of the lung and avoid the risk of tumour transformation inside of the malformed tissue. In fact, even though the link between CPM and lung malignancy has not yet been proven, some cases are known in which a lung cancer developed in an adult patient that had a congenital lung malformation that had never been previously diagnosed.

Since changes in the DNA methylation profile play an important role in cancer development, the aim of our study was to verify if any DNA methylation alteration that is known to be associated to cancer exists in malformed lung tissues, by using high-density beadchips (Illumina) to analyse the entire genome. We included in our study 20 DNA samples extracted from malformed lung tissue, resected from 18 patients (of which 2 had two malformations of different types each), one sample from a childhood lung cancer (pleuropulmonary blastoma, or PPB), and 8 control samples from healthy lung tissue adjacent to the malformations of 8 patients among the ones affected by CPM. The analysis of the methylation values of the entire genome considered together (MultiDimensional Scaling, or MDS) shows that the malformed samples are similar to the controls, with which they form a rather homogeneous group (Figure 1, panel A), while the cancer sample has a higher number of differences and thus lies separately from the other samples (Figure 1, panel B).

Figure 1: MultiDimensional Scaling Plot of the whole-genome methylation values of: (A) malformations (blue) and control tissues (red); (B) malformations (blue), control tissues (red) and cancer sample (green).

Each malformed sample was compared singularly with the control group, obtaining a number of differentially methylated regions ranging from 8 to 100. In almost all samples, a part of these regions was localized near genes that belong to the categories of higher interest for this study, which is, the ones related to cancer, cell proliferation and embryo development (Figure 2, panel A). Moreover, each malformed samples had some differentially methylated regions (a percentage ranging from 30% to 84%) in common with the cancer sample (Figure 2, panel B).

Figure 2: (A) Number of differentially methylated regions found in each sample in proximity of the Genes of Interest (or GOI, in dark orange) or of other genes (in light orange). (B) Number of differentially methylated regions in common with the cancer sample (in dark orange) and their percentage with respect to the total (data label) found in each sample.

In conclusion, in each one of the 20 lung malformation samples included in this study were found differentially methylated regions in genes that could play a role in cancer development. The data showed that congenital lung malformations can have premalignant epigenetic features, that are impossible to predict with clinical information only.

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