Liquid Biopsy Is a Promising Tool for Genetic Testing in Idiopathic Pulmonary Fibrosis

Abstract

Liquid biopsy, which allows the isolation of circulating cell-free (ccf) DNA from blood, is an emerging noninvasive tool widely used in oncology for diagnostic and prognosis purposes. Previous data have shown that serum cfDNA discriminates idiopathic pulmonary fibrosis (IPF) from other interstitial lung diseases. Our study aimed to measure plasma levels of ccfDNA in 59 consecutive therapy-naive and clinically stable IPF patients. The single nucleotide polymorphism (SNP) of the MUC5B gene promoter (rs35705950), associated with increased susceptibility of developing IPF, has been sought in plasma cfDNA and genomic DNA for comparison. Thirty-five age- and sex-matched healthy volunteers were recruited as the control group. Our results show that concentrations of small-size ccfDNA fragments were significantly higher in IPF patients than in controls and inversely correlated with lung function deterioration. Moreover, the median level of 104 ng/mL allowed discriminating patients with mild disease from those more advanced. The rs35705950 polymorphism was found in 11.8% of IPF patients and 8% of controls, with no differences. Complete concordance between ccfDNA and genomic DNA was detected in all control samples, while four out of seven IPF cases (57%) carrying the rs35705950 polymorphism were discordant from genomic DNA (7% of total IPF). Liquid biopsy is a suitable tool with optimistic expectations of application in the field of IPF. In analogy with cancer biology, finding some discrepancies between ccfDNA and genomic DNA in IPF patients suggests that the former may convey specific genetic information present in the primary site of the disease.

Molecular Mechanisms and Cellular Contribution from Lung Fibrosis to Lung Cancer Development

“…Indeed, the TGF-β that is a chemotactic factor for monocytes and macrophages, and triggers in these cell populations the release of PDGF, IL-1β, basic FGF (bFGF), and TNF-α. To this purpose, an upregulation of the TGF-β expression level has been observed both in AECs and macrophages from the lung tissues of IPF patients [23] as well as in IPF induced in vivo model named the bleomycin mouse model [24]. Indeed, to this purpose the alveolar macrophages play an important role in both IPF and lung cancer progression as highlighted in the work of Jovanovic et al [145], who found positive membrane PD-L1 expression in alveolar macrophages of IPF lung tissue samples in 9 samples out of 12.…”

“…Non-fibrillar collagens (such as collagen VI) have been reported to stimulate myofibroblast trans-differentiation, both in vitro and in vivo [201]. Moreover, the deposition of pericellular hyaluronan may also facilitate and maintain myofibroblast trans-differentiation in response to TGF-β [194], while an independent activation of CD44 signalling by hyaluronan may accentuate the TGF-β/SMAD signalling cascade [24]. Myofibroblasts are also able to modify the biological and mechanical properties of ECM through the secretion of MMPs and tissue inhibitors of metalloproteinases (TIMPs) [202].…”

“…As is the case with IPF, there are several hypotheses still under debate regarding the cellular sources of CAFs Recent studies have focused on the identification of common molecular pathways between IPF and LC for a better therapeutic strategy and optimal management of patients with both diseases. There are many common cellular and molecular mechanisms that might predispose patients to the onset and development of IPF and LC such as the activation and proliferation of both myofibroblasts (IPF) and cancer-associated fibroblasts (CAFs), and the alteration of growth factors expression level [24]. Myofibroblasts represent the cellular key players in IPF since their proliferation and activation under profibrotic stimuli lead to the secretion and deposition of extracellular matrix (ECM) proteins, which are responsible for causing fibrosis [25].…”

“…(Figure 1) To date, the approved IPF therapies, Pirfenidone and Nintedanib, are also active in LC. In particular, Nintedanib is approved as a treatment in NSCLC, and Pirfenidone has shown anti-neoplastic effects in preclinical studies [24]. Hence, with this review we would like to summarize and clarify the mechanisms implicated in the development of both IPF and LC patients highlighting the similarities in the pathogenesis of both diseases.…”

“…Hopefully, this would ameliorate the prognosis, opening the possibility of new therapeutic strategies and improving survival among IPF-LC patients. Indeed, there are also common genetic mechanisms shared by both diseases based on mutations in surfactant protein genes (SFTPA2-A1) that lead to impaired protein secretion, endoplasmic reticular stress, and apoptosis, culminating in the onset and progression of IPF or adenocarcinoma [24]. (Figure 1) To date, the approved IPF therapies, Pirfenidone and Nintedanib, are also active in LC.…”