151 Detection of non-metastatic non-small cell lung cancer in urine INTRODUCTION Lung cancer is one of the most commonly diagnosed cancer types worldwide, and accounts for the highest cancer-related mortality in many countries (1). In early-stage patients, local ablative modalities such as radiotherapy and surgery can be curative (2, 3). This is illustrated by a favorable prognosis of patients with stage I and II NSCLC, with a 5-year survival varying from 52 to 93% (4). Despite curative intent treatments, these patients eventually develop recurrences in approximately 30%, mostly attributable to hematogenous metastases (5). These numbers underline the importance of early detection of NSCLC, and motivate the initiation of large-scale screening trials, such as the NLST and NELSON trials, that investigate the value of low-dose computed tomography (LDCT) in detecting lung cancer in at-risk populations (6-9). A critical issue raised by the NLST is the high rate of false positives (96%) found with LDCT screening. Similar concerns regarding potential over-diagnosis were raised following the NELSON trial (9). Although an algorithm accounting for the tumor volume doubling time reduced the number of false positives, still, high numbers of false positives were found, resulting in unnecessary diagnostic procedures. This hampers the implementation of LDCT screening in Europe (10) and emphasizes the urgent need for additional strategies to discriminate between patients with lung cancer and nonmalignant lesions. Plasma-based liquid biopsies are playing an ever-increasing role in the clinical practice of mainly actionable genomic alteration positive advanced-stage NSCLC (11, 12). Tumorshed cell-free DNA (cfDNA) in the blood, often referred to as circulating tumor DNA (ctDNA), can enable non-invasive NSCLC detection through DNA sequencing (13, 14). However, a less known but promising modality for identifying ctDNA is the use of DNA methylation, i.e., the covalent attachment of methyl (CH3) to cytosine bases located in cytosine-guanine (CpG) dinucleotides, involved in the regulation of gene transcription. In many cancer types, epigenetic dysregulation appears at the early stages of oncogenesis through the hypermethylation of promoter regions of tumor suppressor genes (15). Methylation-based ctDNA analysis could thus be of interest to incorporate in a multidimensional lung cancer screening algorithm with LDCT (16-19). Besides plasma, urine offers an alternative viable source of ctDNA (20-23). Plasma ctDNA can translocate to urine if sufficient fragmentation occurs, enabling renal passage. Urine ctDNA allows for the same diagnostics as ctDNA derived from plasma or sputum, including the detection of NSCLC-specific driver mutations (24) and changes in DNA methylation (19, 25). Moreover, urine has several advantages over plasma, as it is truly non-invasive and does not require healthcare professionals to collect and provides a stable environment for DNA when handled correctly (26). 6
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