TMPRSS4: A Novel Tumor Prognostic Indicator for the Stratification of Stage IA Tumors and a Liquid Biopsy Biomarker for NSCLC Patients

Abstract

Relapse rates in surgically resected non-small-cell lung cancer (NSCLC) patients are between 30% and 45% within five years of diagnosis, which shows the clinical need to identify those patients at high risk of recurrence. The eighth TNM staging system recently refined the classification of NSCLC patients and their associated prognosis, but molecular biomarkers could improve the heterogeneous outcomes found within each stage. Here, using two independent cohorts (MDA and CIMA-CUN) and the eighth TNM classification, we show that TMPRSS4 protein expression is an independent prognostic factor in NSCLC, particularly for patients at stage I: relapse-free survival (RFS) HR, 2.42 (95% CI, 1.47–3.99), p < 0.001; overall survival (OS) HR, 1.99 (95% CI, 1.25–3.16), p = 0.004). In stage IA, high levels of this protein remained associated with worse prognosis (p = 0.002 for RFS and p = 0.001 for OS). As TMPRSS4 expression is epigenetically regulated, methylation status could be used in circulating tumor DNA from liquid biopsies to monitor patients. We developed a digital droplet PCR (ddPCR) method to quantify absolute copy numbers of methylated and unmethylated CpGs within the TMPRSS4 and SHOX2 (as control) promoters in plasma and bronchoalveolar lavage (BAL) samples. In case-control studies, we demonstrated that TMPRSS4 hypomethylation can be used as a diagnostic tool in early stages, with an AUROC of 0.72 (p = 0.008; 91% specificity and 52% sensitivity) for BAL and 0.73 (p = 0.015; 65% specificity and 90% sensitivity) for plasma, in early stages. In conclusion, TMPRSS4 protein expression can be used to stratify patients at high risk of relapse/death in very early stages NSCLC patients. Moreover, analysis of TMPRSS4 methylation status by ddPCR in blood and BAL is feasible and could serve as a non-invasive biomarker to monitor surgically resected patients.

SRC family kinase (SFK) inhibitor dasatinib improves the antitumor activity of anti-PD-1 in NSCLC models by inhibiting Treg cell conversion and proliferation

“…The H-score was then calculated following previously published protocols. 17 Cohort of patients with NSCLC to study expression of SFK members: bioinformatic analysis The description of the cohort and the bioinformatic analysis are described in online supplemental material and methods.…”

Anti-Tumor Functions of Prelatent Antithrombin on Glioblastoma Multiforme Cells

“…In addition, this pathway correlates with increased invasion and GB cell migration [ 44 ]. These actions require that the extracellular matrix be degraded by matrix metalloproteinases (MMPs) and several components of the hepsin/transmembrane protease, serine (TMPRSS) subfamily [ 15 , 45 , 46 , 47 , 48 ].…”

Liquid Biopsy is Instrumental for 3PM Dimensional Solutions in Cancer Management

“…EV-based liquid biopsy for EGFR genotyping using bronchoalveolar lavage fluid obtained from tumor sites has been related to highly accurate diagnosis of lung cancer patients, which is associated with the content of double-stranded DNA in EVs that reflects the mutational status of parental cancer cells in NSCLC [ 153 ]. Furthermore, TMPRSS4 methylation status in bronchoalveolar lavage and plasma samples could be also used as a promising biomarker to monitor surgically resected NSCLC patients [ 188 ]. In addition, Li et al have recently introduced a dual-layer precise, efficient, rapid, flexible, easy-to-operate, controllable, and thin (PERFECT) filter system that allows rapid liquid biopsy of lung cancer by separation and detection of exfoliated cancer cells from bronchoalveolar lavage fluid [ 189 ].…”