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The Factors Predicting Concordant Epidermal Growth Factor Receptor (EGFR) Mutation Detected in Liquid/Tissue Biopsy and the Related Clinical Outcomes in Patients of Advanced Lung Adenocarcinoma with EGFR Mutations
Open AccessArticle

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

IDISNA and Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain
Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra, 31008 Pamplona, Spain
CIBERONC, ISC-III, 28029 Madrid, Spain
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Molecular Oncology Laboratory, FIHGUV & Department of Biotechnology, Universitat Politècnica de València, 46022 Valencia, Spain
Department of Medicine, Universitat de Valencia, 46022 Valencia, Spain
Department of Biochemistry and Genetics, School of Sciences, University of Navarra, 31008 Pamplona, Spain
Department of Pathology, University of Navarra Clinic, 31008 Pamplona, Spain
Author to whom correspondence should be addressed.
These authors shared first authorship.
These authors shared senior authorship.
J. Clin. Med. 2019, 8(12), 2134;
Received: 9 October 2019 / Revised: 25 November 2019 / Accepted: 28 November 2019 / Published: 3 December 2019
(This article belongs to the Special Issue Liquid Biopsies in Lung Cancer)
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.
Keywords: NSCLC; TMPRSS4; liquid biopsy; prognosis; DNA methylation NSCLC; TMPRSS4; liquid biopsy; prognosis; DNA methylation
MDPI and ACS Style

Villalba, M.; Exposito, F.; Pajares, M.J.; Sainz, C.; Redrado, M.; Remirez, A.; Wistuba, I.; Behrens, C.; Jantus-Lewintre, E.; Camps, C.; Montuenga, L.M.; Pio, R.; Lozano, M.D.; de Andrea, C.; Calvo, A. TMPRSS4: A Novel Tumor Prognostic Indicator for the Stratification of Stage IA Tumors and a Liquid Biopsy Biomarker for NSCLC Patients. J. Clin. Med. 2019, 8, 2134.

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