TMPRSS4: a novel tumor prognostic indicator for the stratification of stage IA tumors and a liquid biopsy biomarker for NSCLC patients
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...
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| Format: | info:eu-repo/semantics/article |
| Language: | eng |
| Published: |
MDPI AG
2021
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| Online Access: | https://hdl.handle.net/10171/62302 |
| _version_ | 1793400041263595520 |
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| author | Villalba-Esparza, M. (María) Expósito, F. (Francisco) Pajares, M.J. (María José) Sainz, C. (Cristina) Redrado, M. (Miriam) Remirez, A. (Ana) Wistuba, I.I. (Ignacio I.) Behrens, C. (C.) Jantus-Lewintre, E. (Eloisa) Camps, C. (Carlos) Montuenga-Badia, L.M. (Luis M.) Pio, R. (Rubén) Lozano, M.D. (María Dolores) Andrea, C.E. (Carlos Eduardo) de Calvo-González, A. (Alfonso) |
| author_facet | Villalba-Esparza, M. (María) Expósito, F. (Francisco) Pajares, M.J. (María José) Sainz, C. (Cristina) Redrado, M. (Miriam) Remirez, A. (Ana) Wistuba, I.I. (Ignacio I.) Behrens, C. (C.) Jantus-Lewintre, E. (Eloisa) Camps, C. (Carlos) Montuenga-Badia, L.M. (Luis M.) Pio, R. (Rubén) Lozano, M.D. (María Dolores) Andrea, C.E. (Carlos Eduardo) de Calvo-González, A. (Alfonso) |
| author_sort | Villalba-Esparza, M. (María) |
| collection | DSpace |
| description | 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. |
| format | info:eu-repo/semantics/article |
| id | oai:dadun.unav.edu:10171-62302 |
| institution | Universidad de Navarra |
| language | eng |
| publishDate | 2021 |
| publisher | MDPI AG |
| record_format | dspace |
| spelling | oai:dadun.unav.edu:10171-623022024-02-08T13:51:45Z TMPRSS4: a novel tumor prognostic indicator for the stratification of stage IA tumors and a liquid biopsy biomarker for NSCLC patients Villalba-Esparza, M. (María) Expósito, F. (Francisco) Pajares, M.J. (María José) Sainz, C. (Cristina) Redrado, M. (Miriam) Remirez, A. (Ana) Wistuba, I.I. (Ignacio I.) Behrens, C. (C.) Jantus-Lewintre, E. (Eloisa) Camps, C. (Carlos) Montuenga-Badia, L.M. (Luis M.) Pio, R. (Rubén) Lozano, M.D. (María Dolores) Andrea, C.E. (Carlos Eduardo) de Calvo-González, A. (Alfonso) NSCLC TMPRSS4 Liquid biopsy Prognosis DNA methylation 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. 2021-11-02T09:13:02Z 2021-11-02T09:13:02Z 2019 info:eu-repo/semantics/article https://hdl.handle.net/10171/62302 eng info:eu-repo/semantics/openAccess application/pdf MDPI AG |
| spellingShingle | NSCLC TMPRSS4 Liquid biopsy Prognosis DNA methylation Villalba-Esparza, M. (María) Expósito, F. (Francisco) Pajares, M.J. (María José) Sainz, C. (Cristina) Redrado, M. (Miriam) Remirez, A. (Ana) Wistuba, I.I. (Ignacio I.) Behrens, C. (C.) Jantus-Lewintre, E. (Eloisa) Camps, C. (Carlos) Montuenga-Badia, L.M. (Luis M.) Pio, R. (Rubén) Lozano, M.D. (María Dolores) Andrea, C.E. (Carlos Eduardo) de Calvo-González, A. (Alfonso) TMPRSS4: a novel tumor prognostic indicator for the stratification of stage IA tumors and a liquid biopsy biomarker for NSCLC patients |
| title | TMPRSS4: a novel tumor prognostic indicator for the stratification of stage IA tumors and a liquid biopsy biomarker for NSCLC patients |
| title_full | TMPRSS4: a novel tumor prognostic indicator for the stratification of stage IA tumors and a liquid biopsy biomarker for NSCLC patients |
| title_fullStr | TMPRSS4: a novel tumor prognostic indicator for the stratification of stage IA tumors and a liquid biopsy biomarker for NSCLC patients |
| title_full_unstemmed | TMPRSS4: a novel tumor prognostic indicator for the stratification of stage IA tumors and a liquid biopsy biomarker for NSCLC patients |
| title_short | TMPRSS4: a novel tumor prognostic indicator for the stratification of stage IA tumors and a liquid biopsy biomarker for NSCLC patients |
| title_sort | tmprss4: a novel tumor prognostic indicator for the stratification of stage ia tumors and a liquid biopsy biomarker for nsclc patients |
| topic | NSCLC TMPRSS4 Liquid biopsy Prognosis DNA methylation |
| url | https://hdl.handle.net/10171/62302 |
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