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NDN and CD1A are novel prognostic methylation markers in patients with head and neck squamous carcinomas

BACKGROUND: HPV-associated HNSCCs have a distinct etiologic mechanism and better prognosis than those with non-HPV associated HNSCCs. However, even within the each group, there is heterogeneity in survival time. Here, we test the hypothesis that specific candidate gene methylation markers (CCNA1, ND...

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Autores principales: Virani, Shama, Bellile, Emily, Bradford, Carol R., Carey, Thomas E., Chepeha, Douglas B., Colacino, Justin A., Helman, Joseph I., McHugh, Jonathan B., Peterson, Lisa A., Sartor, Maureen A., Taylor, Jeremy MG, Walline, Heather M., Wolf, Greg T., Rozek, Laura S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4628358/
https://www.ncbi.nlm.nih.gov/pubmed/26518708
http://dx.doi.org/10.1186/s12885-015-1806-8
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author Virani, Shama
Bellile, Emily
Bradford, Carol R.
Carey, Thomas E.
Chepeha, Douglas B.
Colacino, Justin A.
Helman, Joseph I.
McHugh, Jonathan B.
Peterson, Lisa A.
Sartor, Maureen A.
Taylor, Jeremy MG
Walline, Heather M.
Wolf, Greg T.
Rozek, Laura S.
author_facet Virani, Shama
Bellile, Emily
Bradford, Carol R.
Carey, Thomas E.
Chepeha, Douglas B.
Colacino, Justin A.
Helman, Joseph I.
McHugh, Jonathan B.
Peterson, Lisa A.
Sartor, Maureen A.
Taylor, Jeremy MG
Walline, Heather M.
Wolf, Greg T.
Rozek, Laura S.
author_sort Virani, Shama
collection PubMed
description BACKGROUND: HPV-associated HNSCCs have a distinct etiologic mechanism and better prognosis than those with non-HPV associated HNSCCs. However, even within the each group, there is heterogeneity in survival time. Here, we test the hypothesis that specific candidate gene methylation markers (CCNA1, NDN, CD1A, DCC, p16, GADD45A) are associated with tumor recurrence and survival, in a well-characterized, prospective, cohort of 346 HNSCC patients. METHODS: Kaplan-Meier curves were used to estimate survival time distributions. Multivariable Cox Proportional Hazards models were used to test associations between each methylation marker and OST/RPFT after adjusting for known or identified prognostic factors. Stratified Cox models included an interaction term between HPV and methylation marker to test for differences in the associations of the biomarker with OST or RPFT across HPV status. RESULTS: Methylation markers were differentially associated with patient characteristics. DNA hypermethylation of NDN and CD1A was found to be significantly associated with overall survival time (OST) in all HNSCC patients (NDN hazard ratio (HR): 2.35, 95 % CI: 1.40-3.94; CD1A HR: 1.31, 95 % CI: 1.01-1.71). Stratification by HPV status revealed hypermethylation of CD1A was associated with better OST and recurrence/persistence-free time (RPFT) (OST HR: 3.34, 95 % CI: 1.88-5.93; RPFT HR: 2.06, 95 % CI: 1.21-3.49), while hypomethylation of CCNA1 was associated with increased RPFT in HPV (+) patients only (HR: 0.31, 95 % CI: 0.13-0.74). CONCLUSIONS: This study is the first to describe novel epigenetic alterations associated with survival in an unselected, prospectively collected, consecutive cohort of patients with HNSCC. DNA hypermethylation of NDN and CD1A was found to be significantly associated with increased overall survival time in all HNSCC patients. However, stratification by the important prognostic factor of HPV status revealed the immune marker, CD1A, and the cell cycle regulator, CCNA1 to be associated with prognosis in HPV (+) patients, specifically. Here, we identified novel methylation markers and specific, epigenetic molecular differences associated with HPV status, which warrant further investigation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-015-1806-8) contains supplementary material, which is available to authorized users.
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spelling pubmed-46283582015-11-01 NDN and CD1A are novel prognostic methylation markers in patients with head and neck squamous carcinomas Virani, Shama Bellile, Emily Bradford, Carol R. Carey, Thomas E. Chepeha, Douglas B. Colacino, Justin A. Helman, Joseph I. McHugh, Jonathan B. Peterson, Lisa A. Sartor, Maureen A. Taylor, Jeremy MG Walline, Heather M. Wolf, Greg T. Rozek, Laura S. BMC Cancer Research Article BACKGROUND: HPV-associated HNSCCs have a distinct etiologic mechanism and better prognosis than those with non-HPV associated HNSCCs. However, even within the each group, there is heterogeneity in survival time. Here, we test the hypothesis that specific candidate gene methylation markers (CCNA1, NDN, CD1A, DCC, p16, GADD45A) are associated with tumor recurrence and survival, in a well-characterized, prospective, cohort of 346 HNSCC patients. METHODS: Kaplan-Meier curves were used to estimate survival time distributions. Multivariable Cox Proportional Hazards models were used to test associations between each methylation marker and OST/RPFT after adjusting for known or identified prognostic factors. Stratified Cox models included an interaction term between HPV and methylation marker to test for differences in the associations of the biomarker with OST or RPFT across HPV status. RESULTS: Methylation markers were differentially associated with patient characteristics. DNA hypermethylation of NDN and CD1A was found to be significantly associated with overall survival time (OST) in all HNSCC patients (NDN hazard ratio (HR): 2.35, 95 % CI: 1.40-3.94; CD1A HR: 1.31, 95 % CI: 1.01-1.71). Stratification by HPV status revealed hypermethylation of CD1A was associated with better OST and recurrence/persistence-free time (RPFT) (OST HR: 3.34, 95 % CI: 1.88-5.93; RPFT HR: 2.06, 95 % CI: 1.21-3.49), while hypomethylation of CCNA1 was associated with increased RPFT in HPV (+) patients only (HR: 0.31, 95 % CI: 0.13-0.74). CONCLUSIONS: This study is the first to describe novel epigenetic alterations associated with survival in an unselected, prospectively collected, consecutive cohort of patients with HNSCC. DNA hypermethylation of NDN and CD1A was found to be significantly associated with increased overall survival time in all HNSCC patients. However, stratification by the important prognostic factor of HPV status revealed the immune marker, CD1A, and the cell cycle regulator, CCNA1 to be associated with prognosis in HPV (+) patients, specifically. Here, we identified novel methylation markers and specific, epigenetic molecular differences associated with HPV status, which warrant further investigation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-015-1806-8) contains supplementary material, which is available to authorized users. BioMed Central 2015-10-30 /pmc/articles/PMC4628358/ /pubmed/26518708 http://dx.doi.org/10.1186/s12885-015-1806-8 Text en © Virani et al. 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Virani, Shama
Bellile, Emily
Bradford, Carol R.
Carey, Thomas E.
Chepeha, Douglas B.
Colacino, Justin A.
Helman, Joseph I.
McHugh, Jonathan B.
Peterson, Lisa A.
Sartor, Maureen A.
Taylor, Jeremy MG
Walline, Heather M.
Wolf, Greg T.
Rozek, Laura S.
NDN and CD1A are novel prognostic methylation markers in patients with head and neck squamous carcinomas
title NDN and CD1A are novel prognostic methylation markers in patients with head and neck squamous carcinomas
title_full NDN and CD1A are novel prognostic methylation markers in patients with head and neck squamous carcinomas
title_fullStr NDN and CD1A are novel prognostic methylation markers in patients with head and neck squamous carcinomas
title_full_unstemmed NDN and CD1A are novel prognostic methylation markers in patients with head and neck squamous carcinomas
title_short NDN and CD1A are novel prognostic methylation markers in patients with head and neck squamous carcinomas
title_sort ndn and cd1a are novel prognostic methylation markers in patients with head and neck squamous carcinomas
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4628358/
https://www.ncbi.nlm.nih.gov/pubmed/26518708
http://dx.doi.org/10.1186/s12885-015-1806-8
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