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

BMC Cancer

Research Article

Emily Bellile¹  Jeremy MG Taylor¹  Maureen A. Sartor²  Justin A. Colacino³  Shama Virani³  Laura S. Rozek⁴  Joseph I. Helman⁵  Greg T. Wolf⁶  Carol R. Bradford⁶  Lisa A. Peterson⁶  Thomas E. Carey⁶  Douglas B. Chepeha⁶  Heather M. Walline⁶  Jonathan B. McHugh⁷ 

[1] Department of Biostatistics, University of Michigan, School of Public Health, Ann Arbor, MI, USA;Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA;Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA;Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA;Department of Otolaryngology, University of Michigan Medical School, Ann Arbor, MI, USA;1415 Washington Heights, Environmental Health Sciences 6630 SPH, 48109-2029, Ann Arbor, MI, USA;Department of Oral-Maxillofacial Surgery, University of Michigan Dental School, Ann Arbor, MI, USA;Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA;Department of Otolaryngology, University of Michigan Medical School, Ann Arbor, MI, USA;Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA;

关键词: Head and neck cancer;    Epigenetics;    Survival;    Recurrence;    DNA methylation;   

DOI  :  10.1186/s12885-015-1806-8

 received in 2015-04-27, accepted in 2015-10-16,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundHPV-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.MethodsKaplan-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.ResultsMethylation 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).ConclusionsThis 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.

【 授权许可】

CC BY   
© Virani et al. 2015