Association between P16INK4a Promoter Methylation and HNSCC: A Meta-Analysis of 21 Published Studies

Shi, Hao; Chen, Xiong; Lü, Cheng; Gu, Changmei; Jiang, Hongwei; Wang, Mengqi; Niu, Xun; Huang, Yangxin; Lü, Meixia

doi:10.1371/journal.pone.0122302

Cited by 22 publications

(14 citation statements)

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“…Other risk factors for HNSCC include epigenetic regulation of gene expression, which may lead to the induction and progression of HNSCC (Bragado et al, 2012;Hakami et al, 2014). Increasing evidence suggests that promoter methylation of tumor-related genes can aggravate the disease in HNSCC (Laytragoon-Lewin et al, 2013;Rettori et al, 2013;Warta et al, 2014;Shi et al, 2015). However, few studies have reported on the prognostic value of promoter methylation in HPV-induced HNSCC.…”

Section: Discussionmentioning

confidence: 99%

Characterization of gene methylation in human papillomavirus associated-head and neck squamous cell carcinoma

et al. 2016

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ABSTRACT. Head and neck squamous cell carcinoma (HNSCC) has become one of the most common forms of cancer worldwide. Hypermethylation-induced silencing of tumor-associated gene has been proposed as an important cofactor in cancer pathology. This paper aimed to characterize the gene methylation patterns in human papillomavirus (HPV) associated-HNSCC. TIMP3 and APC methylation status in neoplastic (N = 92) and non-neoplastic tissues (N = 92) of HNSCC as well as their association with HPV infection were investigated via methylation-specific PCR assays. Results indicated that methylation level of TIMP3 was markedly higher in HPV-positive tumors as compared with HPV-negative tumors. Both TIMP3 and APC methylation were associated with lymph node metastasis and higher clinical stage of tumors. Patients with methylation at TIMP3 or APC had worse prognoses as compared to those without these alterations. This is the first study that shows a possible linkage between HPV infection and APC methylation. Methylation patterns of tumor-related genes may contribute to different disease prognosis in HNSCC according to the HPV infection status.

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Section: Discussionmentioning

confidence: 99%

Characterization of gene methylation in human papillomavirus associated-head and neck squamous cell carcinoma

et al. 2016

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“…Comparative analyses of available HPV+ TCGA cases revealed specific hypermethylated regions downstream of CDKN2A, which correlated with increased transcription of CDKN2A variant p14 (ARF; [184]). CDKN2A is also frequently methylated (23–67 % of cases; [91]) to silence expression of this tumor suppressor [88, 90, 186]; although, degree of methylation and expression changes can vary significantly among individual tumors [187]. The mechanistic and clinical ramifications of this observation are not yet understood.…”

Section: Introductionmentioning

confidence: 99%

“…For most of the methylomics driven studies of HNSCC [183, 185, 188, 189], few cases were analyzed (particularly for HPV+ cases) and additional work is needed to better understanding and interpret the various methylation patterns. How methylomics data is going to be integrated into clinical practice for HNSCC remains to be seen, although prognostic and diagnostic potential of such information is apparent in some cancer types [181, 185, 190].…”

Section: Introductionmentioning

confidence: 99%

Genomic insights into head and neck cancer

Beck

Golemis

2016

Cancers Head Neck

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Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and is frequently impervious to curative treatment efforts. Similar to other cancers associated with prolonged exposure to carcinogens, HNSCCs often have a high burden of mutations, contributing to substantial inter- and intra-tumor heterogeneity. The heterogeneity of this malignancy is further increased by the rising rate of human papillomavirus (HPV)-associated (HPV+) HNSCC, which defines an etiological subtype significantly different from the more common tobacco and alcohol associated HPV-negative (HPV−) HNSCC. Since 2011, application of large scale genome sequencing projects by The Cancer Genome Atlas (TCGA) network and other groups have established extensive datasets to characterize HPV− and HPV+ HNSCC, providing a foundation for advanced molecular diagnoses, identification of potential biomarkers, and therapeutic insights. Some genomic lesions are now appreciated as widely dispersed. For example, HPV− HNSCC characteristically inactivates the cell cycle suppressors TP53 (p53) and CDKN2A (p16), and often amplifies CCND1 (cyclin D), which phosphorylates RB1 to promote cell cycle progression from G1 to S. By contrast, HPV+ HNSCC expresses viral oncogenes E6 and E7, which inhibit TP53 and RB1, and activates the cell cycle regulator E2F1. Frequent activating mutations in PIK3CA and inactivating mutations in NOTCH1 are seen in both subtypes of HNSCC, emphasizing the importance of these pathways. Studies of large patient cohorts have also begun to identify less common genetic alterations, predominantly found in HPV− tumors, which suggest new mechanisms relevant to disease pathogenesis. Targets of these alterations including AJUBA and FAT1, both involved in the regulation of NOTCH/CTNNB1 signaling. Genes involved in oxidative stress, particularly CUL3, KEAP1 and NFE2L2, strongly associated with smoking, have also been identified, and are less well understood mechanistically. Application of sophisticated data-mining approaches, integrating genomic information with profiles of tumor methylation and gene expression, have helped to further yield insights, and in some cases suggest additional approaches to stratify patients for clinical treatment. We here discuss some recent insights built on TCGA and other genomic foundations.

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“…In a recent meta-analysis from six eligible studies, including 261 patients, Hu et al found that p16 INK4a promoter hypermethylation is correlated with an increased risk of endometrial carcinoma [ 33 ]. Similarly, our earlier meta-analysis reported a significant hypermethylation of p16 INK4a promoter in head and neck squamous cell carcinoma (HNSCC) [ 34 ].…”

Section: Discussionmentioning

confidence: 82%

Association between P16INK4a Promoter Methylation and Ovarian Cancer: A Meta-Analysis of 12 Published Studies

et al. 2016

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BackgroundOvarian cancer is the primary cause of death in women diagnosed with gynecological malignancies worldwide. Absence of early symptoms prevents prompt diagnosis or successful therapeutic intervention. P16INK4a is a well-known tumor suppressor gene (TSG). Aberrant methylation of TSG promoter is an important epigenetic silencing mechanism leading to ovarian cancer progression. Studies have reported differences in methylation frequencies of the p16INK4a promoter between ovarian cancer and the corresponding control group. However, the association between p16INK4a promoter methylation and ovarian cancer remains unclear and controversial. Therefore, a meta-analysis was conducted to clarify the relationship between p16INK4a promoter methylation and ovarian cancer.MethodsPubMed, Web of Science, EMBASE and CNKI were searched to identify eligible studies for the evaluation of the association between p16INK4a promoter methylation and ovarian cancer. Odds ratio (ORs) and 95% confidence intervals (95%CI) were calculated to determine the strength of association between p16INK4a promoter methylation and ovarian cancer.ResultsA total of 612 ovarian cancer patients and 289 controls from 12 eligible studies were included in the meta-analysis. Overall, a significant association was observed between p16INK4a methylation status and ovarian cancer risk using a fixed-effects model (OR = 2.02, 95% CI = 1.39–2.94).ConclusionThe results of our meta-analysis show that aberrant methylation of p16INK4a promoter was significantly associated with ovarian cancer. It may represent a promising molecular marker to monitor the disease and provides new insights into the treatment of human ovarian cancer.

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Association between P16INK4a Promoter Methylation and HNSCC: A Meta-Analysis of 21 Published Studies

Cited by 22 publications

References 50 publications

Characterization of gene methylation in human papillomavirus associated-head and neck squamous cell carcinoma

Characterization of gene methylation in human papillomavirus associated-head and neck squamous cell carcinoma

Genomic insights into head and neck cancer

Association between P16INK4a Promoter Methylation and Ovarian Cancer: A Meta-Analysis of 12 Published Studies

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