Hypermethylation, risk factors, clinical characteristics, and survival in 235 patients with laryngeal and hypopharyngeal cancers

Abstract

BACKGROUND.It has been established that promoter hypermethylation occurs in several genes during the pathogenesis of head and neck cancer. The authors investigated the role played by the hypermethylation of 4 cancer‐related genes in the survival of patients who had laryngeal and hypopharyngeal cancer and in the occurrence of second primary tumors.METHODS.Archival paraffin‐embedded tissue (PET) samples were available from patients who were enrolled in a multicentric European case‐control study that was performed between 1979 and 1982 and was followed up to 2000. Genomic DNA extracted from 235 PET samples were analyzed for promoter methylation status of the p16, O6‐methylguanine‐DNA methyltransferase (MGMT), death‐associated protein kinase (DAP‐K), and E‐cadherin genes by using a methylation‐specific polymerase chain reaction assay.RESULTS.Hypermethylation was present in 44% of samples for p16, in 27% of samples for MGMT, in 42% of samples for DAP‐K, and in 43% of samples for E‐cadherin. Hypermethylation of either individual genes or their combination was not associated with mortality from all causes, mortality from upper aerodigestive tract cancer, or the occurrence of second primary tumors.CONCLUSIONS.The analysis of a large series of patients with laryngeal and hypopharyngeal cancer suggested that hypermethylation is a frequent event in laryngeal and hypopharyngeal cancer, but it is not a predictor of mortality or second primary cancer. Cancer 2007. © 2007 American Cancer Society.

Epigenetic screen of human DNA repair genes identifies aberrant promoter methylation of NEIL1 in head and neck squamous cell carcinoma

“…The results include MGMT hypermethylation, which has been previously described in several studies, thus adding plausibility to our screening results. 12,13 Information about epigenetic regulation of SALL3 and FANCB in cancer is rather rare. 20,21 MSH4 was recently shown to be hypermethylated in HNSCC.…”

Promoter methylation of TIMP3 and CDH1 predicts better outcome in head and neck squamous cell carcinoma treated by radiotherapy only

“…For MGMT, TIMP3, CDH1 and DAPK, these rates are within the range that has been published in the literature. Methylation percentages that have been previously described are between 14 and 56.4% for MGMT (14)(15)(16)(17)20,24,26,(29)(30)(31)(32), 3-71.8% for TIMP3 (14,16,33), 2-78% for CDH1 (14,16-19, 28,30-32,34,35) and 7-74.2% for DAPK (16)(17)(18)24,26,30,31,33,36). For RASSF1A, the methylation rate in our patient population was somewhat lower than in the literature [7.5-26% (16,18,22,30,31)].…”

“…The connection of TIMP3 and CDH1 hypermethylation with early stage tumors may be contradictory to several reports suggesting that epigenetic silencing is more common in advanced stage disease (18,24,36). However, the absence of such a relationship (29,32), or even the presence of an inverse one (14,17) has also been described.…”

“…Hematological and solid malignancies suffer from an altered epigenetic balance, of which the presence of promoter hypermethylation and histone modifications are the most (12,13). In HNSCC, the hypermethylation of CpG islands has been described in the promoter region of genes involved in cell cycle control [cyclin A1 (14), p16 INK4A (14)(15)(16)(17)(18)], apoptosis [DAPK (16)(17)(18)], cell adhesion [E-cadherin (CDH1) (14,(16)(17)(18)(19), TIMP3 (14,16)], DNA repair [MGMT (14)(15)(16)(17)20) and ATM (21)], cell proliferation and growth [RASSF1A (16,18,22)] and other cellular processes (23). Notably, the aberrant methylation profile has been observed in bodily fluids such as serum (24) or plasma (25), and for HNSCC in particular, in saliva (16,26) or oral scrapings (27).…”

“…The presence of promoter hypermethylation in the tumor itself has also inconsistently been linked with outcome. Some groups have described epigenetic silencing as being associated with poor prognosis (20,21,28), while others have found no correlation (16,17) or an inverse one (14,29). These differences may be partly attributed to the heterogeneity of the studies including different HNSCC subsites, methodologies and treatments.…”