Inactivation of the Tumor Suppressor Genes Causing the Hereditary Syndromes Predisposing to Head and Neck Cancer via Promoter Hypermethylation in Sporadic Head and Neck Cancers

Abstract

Fanconi anemia (FA) and dyskeratosis congenita (DC) are rare inherited syndromes that cause head and neck squamous cell cancer (HNSCC). Prior studies of inherited forms of cancer have been extremely important in elucidating tumor suppressor genes inactivated in sporadic tumors. Here, we studied whether sporadic tumors have epigenetic silencing of the genes causing the inherited forms of HNSCC. Using bisulfite sequencing, we investigated the incidence of promoter hypermethylation of the 17 Fanconi- and DC-associated genes in sporadic HNSCC. Genes that only showed methylation in the tumor patients were chosen for quantitative methylation-specific PCR (qMSP) in a set of 45 tumor and 16 normal patients. Three gene promoters showed differences in methylation: FancB (FAAP95, FA core complex), FancJ (BRIP1, DNA Helicase/ATPase), and DKC1 (dyskeratin). Bisulfite sequencing revealed that only FancB and DKC1 showed no methylation in normal patients, yet the presence of promoter hypermethylation in tumor patients. On qMSP, 1/16 (6.25%) of the normal mucosal samples from non-cancer patients and 14/45 (31.1%) of the tumor patients demonstrated hypermethylation of the FancB locus (p < 0.05). These results suggest that inactivation of FancB may play a role in the pathogenesis of sporadic HNSCC.

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

“…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. 22 No data on aberrant promoter methylation have been published so far for NEIL1, APEX2 and TREX2.…”

Pyrosequencing-based DNA methylation profiling of Fanconi anemia/BRCA pathway genes in laryngeal squamous cell carcinoma

“…Though, no evidence for aberrant methylation was found in this report. Smith et al (33) showed BRIP1 and FANCB to be higher and more frequently methylated compared to normal mucosa. The authors suggest that FANCB inactivation play important role in HNSCC pathogenesis as the hypermethylation was detected almost exclusively in cancerous samples.…”

“…Hypermethylation of tumor suppressor (24,25), cancer of the breast (26), ovary (27), bladder (28), cervix (29), testis (30) and lung (31). In HNSCC sporadic epigenetic events involving FA/BRCA-related genes have been previously documented in several reports (32)(33)(34). FANCF has been demonstrated to be often hypermethylated and associated with alcohol and tobacco use and poor prognosis (31).…”

“…FANCF has been demonstrated to be often hypermethylated and associated with alcohol and tobacco use and poor prognosis (31). Moreover, altered methylation patterns of FANCB and BRIP1 have been recently demonstrated in HNSCC and FANCB inactivation is supposed to contribute to HNSCC pathogenesis (33). However, the defects of FA-genes among sporadic HNSCC still remain poorly explained.…”

DNA Repair Capacity and the Risk of Head and Neck Cancer

“…The results are meaningful as that time it was the largest genetic epidemiologic study on the upper aerodigestive tract in Europe. Almost the same time there was published a large analysis of genetic polymorphism in breast cancer (Smith et al,2010 Altogether, the hypothesis of a significant impact of polymorphism of DNA repair genes besides many research efforts was not sufficiently proven but it does not eliminate DNA repair from cancer risk estimation. Its moderate effect was shown and a necessity of genegene interaction was suggested.…”