Human papillomavirus‐16 DNA methylation patterns support a causal association of the virus with oral squamous cell carcinomas

Abstract

Infection with human papillomavirus-16 (HPV-16) is the cause of most anogenital carcinomas. This virus is also detected in about 20% of all head and neck squamous cell carcinomas. While there is strong evidence for a causal etiological role in the case of tonsillar carcinomas, causal association with malignant lesions of the oral cavity is not yet conclusive. Our previous investigations of HPV-16 DNA methylation in anogenital sites have identified hypermethylation of the L1 gene and part of the long control region in many malignant lesions, but rarely in asymptomatic infections and low-grade precancerous lesions. Here, we report hypermethylation of this diagnostically important segment of the viral DNA in 10 out of 12 HPV-16 positive oral carcinomas from Mexican patients. These data indicate epigenetic changes of HPV-16 in oral carcinomas similar to those in anogenital carcinomas, suggesting carcinogenic processes under the influence of HPV-16 in most if not all of these oral malignant lesions. ' 2007 Wiley-Liss, Inc.Key words: papillomavirus; carcinoma; head and neck cancer; oral cavity; DNA methylation; DNA recombination; etiology; progression; Infection with human papillomaviruses (HPVs), notably with high-risk HPV types such as HPV-16 and 18, is a necessary step in the etiology of anogenital cancers, specifically carcinoma of the cervix uteri. This notion is based on epidemiological research that identified a high relative risk of carcinogenic progression associated with high-risk HPV infection, DNA diagnosis that confirmed the presence and transcription of HPV genomes in all cervical carcinomas, and the study of HPV oncoproteins that catalyze a variety of molecular mechanisms that convert normal into malignant cells. [1][2][3][4][5][6] In case of head and neck squamous cell carcinomas (HNSCCs), an HPV dependent etiology is not as consistently confirmed as in anogenital cancers. Approximately 80% of all HNSCCs do not contain HPV genomes, and must therefore originate from HPV independent etiological processes, likely including mutational events triggered by tobacco and alcohol consumption. However, there is extensive evidence that a proportion of all HNSCCs contain DNA of high-risk HPV types. 7-14 Among head and neck sites, squamous cell carcinomas of the tonsils have the strongest statistical support for an HPV dependent etiology. 9,[15][16][17] There is less strength and consistency for a linkage between HPV infection and carcinogenesis at sites of the oral mucosa such as tongue, palate, floor of mouth and gingiva. Nevertheless, epidemiological studies have established statistical evidence for a causal association of HPVs and malignancies even for these oral sites. 9,16 In addition, analysis of some HPV containing oral carcinomas revealed recombination between HPV genomes and cellular DNA as well as HPV oncogene expression, [10][11][12][13][18][19][20] properties that are generally viewed as support of carcinogenic processes under the influence of HPVs. On the basis of these observations one must conclude ...

Methylation of Twelve CpGs in Human Papillomavirus Type 16 (HPV16) as an Informative Biomarker for the Triage of Women Positive for HPV16 Infection

“…During carcinogenesis, the process is progressively dysregulated, beginning at the earliest stages of neoplasia. Many HPV DNA methylation studies have focused on the viral long control region (LCR) and 3 0 terminus of the L1 open reading frame (ORF) and have generally reported that the LCR sites were minimally methylated in most lesions, whereas the L1 sites were methylated more frequently in ICC than premalignant lesions (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Other studies have reported an inverse relationship between elevated methylation in the E6 ORF and high-grade CIN (32,33).…”

Methylation in oral cancer and pre-cancerous lesions (Review)

“…Betel nut chewing has been implicated in oscc, leukoplakia and oral submucous fibrosis (progressive inflammation and fibrosis of connective tissue) (6). Other predisposing factors for oral cancer include alcohol use, gender, age and infection by human papillomavirus (7,8).…”

Analysis of p16_{<i>CDKN2A</i>} Methylation and HPV-16 Infection in Oral Mucosal Dysplasia

“…In contrast to cervical cancer, in which HPV has been established as a primary cause, oral cavity cancers are caused primarily by tobacco use, and high-risk HPV might be a cofactor for oral carcinogenesis [15,27] . Studies using squamous cell carcinoma samples suggest that high-risk HPV infection could interfere in epigenetic regulation [28] , specifically in the induction of the p16 CDKN2A gene methylation [12,23,29] .…”

“…Recent evidence suggests that epigenetics is an important mechanism in oral carcinogenesis [12][13][14][15][16] . DNA methylation is the addition of methyl radicals to specific regions of DNA that predominantly contain cytosine nucleotides.…”