A causal role for human papillomavirus in head and neck cancer.
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Carcinoma, Squamous Cell↗
Biomedical subjects
M L Gillison
Publications and source records attributed to M L Gillison.
Human papillomavirus-associated head and neck squamous cell carcinoma: mounting evidence for an etiologic role for human papillomavirus in a subset of head and neck cancers.
There is increasing molecular and epidemiologic evidence that human papillomavirus (HPV) is associated with a distinct subset of head and neck squamous cell carcinomas. The strength and consistency of HPV DNA presence in oropharyngeal cancers bolster the argument that this association is likely causal. HPV-positive tonsillar cancer in particular is emerging as a specific disease entity with distinct molecular, pathologic, and clinical characteristics. Recent data suggest that the incidence of tonsillar carcinoma in the United States is increasing, despite a decline in tobacco use, supporting the existence of other important risk factors such as HPV infection. Individuals with a history of an HPV-associated anogenital cancer and HIV-infected men are at increased risk for tonsillar carcinoma. This review focuses on the recent literature (since 1998) investigating the relationship between HPV and head and neck cancer development, using the current paradigm for causal inference in epidemiologic research attributed to Sir A. Bradford Hill. Data examining the association of HPV with pathogenesis of head and neck squamous cell carcinoma before 1999 were previously reviewed in this journal.
Adult↗
Evidence for a causal association between human papillomavirus and a subset of head and neck cancers.
BACKGROUND: High-risk human papillomaviruses (HPVs) are etiologic agents for anogenital tract cancers and have been detected in head and neck squamous cell carcinomas (HNSCCs). We investigated, retrospectively, an etiologic role for HPVs in a large series of patients with HNSCC. METHODS: Tumor tissues from 253 patients with newly diagnosed or recurrent HNSCC were tested for the presence of HPV genome by use of polymerase chain reaction (PCR)-based assays, Southern blot hybridization, and in situ hybridization. The viral E6 coding region was sequenced to confirm the presence of tumor-specific viral isolates. Exons 5-9 of the TP53 gene were sequenced from 166 specimens. The hazard of death from HNSCC in patients with and without HPV-positive tumors was determined by proportional hazards regression analysis. RESULTS: HPV was detected in 62 (25%) of 253 cases (95% confidence interval [CI] = 19%-30%). High-risk, tumorigenic type HPV16 was identified in 90% of the HPV-positive tumors. HPV16 was localized specifically by in situ hybridization within the nuclei of cancer cells in preinvasive, invasive, and lymph node disease. Southern blot hybridization patterns were consistent with viral integration. Poor tumor grade (odds ratio [OR] = 2.4; 95% CI = 1.2- 4.9) and oropharyngeal site (OR = 6.2; 95% CI = 3.1-12.1) independently increased the probability of HPV presence. As compared with HPV-negative oropharyngeal cancers, HPV-positive oropharyngeal cancers were less likely to occur among moderate to heavy drinkers (OR = 0.17; 95% CI = 0.05-0.61) and smokers (OR = 0.16; 95% CI = 0.02-1.4), had a characteristic basaloid morphology (OR = 18.7; 95% CI = 2.1-167), were less likely to have TP53 mutations (OR = 0.06; 95% CI = 0.01-0. 36), and had improved disease-specific survival (hazard ratio [HR] = 0.26; 95% CI = 0.07-0.98). After adjustment for the presence of lymph node disease (HR = 2.3; 95% CI = 1.4- 3.8), heavy alcohol consumption (HR = 2.6; 95% CI = 1.4-4.7), and age greater than 60 years old (HR = 1.4; 95% CI = 0.8-2.3), all patients with HPV-positive tumors had a 59% reduction in risk of death from cancer when compared with HPV-negative HNSCC patients (HR = 0.41; 95% CI = 0.20-0.88). CONCLUSIONS: These data extend recent molecular and epidemiologic studies and strongly suggest that HPV-positive oropharyngeal cancers comprise a distinct molecular, clinical, and pathologic disease entity that is likely causally associated with HPV infection and that has a markedly improved prognosis.
Adolescent↗
Detection and quantitation of human papillomavirus (HPV) DNA in the sera of patients with HPV-associated head and neck squamous cell carcinoma.
The human papillomavirus (HPV) has been implicated as an etiological factor in a subset of head and neck squamous cell carcinoma (HNSCC). Because circulating tumor DNA has previously been detected in the sera of patients with advanced HNSCC (stage III or IV), we hypothesized that HPV DNA might be present in the sera of HPV-positive HNSCC patients. Serum DNA extracts from 70 patients with HNSCC were screened for HPV using conventional PCR and a real-time quantitative assay. All samples subjected to conventional PCR were further tested by dot blot hybridization, and positives were confirmed by Southern blotting. Paired tumor DNA from archived tissues was then similarly screened for HPV genomic material (n = 51) or tested by in situ hybridization (n = 19). HPV-16 DNA was detected with L1 primers in 0 of 65 sera and in 15 of 70 (21%) tumors. Conventional PCR with E7 primers and Southern blot hybridization detected HPV-16 DNA in four (6%) sera. Using real-time quantitative PCR, six samples were found to contain various levels of circulating HPV DNA (mean, 12 copies/ml; range, <1-35.) All six serum-positive patients had corresponding tumors positive for E7. Four of these patients with HPV-positive tumors later developed distant metastases, suggesting that HPV DNA in serum may represent occult hematogenous spread of cancer cells in this subset of patients. Although a much larger prospective trial is required, the presence of HPV genomic material in serum DNA of HPV-positive HNSCC patients may serve as a useful marker of early metastatic disease.
Adult↗
Larynx preservation in head and neck cancers. A discussion of the National Comprehensive Cancer Network Practice Guidelines.
The management of advanced cancers of the larynx and hypopharynx has become increasingly complex as different treatment modalities, including surgery, radiation, and chemotherapy, have been combined with the goal of improving local disease control and disease-specific survival. A union of 17 comprehensive cancer centers in the United States, the National Comprehensive Care Network (NCCN), was formed in 1995 to promote state-of-the-art cancer care. To achieve this goal, multidisciplinary panels of experts from member institutions have created disease-specific practice guidelines for the evaluation and treatment of cancer patients, including those with head and neck cancers. Although detailed analysis of surgical methods and radiation techniques are beyond the scope of this article, the evolving laryngeal preservation strategies for patients with advanced, resectable hypopharyngeal or laryngeal (including supraglottic and glottic) cancers are reviewed using relevant sections of the NCCN practice guidelines as a framework for discussion.
Antineoplastic Agents↗
Human papillomavirus in head and neck squamous cell carcinoma: are some head and neck cancers a sexually transmitted disease?
There is abundant epidemiologic and virologic evidence that high-risk human papillomaviruses (HPVs) are tumorigenic in human epithelia, particularly in the cervix, where HPV infection is necessary for cancer development. HPV DNA has been detected in a proportion of head and neck squamous cell carcinomas (HNSCCs) in numerous case series. The mere presence of the virus in tumor specimens, by itself, does not imply a causal relationship. However, recent studies support an etiologic role for HPVs in a subset of HNSCC, particularly poorly differentiated tumors arising from Waldeyer's tonsillar ring. Epidemiologic studies have shown that exposure to HPV increases the risk of HNSCC, and HPV infection may interact with alcohol and tobacco exposure in tumor promotion. Molecular studies indicate that transcriptionally active virus is confined to tumor cells. It will be important to clarify further the role that HPV has in HNSCC development, because HPV-based therapeutic vaccines which are currently being developed for cervical cancer may also be of benefit in the management of HNSCC.
Carcinoma, Squamous Cell↗
Human herpesvirus-8.
Our current understanding of Kaposi's sarcoma (KS) has evolved from initial descriptions of this "idiopathic sarcoma" to a progressively detailed characterization of its probable infectious origin. This article traces the explosive discovery of human herpesvirus-8 (HHV-8) and its etiologic associations with KS, Castleman's disease, and primary effusion lymphomas. A framework for understanding how viral infection leads to development of these unusual disease is presented. The possible role of HHV-8 in tumorigenesis, through viral manipulation of signal transduction pathways and cell cycle control, is discussed.
Castleman Disease↗
Karyoplasmic interaction selection strategy: a general strategy to detect protein-protein interactions in mammalian cells.
We describe a strategy and reagents for study of protein-protein interactions in mammalian cells, termed the karyoplasmic interaction selection strategy (KISS). With this strategy, specific protein-protein interactions are identified by reconstitution of the functional activity of the yeast transcriptional activator GAL4 and the resultant transcription of a GAL4-regulated reporter gene. Reconstitution of GAL4 function results from specific interaction between two chimeric proteins: one contains the DNA-binding domain of GAL4; the other contains a transcriptional activation domain. Transcription of the reporter gene occurs if the two chimeric proteins can form a complex that reconstitutes the DNA-binding and transcriptional activation functions of GAL4. Using the KISS system, we demonstrate specific interactions for sequences from three different pairs of proteins that complex in the cytoplasm. In addition, we demonstrate that reporter genes encoding cell surface or drug-resistance markers can be specifically activated as a result of protein-protein interactions. With these selectable markers, the KISS system can be used to screen specialized cDNA libraries to identify novel protein interactions.
Amino Acid Sequence↗
Discrimination between related DNA sites by a single amino acid residue of Myc-related basic-helix-loop-helix proteins.
A yeast genetic system was developed to study how the basic regions of basic-helix-loop-helix (bHLH) proteins distinguish between related consensus bHLH binding sites, with nucleotide sequence CANNTG. The yeast bHLH protein CBF1 binds to the sequence CAC(A/G)TG found in the yeast centromere element CDE1 and in promoter regions of several yeast genes involved in methionine biosynthesis. Using a functional assay to rescue a mutant cbf1 yeast strain from methionine auxotrophy, we determined that the basic region of CBF1 could be replaced by the homologous region of either the vertebrate USF transcription factor or c-Myc, both of which bind CACGTG. The homologous region of the AP4 transcription factor, which recognizes the sequence CAGCTG, could not functionally replace the CBF1 basic region. However, only a single substitution, Met----Arg, in the AP4 basic region of the inactive chimera CBF-AP4 was sufficient to restore CBF1 function. In randomization experiments, only arginine or lysine provided functional substitutions at the AP4 methionine position. The results suggest that this conserved arginine residue in the basic regions of Myc-related bHLH proteins discriminates between CAC(A/G)TG and related sites.
Amino Acid Sequence↗
Drug concentration-dependent DNA lesions are induced by the lipid-soluble antifolate, piritrexim (BW301U).
The lipid-soluble folate antagonist, 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidin e (piritrexim; BW301U), induced misincorporation of dUMP in human B (SB)- and T (MOLT-4)-lymphoblastoid cells, and in human promyelocytic leukemia cells (HL-60). Analysis by alkaline sucrose gradients and alkaline elution indicated that 3H-DNA that had been labeled for 15 min distributed into progressively smaller DNA fragment sizes in a drug concentration-dependent manner from 0 microM to 50 microM piritrexim. This phenomenon was observed regardless of the labeled nucleotide precursor employed for detection of newly synthesized DNA [( 3H]deoxyuridine, [3H]deoxyadenosine, or [3H]deoxycytidine). In contrast, formaldehyde denaturation and sedimentation of DNA in neutral denaturing sucrose gradients released only 3-4% of the newly synthesized DNA as 3S-6S fragments (80-200 nucleotides), whereas the remaining population of newly synthesized DNA pelleted to the bottom of the tube. Failure to detect DNA fragmentation under neutral conditions to the extent observed under alkaline conditions indicated the presence of apurinic and apyrimidinic sites in DNA--lesions which would be expected in DNA undergoing excision-repair of misincorporated dUMP. Cytotoxicity resulting from dUMP misincorporation was consistent with the enhanced toxicity of piritrexim which was observed when HL-60 cells or MOLT-4 cells were exposed concurrently to exogenous deoxyuridine. Deoxyuridine-enhanced toxicity was demonstrated to be concentration dependent for both cell lines when piritrexim concentrations were marginally toxic. The cytotoxic effect of dUMP misincorporation was further substantiated by the observation that MOLT-4 cells treated with 0.5 microM piritrexim alone eventually developed resistance to the drug, whereas treatment with both piritrexim and 10 microM deoxyuridine prevented the selection of piritrexim-resistant cells.
B-Lymphocytes↗