Human papillomavirus 16 and head and neck squamous cell carcinoma

Evidence suggests that human papillomavirus (HPV)16 seropositivity reflects past HPV16 exposure and is associated with risk for head and neck squamous cell carcinoma (HNSCC). Our objectives were to test the hypothesis that HPV16 seropositivity is associated with risk for HNSCC, to correlate HPV16 seropositivity with HPV16 tumor DNA, and to correlate HPV16 seropositivity and HPV16 DNA with sexual history and patient survival. In a case-control study of approximately 1,000 individuals, we assessed serology to the HPV16 L1 protein and in cases only, assayed tumors for HPV16 DNA. HPV16 seropositivity was associated with 1.5- and 6-fold risks for tumors of the oral cavity and pharynx, respectively. There was a dose response trend for HPV16 titer and increasing risk of HNSCC (p < 0.0001) and HPV16 tumor DNA (p < 0.0001). In cases, HPV16 DNA and seropositivity were significantly associated with sexual activity; odds ratios (ORs) of 12.8 and 3.7 were observed for more than 10 oral sexual partners and ORs of 4.5 and 3.2 were associated with a high number of lifetime sexual partners, respectively. Finally, HPV16 seropositivity and HPV16 tumor DNA were associated with hazard ratios of 0.4 and 0.5, respectively, indicating better survival for HPV positive individuals. HPV16 seropositivity was associated with risk for HNSCC, with greatest risk for pharyngeal cancer. We observed dose response relationships between serology titer and both risk for HNSCC and HPV16 tumor DNA. In cases, HPV16 tumor DNA and positive serology were associated with sexual history and improved disease free survival.     

Smoking modifies the relationship between XRCC1 haplotypes and HPV16‐negative head and neck squamous cell carcinoma

Reports on the relationship between head and neck squamous cell carcinoma (HNSCC) and polymorphisms in X‐ray cross complementing group 1 (XRCC1) have been inconsistent. We hypothesized this may be due to not accounting for Human papillomavirus type‐16 (HPV16) and thus examined whether smoking modified the association between XRCC1 haplotypes and HNSCC risk within HPV16 serologic strata. Cases were diagnosed in Greater Boston, Massachusetts. Controls were matched to cases on age, gender and residential town. Genotyping was conducted on three XRCC1 polymorphisms (Arg194Trp, Arg280His and Arg399Gln) and serology was used to determine HPV16 exposure. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for age, sex, race, education, smoking, alcohol consumption and HPV16 serology. There was no overall association between XRCC1 polymorphisms and HNSCC risk. Smoking did not modify the association between XRCC1 polymorphisms and HNSCC risk among the HPV16 seropositive (p_interaction = 0.89) but it did for the HPV16 seronegative (p_interaction=0.04). Among the HPV16 seronegative, heavy smokers with a haplotype containing a variant allele had an increased HNSCC risk (haplotype with 399Gln: OR, 1.35; 95% CI, 0.97–1.86), whereas never/light smokers with variant alleles may have a reduced risk. In sum, the association between XRCC1 and HNSCC risk differed by HPV16 status and smoking. Among the HPV16 seronegative, heavy smokers with XRCC1 variant alleles had an increased HNSCC risk. There was no relationship between XRCC1 and HPV16‐related HNSCC, regardless of smoking. Our findings underscore the importance of accounting for HPV16 exposure even when studying susceptibility to HNSCC. © 2009 Wiley‐Liss, Inc.     

The interplay between HPV and host immunity in head and neck squamous cell carcinoma

Persistent infection with human papillomavirus (HPV) type 16 is a major risk factor for the development of head and neck squamous cell carcinoma (HNSCC), in particular oropharyngeal squamous cell carcinoma (OPSCC). The oropharyngeal epithelium differs from the mucosal epithelium at other commonly HPV16‐infected sites (i.e., cervix and anogenital region) in that it is juxtaposed with the underlying lymphatic tissue, serving a key immunologic function in the surveillance of inhaled and ingested pathogens. Therefore, the natural history of infection and immune response to HPV at this site may differ from that at other anatomic locations. This review summarizes the literature concerning the adaptive immune response against HPV in the context of HNSCC, with a focus on the T‐cell response. Recent studies have shown that a broad repertoire of tumor‐infiltrating HPV‐specific T‐cells are found in nearly all patients with HPV‐positive tumors. A systemic response is found in only a proportion of these. Furthermore, the local response is more frequent in OPSCC patients than in cervical cancer patients and HPV‐negative OPSCC patients. Despite this, tumor persistence may be facilitated by abnormalities in antigen processing, a skewed T‐helper cell response, and an increased local prevalence of T‐regulatory cells. Nonetheless, the immunologic profile of HPV‐positive vs. HPV‐negative HNSCC is associated with a significantly better outcome, and the HPV‐specific immune response is suggested to play a role in the significantly better response to therapy of HPV‐positive patients. Immunoprofiling may prove a valuable prognostic tool, and immunotherapy trials targeting HPV are underway, providing hope for decreasing treatment‐related toxicity.     

头颈部鳞状细胞癌靶向治疗进展

每年全世界大约有65万例新的头颈癌病例出现,其中绝大多数是头颈部鳞状细胞癌.晚期头颈部鳞状细胞癌的治疗需要综合治疗,尽管放化疗及手术治疗手段在不断发展,但是预后仍不理想且具有一定的毒副反应.靶向治疗是目前治疗研究头颈部鳞癌的热点,其在针对头颈部鳞癌的治疗特别是对局部晚期或复发/转移性头颈部鳞癌治疗中展现出了希望.本文综...     

Human papilloma virus integration sites and genomic signatures in head and neck squamous cell carcinoma

A prevalence of around 26% of human papillomavirus (HPV) in head and neck squamous cell carcinoma (HNSCC) has been previously reported. HPV induced oncogenesis mainly involving E6 and E7 viral oncoproteins. In some cases, HPV viral DNA has been detected to integrate with the host genome and possibly contributes to carcinogenesis by affecting the gene expression. We retrospectively assessed HPV integration sites and signatures in 80 HPV positive patients with HNSCC, by using a double capture‐HPV method followed by next‐generation Sequencing. We detected HPV16 in 90% of the analyzed cohort and confirmed five previously described mechanistic signatures of HPV integration [episomal (EPI), integrated in a truncated form revealing two HPV‐chromosomal junctions colinear (2J‐COL) or nonlinear (2J‐NL), multiple hybrid junctions clustering in a single chromosomal region (MJ‐CL) or scattered over different chromosomal regions (MJ‐SC) of the human genome]. Our results suggested that HPV remained episomal in 38.8% of the cases or was integrated/mixed in the remaining 61.2% of patients with HNSCC. We showed a lack of association of HPV genomic signatures to tumour and patient characteristics, as well as patient survival. Similar to other HPV associated cancers, low HPV copy number was associated with worse prognosis. We identified 267 HPV‐human junctions scattered on most chromosomes. Remarkably, we observed four recurrent integration regions: PDL1/PDL2/PLGRKT (8.2%), MYC/PVT1 (6.1%), MACROD2 (4.1%) and KLF5/KLF12 regions (4.1%). We detected the overexpression of PDL1 and MYC upon integration by gene expression analysis. In conclusion, we identified recurrent targeting of several cancer genes such as PDL1 and MYC upon HPV integration, suggesting a role of altered gene expression by HPV integration during HNSCC carcinogenesis.     

Prevalence and physical status of human papillomavirus in squamous cell carcinomas of the head and neck

Fresh-frozen biopsies were obtained from 61 patients at diagnosis of squamous cell carcinoma of the head and neck (HNSCC) for study of the prevalence and physical status of human papillomavirus (HPV) DNA. The frequency of HPV DNA and genotypes were determined by SPF10 PCR screening with a general probe hybridization and INNO-LiPA HPV genotyping assay. In addition, a single-phase PCR with primers FAP 59/64 and a nested PCR with primers CP 65/70 and CP 66/69 served to detect particularly cutaneous HPV types. By the sensitive SPF10 PCR and INNO-LiPA assay, 37 of 61 (61%) samples were positive for HPV. HPV-16 was the most frequently detected type (31 of 37, 84%). Multiple infections were found in 8 of 37 (22%) of the HPV-positive samples, and co-infection by HPV-16 and HPV-33 was predominant. No cutaneous HPV types were detected. Patients with HPV-positive tumors had similar prognosis as those with HPV-negative ones. Real-time PCR analysis of the HPV-16 positive samples indicated the presence of integrated (11 of 23, 48%), episomal (8 of 23, 35%) and mixed forms (4 of 23, 17%) of HPV DNA. The viral load of HPV DNA exhibited large variation. The median copy numbers of E6 DNA in tonsillar specimens were approximately 80,000 times higher than that in nontonsillar HNSCC ones. Patients with episomal viral DNA were more frequently found to have large (T3-T4) tumors at diagnosis than were those with integrated or mixed forms.     

Cancer stem cell related markers of radioresistance in head and neck squamous cell carcinoma

Despite recent advances in understanding of the molecular pathogenesis and improvement of treatment techniques, locally advanced head and neck squamous cell carcinoma (HNSCC) remains associated with an unfavorable prognosis. Compelling evidence suggests that cancer stem cells (CSC) may cause tumor recurrence if they are not eradicated by current therapies as radiotherapy or radio-chemotherapy. Recent in vitro studies have demonstrated that CSCs may be protected from treatment-induced death by multiple intrinsic and extrinsic mechanisms. Therefore, early determination of CSC abundance in tumor biopsies prior-treatment and development of therapeutics, which specifically target CSCs, are promising strategies to optimize treatment. Here we provide evidence that aldehyde dehydrogenase (ALDH) activity is indicative for radioresistant HNSCC CSCs. Our study suggests that ALDH⁺ cells comprise a population that maintains its tumorigenic properties in vivo after irradiation and may provide tumor regrowth after therapy. We found that ALDH activity in HNSCC cells can be attributed, at least in part, to the ALDH1A3 isoform and inhibition of the ALDH1A3 expression by small interfering RNA (siRNA) decreases tumor cell radioresistance. The expression dynamic of ALDH1A3 upon irradiation by either induction or selection of the ALDH1A3 positive population correlates to in vivo curability, suggesting that changes in protein expression during radiotherapy are indicative for tumor radioresistance. Our data indicate that ALDH1A3⁺ HNSCC cells may contribute to tumor relapse after irradiation, and inhibition of this cell population might improve therapeutic response to radiotherapy.     

Role of miRNA in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. Evidence suggests that miRNAs play an important role in progression, recurrence, metastasis and postoperative survival of HNSCC. Studies have investigated the utility of miRNAs as diagnostic/prognostic tools and as potential therapeutic targets and biomarkers that may improve the management and outcomes of HNSCC. The aim of this article is to review the current literature on aberrant expression profiles of miRNAs in biopsy samples of HNSCC and their role in cancer development, metastasis, prognosis and survival of these patients. This review gives an overview that miRNAs deregulation play major role in the development of HNSCC. They offer the potential to be used as biomarkers or novel therapeutic targets. Future research is required to test their use in both of these fields.     

The national landscape of human papillomavirus‐associated oropharynx squamous cell carcinoma

The head and neck squamous cell carcinoma (HNC) landscape is evolving with human papillomavirus (HPV) being a rising cause of oropharynx carcinoma (OPC). This study seeks to investigate a national database for HPV‐associated oropharynx carcinoma (HPV‐OPC). Using the National Cancer Data Base, we analyzed 22,693 patients with HPV‐OPC and known HPV status. Chi‐square tests and logistic regression models were utilized to examine differences between HPV positive and HPV negative OPC. 14,805 (65.2%) patients were HPV positive. Mean age at presentation was 58.4 years with HPV‐HNC patients being 2.8 years younger compared to the HPV‐negative cohort (58.4 vs. 61.2 years, p < 0.001). 67.6% of white patients were HPV‐positive compared to 42.3% of African American patients and 57.1% of Hispanics (p < 0.001). When combining race and socioeconomic status (SES), we found African American patients in high SES groups had HPV‐OPC prevalence that was significantly higher than African American patients in low SES groups (56.9% vs. 36.3%, p < 0.001). Geographic distribution of HPV‐OPC was also analyzed and found to be most prevalent in Western states and least prevalent in the Southern states (p < 0.001). The distribution of HPV‐OPC is variable across the country and among racial and socioeconomic groups. A broad understanding of these differences in HPV‐OPC should drive educational programs and improve clinical trials that benefit both prevention and current treatments.     

头颈部鳞癌相关生物标志物与免疫治疗预后的关系

头颈部鳞癌(HNSCC)是世界上第六大常见的恶性肿瘤,每年发病超过55万,死亡超过30万人,吸烟和饮酒是其主要危险因素.HNSCC的治疗方案主要是基于TNM分期、以外科手术为主的综合疗法(放疗、化疗及生物治疗).对于HNSCC的治疗,其5年生存率近年来一直没有改善,因此,需要新的治疗方法提高患者生存率,改善患者生活质量...