No association between HPV infection and the neoplastic progression of esophageal squamous cell carcinoma: result from a cross-sectional study in a high-risk region of China

Esophageal cancer is a leading cause of cancer death, especially in developing countries. In high-risk regions, squamous cell carcinoma is the most common type of esophageal cancer, and its etiology remains poorly understood. The purpose of this study was to evaluate the association between human papillomavirus (HPV) infection and esophageal squamous cell carcinoma (ESCC) and related precursor lesions in a high-risk area of China. We conducted a cross-sectional study among adult inhabitants of Linxian, China. All subjects were interviewed about potential risk factors, had the length of their esophagus sampled by a balloon cytology examination and underwent endoscopy with mucosal iodine staining and biopsy of all unstained lesions. A multivalent HPV hybridization probe, Digene Hybrid Capture II (Gaithersburg, MD), which recognizes high-risk types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68, was used to determine the HPV infection status of the cytologic specimens, and the endoscopic biopsies were used to classify each subject's esophageal disease. 740 subjects completed the cytologic and endoscopic exams, and 702 had adequate cytologic and biopsy specimens. Using a cutpoint of > or =3.0 pg/ml of HPV DNA to define a positive test, HPV positivity was identified in 13% (61/475) of subjects without squamous dysplasia, 8% (8/102) with mild dysplasia, 7% (6/83) with moderate dysplasia, 16% (6/38) with severe dysplasia and zero (0/4) with invasive ESCC. Changing the cutpoint defining a positive test did not change the association of HPV infection and dysplasia grade. In this high-risk population, infection of esophageal cells with high-risk HPV types occurs in 13% of asymptomatic adults with no evidence of squamous dysplasia and a similar proportion of individuals with mild, moderate or severe dysplasia. This suggests that HPV infection is not a major risk factor for ESCC in this high-risk Chinese population. Further studies are warranted to determine if infection with this agent is associated with neoplastic progression in a subset of cases.     

Role of human papillomaviruses in esophageal squamous cell carcinoma

Esophageal cancer (EC) is responsible for almost half a million deaths worldwide annually and has a multifactorial etiology, which may account for its geographical variation in incidence. In the last 30 years the potential of human papillomaviruses (HPV) as oncogenes or co‐factors in the tumorigenic process of esophageal squamous cell carcinoma (ESCC) has been widely studied. While the etiology of HPV in cervical and certain other anogenital and aerodigestive cancers has been established, results regarding its role in EC have been largely inconclusive. A causal association can be evaluated only with a case‐control study, where normal controls are compared to ESCC cases for the presence of HPV. We reviewed all studies investigating ESCC tissue for HPV DNA and identified 139 that met our inclusion criteria, of which only 22 were case‐control studies. Our results support previous findings of higher levels of HPV detection in high‐risk ESCC regions than in areas of low risk. In addition, we confirm that the role of HPV in ESCC remains unclear, despite an accumulation of studies on the subject. The variations in investigative technique, study design and sample types tested may account for the lack of consistency in results. There is a need for a meta‐analysis of all case‐control studies to date, and for large, well‐designed case‐control studies with adequate power to investigate the association. The potential benefits of prophylactic HPV vaccines could be evaluated if HPV is identified as an etiological factor in EC, highlighting the need for further research in this area.     

Human papillomavirus in high- and low-risk areas of oesophageal squamous cell carcinoma in China

To examine the potential roles of human papillomavirus (HPV) in oesophageal squamous cell carcinoma (ESCC) development, we examined the presence of HPV DNA in paraffin-embedded ESCC tissues collected from two areas with different ESCC incidence rates in China, that is, Gansu (n=26) and Shandong (n=33), using PCR with SPF10 primers, or PCR with GP5+/GP6+ primers combined with Southern blot hybridisation. HPV genotype was determined by the INNO-LiPA HPV genotyping kit. HPV DNA was detected in 17 cases (65%) in Gansu, where ESCC incidence is much higher than in Shandong, where HPV was positive in two samples (6%). HPV genotypes 16 and 18 were detected in 79 and 16% of HPV-positive samples, respectively. Real-time PCR analysis suggested the presence of integrated form of HPV DNA in all the HPV-16-positive samples, but its viral load was estimated to be only <1-2 copies cell(-1). We could not detect HPV 16/18 E6 protein expression by immunostaining in any of the HPV-16-positive samples. Neither p16(INK4a) nor p53 expression was related to HPV presence in ESCCs. Further studies seem warranted to examine the possible aetiological roles of HPV in ESCC.     

食管鳞状细胞癌预后的多因素分析

目的:通过对食管鳞状细胞癌(ESCC)多个临床病理因素进行分析,探讨影响其预后的因素。方法:对1986-2002年接受根治性手术治疗的1325例ESCC患者的预后进行回顾性研究。选取性别、年龄、肿瘤长径、分化程度、浸润深度、淋巴结转移和临床分期7个可能对ESCC患者预后有影响的指标,通过Kaplan-Meier生存分析及Cox比例风险模型进行单因素及多因素分析,筛选出影响ESCC患者预后的因素。结果:1 325例ESCC患者术后1、3、5和10年累计生存率分别为72.0%、53.0%、41.0%和1.06%。Kaplan-Meier单因素生存分析结果显示,不同肿瘤长径、分化程度、浸润深度、淋巴结转移和临床分期的ESCC患者5年生存率差异有统计学意义,P<0.01;淋巴结转移阳性组5年生存率为19.4%明显低于淋巴结转移阴性组的50.2%。肿瘤长径大、分化程度低、肿瘤浸润深度深、临床分期晚和有淋巴结转移患者其5年生存率低,预后差。COX多因素分析亦表明分化程度、浸润深度、淋巴结转移和临床分期是影响ESCC预后的相关因素P<0.01。而不同年龄和性别患者5年生存率差异无统计学意义,P>0.05。结论:肿瘤浸润深度、分化程度、淋巴结转移和临床分期可能是判断ESCC预后的独立指标。     

No role for human papillomavirus in esophageal squamous cell carcinoma in China

Certain regions of China have high rates of esophageal squamous cell carcinoma (ESCC). Previous studies of human papillomavirus (HPV), a proposed causal factor, have produced highly variable results. We attempted to evaluate HPV and ESCC more definitively using extreme care to prevent DNA contamination. We collected tissue and serum in China from 272 histopathologically‐confirmed ESCC cases with rigorous attention to good molecular biology technique. We tested for HPV DNA in fresh‐frozen tumor tissue using PCR with PGMY L1 consensus primers and HPV16 and 18 type‐specific E6 and E7 primers, and in formalin‐fixed paraffin‐embedded tumor tissue using SPF₁₀ L1 primers. In HPV‐positive cases, we evaluated p16^INK4a overexpression and HPV E6/E7 seropositivity as evidence of carcinogenic HPV activity. β‐globin, and thus DNA, was adequate in 98.2% of the frozen tumor tissues (267/272). Of these, 99.6% (95% confidence interval (CI) = 97.9–100.0%) were negative for HPV DNA by PGMY, and 100% (95% CI = 98.6–100%) were negative by HPV16/18 E6/E7 PCR. In the corresponding formalin‐fixed paraffin‐embedded tumor specimens, 99.3% (95% CI = 97.3–99.9%) were HPV negative by SPF₁₀. By PGMY, 1 case tested weakly positive for HPV89, a noncancer causing HPV type. By SPF₁₀, 2 cases tested weakly positive: 1 for HPV16 and 1 for HPV31. No HPV DNA‐positive case had evidence of HPV oncogene activity as measured by p16^INK4a overexpression or E6/E7 seropositivity. This study provides the most definitive evidence to date that HPV is not involved in ESCC carcinogenesis in China. HPV DNA contamination cannot be ruled out as an explanation for high HPV prevalence in ESCC tissue studies with less stringent tissue procurement and processing protocols.     

OGT蛋白在食管鳞状细胞癌中的表达及其临床意义

目的:探讨OGT蛋白在食管鳞状细胞癌（ESCC）组织中的表达及其与临床病理的关系。方法:收集66例ESCC组织标本及其癌旁组织标本,免疫组化法测定OGT蛋白的表达。结果:OGT在ESCC组织的表达明显高于癌旁组织(P<0.05),OGT的高表达与TNM 分期、病理分级相关(P<0.05),而与性别、年龄及淋巴结转移无相关性(P>0.05)。结论:OGT在食管癌组织中表达增高,提示OGT的异常高表达在食管癌的发生发展中起重要作用。     

DCC promoter hypermethylation in esophageal squamous cell carcinoma

Deleted in Colorectal Cancer (DCC) is a putative tumor suppressor gene, whose loss has been implicated in colorectal tumorigenesis. Decreased or loss of DCC expression has been demonstrated in a number of human cancers, including esophageal cancer. In this study, we analyzed esophageal squamous cell carcinoma (ESCC) cell lines and primary ESCCs as well as normal esophageal tissues for DCC methylation by bisulfite sequencing, methylation-specific PCR (MSP) and/or quantitative methylation-specific PCR (qMSP). When a qMSP cut-off value for positivity was set to 1.0, DCC methylation was detected in 10 of 12 ESCC cell lines tested, 74% of primary ESCCs (n = 70), 0% of corresponding normal esophageal tissues (n = 20) and 0% of normal esophagus from healthy individuals (n = 19). DCC expression was undetectable in the majority of ESCC cell lines, and treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine reactivated gene expression. DCC overexpression suppressed colony formation in ESCC cell lines, suggesting that DCC may function as a tumor suppressor gene in the esophagus. However, DCC methylation was not associated with any clinical or pathologic parameters measured. We have demonstrated that DCC methylation is a frequent and cancer-specific event in primary ESCCs, suggesting that DCC and associated pathways may represent a new diagnostical therapeutic target.     

蛋白水解诱导因子在食管鳞状细胞癌中的表达

目的:研究蛋白水解诱导因子(proteolysis-inducing factor,PIF)在食管鳞状细胞癌中的表达及意义.方法:应用免疫组化方法,检测PIF在107例食管鳞状细胞癌病人癌组织以及其中35例癌旁正常组织以及8例食管良性疾病标本中的表达情况,并探讨PIF表达与食管癌临床分期、肿瘤分化程度的关系.结果:食管鳞状细胞癌组织中存在PIF表达,其表达与食管良性疾病对照组中的表达差异有统计学意义(P<0.05),肿瘤组织中表达PIF的个体其癌旁正常组织中亦有PIF表达,PIF表达在肿瘤分化、是否侵及浆膜层、有无淋巴结转移和肿瘤分期中的差异无统计学显著性(P﹥0.05).结论:食管鳞状细胞癌组织中存在PIF表达,其表达与肿瘤分化、是否侵及浆膜层、有无淋巴结转移和肿瘤分期无关.     

MicroRNA-381 increases radiosensitivity in esophageal squamous cell carcinoma

Background: Radiation resistance poses a major clinical challenge in treatment of esophageal squamous cell carcinoma (ESCC). However, the mechanisms of radioresistance has not been fully elucidated. Since accumulating evidence demonstrates that aberrant expression of microRNAs (miRNAs) contributes to cancer sensitivity to radiation, we aimed to identify miRNAs associated with radioresistance of ESCC. Methods: In this study, we used GeneChip miRNA Array to perform an comparison of miRNAs expression in tissues from primary ESCC and recurrent ESCC in situ after radiotherapy. Differential expressions of miRNAs were comfirmed by quantitative Real-Time PCR in tissues and six ESCC cell lines. Cell radiosensitivity were determined by colony formation assay. Functional analyses of miRNA-381 in ESCC cells growth and metastasis were performed by MTT and Transwell Assays. In vivo assays of the functions of miRNA-381 were performed in tumor xenografts. Results: One miRNA candidate, miRNA-381, was found to be downregulated in radiation resistance tissues and cells. Enforced expression of miRNA-381 increased radiosensitivity of ESCC cells and promoted nonaggressive phenotype including decreased cellular proliferation and migration. In contrast, inhibition of miRNA-381 in ESCC cells promoted radiation resistance and development of an aggressive phenotype. In vivo assays extended the significance of these results, showing that miRNA-381 overexpression decreased the tumor growth and the resistance to radiation treatment in tumor xenografts. Conclusions: Together, our work reveals miRNA-381 expression as a critical determinant of radiosensitivity in esophageal cancer cells.     

HPV感染在口腔鳞癌中的研究进展

口腔鳞状细胞癌(OSCC)是头颈部最常见的恶性肿瘤,预后较差,整体5年生存率较低,世界卫生组织预计在未来十几年中OSCC的发病率将持续上升。除了烟草、槟榔、饮酒等因素,人乳头瘤病毒(HPV)感染也被确定为危险因素,HPV的感染与OSCC的发生及预后有着密切的关系,目前研究表明,HPV感染逐渐成为OSCC的主要致病因素。HPV感染引起的OSCC可能会成为OSCC中一种发病机制、肿瘤微环境、生物学行为和预后都相对独特的一种类型。笔者通过广泛查阅文献,围绕HPV在OSCC中作用机制、HPV阳性OSCC的特征及HPV与OSCC治疗和预防的相关性的研究进展进行总结。     

HPV16 semiquantitative viral load and serologic biomarkers in oral and oropharyngeal squamous cell carcinomas

A considerable subset of oropharyngeal squamous cell carcinomas (SCCs) are positive for human papillomavirus (HPV); however, delineating etiologically-associated HPV infections from SCCs with concurrent HPV infection unrelated to tumorigenesis is challenging. Viral load assessment in biopsy specimens may help facilitate such differentiation. HPV16 viral load and serologic markers were assessed among oral and oropharyngeal cases from a multinational study conducted by the International Agency for Research on Cancer (IARC). HPV16 viral load, measured semiquantitatively by PCR-enzyme immunoassay, was dichotomized as high or low based on the median optical density value. Serologic antibodies to HPV16 virus-like particles (VLPs) and to HPV16 E6 and E7 proteins were measured by ELISA. Compared to HPV DNA-negative cases (n = 852), HPV16 DNA-positive cases with high viral load (n = 26) were significantly more likely to originate in the oropharynx (odds ratio [OR], 12.0; 95% confidence interval [CI], 5.2-27.5) and, after adjustment for tumor site (AdjOR), have antibodies against HPV16 VLPs (AdjOR, 14.6; 95% CI, 6.0-35.6), E6 (AdjOR, 57.6; 95% CI, 21.4-155.3) and E7 (AdjOR, 25.6; 95% CI, 9.3-70.8). HPV16 DNA-positive cases with low viral load (n = 27) were more commonly oropharyngeal (OR, 2.7; 95% CI, 1.1-6.2) and seropositive for HPV16 VLPs (AdjOR, 2.7; 95% CI, 1.1-6.9), E6 (AdjOR, 3.0; 95% CI, 0.7-14.0) and E7 (AdjOR, 3.5; 95% CI, 0.7-16.3), compared to HPV DNA-negative cases; the associations, however, were neither as strong nor as significant as the associations for high viral load. As there appears to be a strong association between HPV16 serologic markers and viral load, in the absence of data on serologic markers, HPV16 viral load may be used to help delineate the subset of HPV16 DNA-positive oral and oropharyngeal cancers that may be the consequence of HPV infection.     

Human papillomavirus tumor infection in esophageal squamous cell carcinoma

The association between human papillomavirus (HPV) and esophageal squamous cell carcinoma (ESCC) has been recognized for over three decades. Recently, multiple meta-analyses have drawn upon existing literature to assess the strength of the HPV-ESCC linkage. Here, we review these analyses and attempt to provide a clinically-relevant overview of HPV infection in ESCC. HPV-ESCC detection rates are highly variable across studies. Geographic location likely accounts for a majority of the variation in HPV prevalence, with high-incidence regions including Asia reporting significantly higher HPV-ESCC infection rates compared with low-incidence regions such as Europe, North America, and Oceania. Based on our examination of existing data, the current literature does not support the notion that HPV is a prominent carcinogen in ESCC. We conclude that there is no basis to change the current clinical approach to ESCC patients with respect to tumor HPV status.     

蛋白水解诱导因子在食管鳞状细胞癌中的表达

目的：研究蛋白水解诱导因子（proteolysis-inducing factor,PIF）在食管鳞状细胞癌中的表达及意义。方法：应用免疫组化方法,检测PIF在107例食管鳞状细胞癌病人癌组织以及其中35例癌旁正常组织以及8例食管良性疾病标本中的表达情况,并探讨PIF表达与食管癌临床分期、肿瘤分化程度的关系。结果：食管鳞状细胞癌组织中存在PIF表达,其表达与食管良性疾病对照组中的表达差异有统计学意义（P〈0．05）,肿瘤组织中表达PIF的个体其癌旁正常组织中亦有PIF表达,PIF表达在肿瘤分化、是否侵及浆膜层、有无淋巴结转移和肿瘤分期中的差异无统计学显著性（P〉0．05）。结论：食管鳞状细胞癌组织中存在PIF表达,其表达与肿瘤分化、是否侵及浆膜层、有无淋巴结转移和肿瘤分期无关。     

老年食管鳞状细胞癌的放疗疗效及预后因素分析

目的:探讨老年食管鳞状细胞癌的临床特点、放疗疗效及其预后的相关因素。方法:回顾性分析2003年1月至2008年1月在我院接受放射治疗的299例食管鳞状细胞癌患者的临床资料,运用SPSS 16.0软件分析生存率及预后的影响因素（＜65岁为非老年组,≥65岁为老年组）。结果:老年组和非老年组总有效率分别为56.0%、91.3%（P=0.000）。老年组患者的近期疗效与化疗史（P=0.001）和放疗剂量（P=0.005）有关,非老年组的近期疗效与患者的民族有关（P=0.001）。而性别、吸烟史、饮酒史、病变长度、病变部位、临床分期、分化程度、淋巴结转移、KPS评分等临床因素与近期疗效无明显相关性（P均＞0.05）。老年组和非老年组患者的中位生存时间分别为42个月、41个月,经Log-Rank检验,两组患者生存时间的差异无统计学意义（P=0.954）。多因素分析显示放疗剂量≥60Gy的老年食管鳞癌患者预后比放疗剂量＜60Gy的患者好（P=0.023,95%CI:0.432~0.939）,放疗近期疗效达缓解的患者比近期疗效无缓解的患者预后好(P=0.001,95%CI:1.339~2.885);而放疗方式、化疗史、病理分型与预后无相关性（P均＞0.05）。结论:非老年组的放疗近期疗效优于老年组;老年组的近期疗效与化疗史、放疗剂量有关;放疗剂量≥60Gy、近期疗效达缓解的老年食管癌患者预后相对较好。     

食管鳞癌中差异表达的lncRNA的筛选及分析

目的:筛查及分析食管鳞癌中长链非编码RNA(lncRNA)及mRNA的差异表达谱,以及这些差异lncRNAs的功能、互作分子.方法:通过对3对食管鳞癌/癌旁组织的基因芯片筛选及生物信息学分析,预测这些差异表达的lncRNAs潜在靶点、通路,及其与临近编码基因、转录因子的相关性.结果:按FC 值≥2.0且P值≤0.05的标准,共筛选得到癌及癌旁组织差异表达的lncRNA 182个,mRNA 108个,GO聚类和KEGG分析发现差异lncRNAs潜在靶标基因与细胞周期调控、细胞分化、细胞外基质等活性密切相关,进一步生物分析得到lncRNA NONHSAT015779、NONHSAT08197、NONHSAT112918和NONHSAT115190等17个lncRNAs可能与食管鳞癌发生发展密切相关.结论:与癌旁组织相比,lncRNAs在食管鳞癌组织中显示不同的表达模式,这些差异表达的lncRNAs可能在食管鳞癌发生和发展中发挥重要作用.     

高迁移率族蛋白B1在食管鳞癌的研究进展

高迁移率族蛋白B1（high mobility group protein box 1,HMGB1）为高迁移率族（high mobility group,HMG）成员之一,存在于真核生物细胞内。HMGB1是一种具有广泛作用的DNA结合蛋白,参与细胞内DNA的重组、修复及转录。细胞外的HMGB1不仅促进炎症反应,还在恶性肿瘤的生长、侵袭、转移等过程中发挥重要作用。近年来研究发现,HMGB1与食管鳞癌的发生、诊断、治疗及预后关系密切,本文就其研究进展予以综述。     

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.     

食管鳞癌患者血清细胞质胸苷激酶表达的临床研究

目的：探讨食管鳞癌患者血清细胞质胸苷激酶（TK1）的表达水平及其与临床特征的相关性。方法：选择具有完整临床病理及随访资料结果的50例食管鳞癌患者,采用增强化学发光法（ECLA）检测其血清TK1的表达水平,同时随机检测50例健康体检者（正常对照组）血清TK1的含量。对患者术前、术后1周及术后1月TK1水平进行监测。结果：截止2012年3月31日,人组50例食管鳞癌患者均存活,5例出现局部区域复发。尚未发现远处转移患者食管鳞癌组TK1水平[2.35（1.24—3.75）pm／L],显著高于正常对照组[1.06（0.58—1.26）pm／L]（P〈00.5）,食管鳞癌患者术前TK1水平[2.35（1.24—3.75）pm／L]高于术后1周组[2.05（1.15—2.87）pm／L]、术后1月组[1.35（0.76—1.86）pm／L],差异有统计学意义（P〈0.05）。影像学或内镜确诊患者复发前均发现TK1水平动态上升。结论：血清TK1检测在食管鳞癌的早期诊断、疗效监测、判断预后等方面具有一定的临床应用价值。     

Differentiation-related zinc finger protein 750 suppresses cell growth in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is a deadly squamous cell carcinoma (SCC) of the esophagus. Development of SCCs is associated with the deregulation of the squamous cell lineage program and/or keratinocyte terminal differentiation by genomic and genetic aberrations; thus, these processes must be tightly controlled to maintain normal squamous cell development. Zinc finger protein 750 (ZNF750) is a gene involved in keratinocyte terminal differentiation and is frequently mutated and putatively silenced in ESCC, which implicates its function as a potential differentiation-related suppressor of ESCC. The present study aimed to elucidate the relationship between ZNF750 function to induce keratinocyte differentiation and tumor suppression in ESCC. The results demonstrated that chemical manipulation of esophageal keratinocyte differentiation in mouse normal esophageal epithelial organoids (mNEEO) implicated the involvement of the mouse homologue of ZNF750, Zfp750, in keratinocyte differentiation in premalignant cells. Bioinformatics analyses of data from high ZNF750-expressing ESCC tumors obtained from public databases and ZNF750-overexpressing ESCC cells compared with low ZNF750-expressing ESCC tumors and GFP-expressing ESCC cells, respectively, revealed enrichment of keratinocyte differentiation-related gene sets in these samples. Finally, the induction through to terminal differentiation of the keratinocyte by all-trans retinoic acid on parental ESCC cell lines led to the upregulation of the terminal differentiation marker Involucrin and a decrease in cell viability similar to that observed in ZNF750-overexpressing ESCC cells. The results of the present study demonstrated a functional link between the ability of ZNF750 to induce cell differentiation through to terminal differentiation and its function as a growth suppressor in ESCC. This study provides improved understanding of the role of ZNF750, a frequently mutated differentiation-related gene in ESCC, and its effects in ESCC pathogenesis.     

Differential HPV16 variant distribution in squamous cell carcinoma,adenocarcinoma and adenosquamous cell carcinoma

Human Papillomavirus 16 (HPV16) causes 70% of invasive cervical cancers (ICC) worldwide. Interaction between HPV16 genetic diversity, host genetics and target tissue largely determine the chances to trigger carcinogenesis. We have analyzed the differential prevalence of viral variants in 233 HPV16‐monoinfected squamous (SCC), glandular (ADC) and mixed (ADSC) ICCs from four continents, assessing the contribution of geographical origin and cancer histology. We have further quantified the contribution of viral variants and cancer histology to differences in age at tumor diagnosis. The model fitted to the data explained 97% of the total variance: the largest explanatory factors were differential abundance among HPV16 variants (78%) and their interaction with cancer histology (9.2%) and geography (10.1%). HPV16_A1‐3 variants were more prevalent in SCC while HPV16_D variants were increased in glandular ICCs. We confirm further a non‐random geographical structure of the viral variants distribution. ADCs were diagnosed at younger ages than SCCs, independently of the viral variant triggering carcinogenesis. HPV16 variants are differentially associated with histological ICCs types, and ADCs are systematically diagnosed in younger women. Our results have implications for the implementation of cervical cancer screening algorithms, to ensure proper early detection of elusive ADCs.