{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:59:43Z","timestamp":1792789183061,"version":"4.5.0"},"reference-count":47,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["82003285"],"award-info":[{"award-number":["82003285"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Beijing Xisike Clinical Oncology Research Foundation","award":["Y-2024AZ(NSCLC)MS-0045"],"award-info":[{"award-number":["Y-2024AZ(NSCLC)MS-0045"]}],"id":[{"id":"https:\/\/ror.org\/05sfnze82","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: This study aimed to investigate the prevalence of human papillomavirus (HPV) infection in Chinese patients with esophageal squamous cell carcinoma (ESCC) and its association with driver gene mutations (EGFR, KRAS, PIK3CA, PTEN), clinicopathological features, and prognosis. Methods: A retrospective cohort of 120 Chinese ESCC patients was analyzed. HPV infection status and typing were determined by polymerase chain reaction (PCR)-based reverse hybridization in tumor tissues; EGFR, KRAS, PIK3CA, and PTEN mutations were assessed by Sanger sequencing. Associations with clinicopathological variables and survival were evaluated. Results: The HPV infection rate was 44.2%, with 37.5% single-type and 6.7% mixed infections, predominantly high-risk types. No EGFR or KRAS mutations were detected, whereas PTEN and PIK3CA mutations were found in 16.7% and 6.7% of patients, respectively, and were mutually exclusive. HPV-negative tumors more frequently showed lymphovascular invasion (p = 0.03) and PTEN mutations (p = 0.017). HPV positivity was associated with better recurrence-free survival and overall survival. Conclusions: HPV infection is prevalent in Chinese ESCC and may delineate a distinct molecular profile; HPV-negative ESCC was more frequently associated with aggressive clinicopathological features, including lymphovascular invasion and PTEN mutations. These findings support subtype-stratified prevention and treatment strategies for ESCC.<\/jats:p>","DOI":"10.3390\/cancers18193103","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T10:16:28Z","timestamp":1790244988000},"page":"3103","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Distinct Molecular Landscape and Clinical Subtype of HPV-Positive Esophageal Squamous Cell Carcinoma"],"prefix":"10.3390","volume":"18","author":[{"given":"Hang","family":"Li","sequence":"first","affiliation":[{"name":"Departments of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai 200032, China"},{"name":"Institute of Thoracic Oncology, Fudan University, Shanghai 200032, China"},{"name":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"given":"Xuxia","family":"Shen","sequence":"additional","affiliation":[{"name":"Institute of Thoracic Oncology, Fudan University, Shanghai 200032, China"},{"name":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China"},{"name":"Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Yan","family":"Jin","sequence":"additional","affiliation":[{"name":"Institute of Thoracic Oncology, Fudan University, Shanghai 200032, China"},{"name":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China"},{"name":"Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Hong","family":"Hu","sequence":"additional","affiliation":[{"name":"Departments of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai 200032, China"},{"name":"Institute of Thoracic Oncology, Fudan University, Shanghai 200032, China"},{"name":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"supervision","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Jiaqing","family":"Xiang","sequence":"additional","affiliation":[{"name":"Departments of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai 200032, China"},{"name":"Institute of Thoracic Oncology, Fudan University, Shanghai 200032, China"},{"name":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]},{"given":"Yawei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Departments of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai 200032, China"},{"name":"Institute of Thoracic Oncology, Fudan University, Shanghai 200032, China"},{"name":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"supervision","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6875","DOI":"10.1002\/cam4.3338","article-title":"Global trends in the incidence and mortality of esophageal cancer from 1990 to 2017","volume":"9","author":"Fan","year":"2020","journal-title":"Cancer Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s40364-024-00718-2","article-title":"Global, regional, and national burden of esophageal cancer: A systematic analysis of the Global Burden of Disease Study 2021","volume":"13","author":"Jin","year":"2025","journal-title":"Biomark. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1002\/ijc.35003","article-title":"Analysis of the incidence and mortality trends of esophageal cancer in cancer registry areas of China and Japan","volume":"155","author":"Guo","year":"2024","journal-title":"Int. J. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1007\/s12029-019-00328-4","article-title":"A Multinational Assessment of Gastric, Esophageal, and Colorectal Cancer Burden: A Report of Disease Incidence, Prevalence, and Fatality","volume":"51","author":"Florea","year":"2020","journal-title":"J. Gastrointest. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"216127","DOI":"10.1016\/j.canlet.2023.216127","article-title":"Burden of gastrointestinal cancers in China from 1990 to 2019 and projection through 2029","volume":"560","author":"Chen","year":"2023","journal-title":"Cancer Lett."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Jain, M., Yadav, D., Jarouliya, U., Chavda, V., Yadav, A.K., Chaurasia, B., and Song, M. (2023). Epidemiology, Molecular Pathogenesis, Immuno-Pathogenesis, Immune Escape Mechanisms and Vaccine Evaluation for HPV-Associated Carcinogenesis. Pathogens, 12.","DOI":"10.3390\/pathogens12121380"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1007\/s10147-023-02337-7","article-title":"Carcinogenesis and management of human papillomavirus-associated cervical cancer","volume":"28","author":"Kusakabe","year":"2023","journal-title":"Int. J. Clin. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Dong, Z., Hu, R., Du, Y., Tan, L., Li, L., Du, J., Bai, L., Ma, Y., and Cui, H. (2020). Immunodiagnosis and Immunotherapeutics Based on Human Papillomavirus for HPV-Induced Cancers. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.586796"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-3-030-67452-6_1","article-title":"Human Papillomavirus-Associated Cancers","volume":"1313","author":"Alhamlan","year":"2021","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Uzelac, M., Barakchi, A., Beldona, V., John, D., Chakladar, J., Li, W.T., and Ongkeko, W.M. (2022). Effects of Human Papilloma Virus E6\/E7 Oncoproteins on Genomic Structure in Head and Neck Squamous Cell Carcinoma. Cancers, 14.","DOI":"10.3390\/cancers14246190"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e29881","DOI":"10.1016\/j.heliyon.2024.e29881","article-title":"Genetically engineered mouse model of HPV16 E6\u2013E7 with vaginal-cervical intraepithelial neoplasia and decreased immunity","volume":"10","author":"Du","year":"2024","journal-title":"Heliyon"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Riva, G., Albano, C., Gugliesi, F., Pasquero, S., Pacheco, S.F.C., Pecorari, G., Landolfo, S., Biolatti, M., and Dell\u2019Oste, V. (2021). HPV Meets APOBEC: New Players in Head and Neck Cancer. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22031402"},{"key":"ref_14","first-page":"287","article-title":"Human papillomavirus tumor infection in esophageal squamous cell carcinoma","volume":"6","author":"Ludmir","year":"2015","journal-title":"J. Gastrointest. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1017\/S0950268814000016","article-title":"Association between human papillomavirus (HPV) and oesophageal squamous cell carcinoma: A meta-analysis","volume":"142","author":"Hardefeldt","year":"2014","journal-title":"Epidemiol. Infect."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1128\/JCM.40.3.779-787.2002","article-title":"GP5+\/6+ PCR followed by reverse line blot analysis enables rapid and high-throughput identification of human papillomavirus genotypes","volume":"40","author":"Pol","year":"2002","journal-title":"J. Clin. Microbiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1111\/j.1399-0039.1994.tb02371.x","article-title":"A method for typing polymorphism at the HLA-A locus using PCR amplification and immobilized oligonucleotide probes","volume":"44","author":"Bugawan","year":"1994","journal-title":"Tissue Antigens"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.lungcan.2012.09.018","article-title":"Frequency of well-identified oncogenic driver mutations in lung adenocarcinoma of smokers varies with histological subtypes and graduated smoking dose","volume":"79","author":"Li","year":"2013","journal-title":"Lung Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5463","DOI":"10.1073\/pnas.74.12.5463","article-title":"DNA sequencing with chain-terminating inhibitors","volume":"74","author":"Sanger","year":"1977","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1016\/S0140-6736(03)14955-0","article-title":"Management of women who test positive for high-risk types of human papillomavirus: The HART study","volume":"362","author":"Cuzick","year":"2003","journal-title":"Lancet"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1093\/jnci\/87.11.796","article-title":"Prevalence of human papillomavirus in cervical cancer: A worldwide perspective","volume":"87","author":"Bosch","year":"1995","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5241","DOI":"10.1007\/s00432-022-04322-5","article-title":"Human papillomavirus is an important risk factor for esophageal carcinoma in a Chinese population","volume":"149","author":"Yuan","year":"2023","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1007\/s00428-020-02860-2","article-title":"Early esophageal squamous cell carcinoma in a western series is not associated with active HPV infection","volume":"477","author":"Kanaan","year":"2020","journal-title":"Virchows Arch."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1093\/jnci\/djr499","article-title":"InterSCOPE study: Associations between esophageal squamous cell carcinoma and human papillomavirus serological markers","volume":"104","author":"Sitas","year":"2012","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1111\/nyas.14509","article-title":"Human papillomavirus infection in esophageal squamous cell carcinoma and esophageal adenocarcinoma: A concise review","volume":"1482","author":"Rajendra","year":"2020","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1111\/nyas.13858","article-title":"Risk factors for esophageal cancer: Emphasis on infectious agents","volume":"1434","author":"Brcic","year":"2018","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Guo, L., Yang, F., Yin, Y., Liu, S., Li, P., Zhang, X., Chen, D., Liu, Y., Wang, J., and Wang, K. (2018). Prevalence of human papillomavirus type-16 in head and neck cancer among the Chinese population: A meta-analysis. Front. Oncol., 8.","DOI":"10.3389\/fonc.2018.00619"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Li, R., Li, J., Wang, Q., Zhao, Y., Zhu, L., Zhu, Y., and Wang, X. (2025). HPV associated oropharyngeal cancer in eastern China over the last 7 years: Is the incidence in Chinese truly exceptionally low?. BMC Public Health, 25.","DOI":"10.1186\/s12889-025-24688-8"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1002\/ijc.33514","article-title":"The unveiled reality of human papillomavirus as risk factor for oral cavity squamous cell carcinoma","volume":"149","author":"Nauta","year":"2021","journal-title":"Int. J. Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1002\/cncr.30353","article-title":"The prognostic role of sex, race, and human papillomavirus in oropharyngeal and nonoropharyngeal head and neck squamous cell cancer","volume":"123","author":"Fakhry","year":"2017","journal-title":"Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1716","DOI":"10.1001\/jamaoncol.2023.4042","article-title":"Circulating Tumor HPV DNA for Surveillance of HPV-Positive Oropharyngeal Squamous Cell Carcinoma: A Narrative Review","volume":"9","author":"Brenner","year":"2023","journal-title":"JAMA Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.ebiom.2017.02.025","article-title":"Identification of an atypical etiological head and neck squamous carcinoma subtype featuring the CpG island methylator phenotype","volume":"17","author":"Brennan","year":"2017","journal-title":"eBioMedicine"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"100250","DOI":"10.1016\/j.modpat.2023.100250","article-title":"Different Mutational Landscapes in Human Papillomavirus-Induced and Human Papillomavirus-Independent Invasive Penile Squamous Cell Cancers","volume":"36","author":"Ermakov","year":"2023","journal-title":"Mod. Pathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1038\/nrc.2017.117","article-title":"Impact of oncogenic pathways on evasion of antitumour immune responses","volume":"18","author":"Spranger","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Mena, M., Wang, X., Tous, S., Quiros, B., Clavero, O., Alejo, M., Morey, F., Taberna, M., Leon Vintro, X., and Lloveras Rubio, B. (2022). Concordance of p16(INK4a) and E6*I mRNA among HPV-DNA-Positive Oropharyngeal, Laryngeal, and Oral Cavity Carcinomas from the ICO International Study. Cancers, 14.","DOI":"10.3390\/cancers14153787"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1007\/s11033-022-07952-7","article-title":"HPV 16 E6 promotes growth and metastasis of esophageal squamous cell carcinoma cells in vitro","volume":"50","author":"Hu","year":"2023","journal-title":"Mol. Biol. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"41","DOI":"10.3892\/mco.2020.2205","article-title":"Relationship between cervical esophageal squamous cell carcinoma and human papilloma virus infection and gene mutations","volume":"14","author":"Fukahori","year":"2021","journal-title":"Mol. Clin. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1016\/j.jtho.2022.01.012","article-title":"Osimertinib Plus Durvalumab in Patients With EGFR-Mutated, Advanced NSCLC: A Phase 1b, Open-Label, Multicenter Trial","volume":"17","author":"Ahn","year":"2022","journal-title":"J. Thorac. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"15324","DOI":"10.1038\/s41598-017-14909-5","article-title":"Comprehensive genomic analysis of oesophageal squamous cell carcinoma reveals clinical relevance","volume":"7","author":"Du","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"The Cancer Genome Atlas Research Network (2017). Integrated genomic characterization of oesophageal carcinoma. Nature, 541, 169\u2013175.","DOI":"10.1038\/nature20805"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Tao, H., Song, S.J., Fan, Z.W., Li, W.T., Jin, X., Jiang, W., Bai, J., and Shi, Z.Z. (2024). PKCiota Inhibits the Ferroptosis of Esophageal Cancer Cells via Suppressing USP14-Mediated Autophagic Degradation of GPX4. Antioxidants, 13.","DOI":"10.3390\/antiox13010114"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1038\/nature12881","article-title":"Landscape of genomic alterations in cervical carcinomas","volume":"506","author":"Ojesina","year":"2014","journal-title":"Nature"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1158\/1078-0432.CCR-13-3310","article-title":"Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas","volume":"21","author":"Seiwert","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2673","DOI":"10.1002\/cncr.28797","article-title":"High-risk human papillomavirus infection associated with telomere elongation in patients with esophageal squamous cell carcinoma with poor prognosis","volume":"120","author":"Zhang","year":"2014","journal-title":"Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s13027-018-0210-9","article-title":"Prognostic role of HPV infection in esophageal squamous cell carcinoma","volume":"13","author":"Bognar","year":"2018","journal-title":"Infect. Agents Cancer"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.canlet.2012.07.018","article-title":"HPV infection in Brazilian patients with esophageal squamous cell carcinoma: Interpopulational differences, lack of correlation with surrogate markers and clinicopathological parameters","volume":"326","author":"Herbster","year":"2012","journal-title":"Cancer Lett."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1007\/s00432-020-03218-6","article-title":"Active HPV infection and its influence on survival in head and neck squamous-cell cancer","volume":"146","author":"Majchrzyk","year":"2020","journal-title":"J. Cancer Res. Clin. Oncol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/19\/3103\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T04:26:27Z","timestamp":1790396787000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/19\/3103"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,24]]},"references-count":47,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["cancers18193103"],"URL":"https:\/\/doi.org\/10.3390\/cancers18193103","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,24]]}}}