Genomic characterization of clonal evolution during oropharyngeal carcinogenesis driven by human papillomavirus 16
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Secondary prevention via earlier detection would afford the greatest chance for a cure in premalignant lesions. We investigated the exomic profiles of non-malignant and malignant changes in head and neck squamous cell carcinoma (HNSCC) and the genomic blueprint of human papillomavirus (HPV)-driven carcinogenesis in oropharyngeal squamous cell carcinoma (OPSCC). Whole-exome (WES) and whole-genome (WGS) sequencing were performed on peripheral blood and adjacent non-tumor and tumor specimens obtained from eight Korean HNSCC patients from 2013 to 2015. Next-generation sequencing yielded an average coverage of 94.3× for WES and 35.3× for WGS. In comparative genomic analysis of non-tumor and tumor tissue pairs, we were unable to identify common cancer-associated early mutations and copy number alterations (CNA) except in one pair. Interestingly, in this case, we observed that non-tumor tonsillar crypts adjacent to HPV-positive OPSCC appeared normal under a microscope; however, this tissue also showed weak p16 expression. WGS revealed the infection and integration of high-risk type HPV16 in this tissue as well as in the matched tumor. Furthermore, WES identified shared and tumor-specific genomic alterations for this pair. Clonal analysis enabled us to infer the process by which this transitional crypt epithelium (TrCE) evolved into a tumor; this evolution was accompanied by the subsequent accumulation of genomic alterations, including an ERBB3 mutation and large-scale CNAs, such as 3q27-qter amplification and 9p deletion. We suggest that HPV16-driven OPSCC carcinogenesis is a stepwise evolutionary process that is consistent with a multistep carcinogenesis model. Our results highlight the carcinogenic changes driven by HPV16 infection and provide a basis for the secondary prevention of OPSCC.
Abstract
Secondary prevention via earlier detection would afford the greatest chance for a cure in premalignant lesions. We investigated the exomic profiles of non-malignant and malignant changes in head and neck squamous cell carcinoma (HNSCC) and the genomic blueprint of human papillomavirus (HPV)-driven carcinogenesis in oropharyngeal squamous cell carcinoma (OPSCC). Whole-exome (WES) and whole-genome (WGS) sequencing were performed on peripheral blood and adjacent non-tumor and tumor specimens obtained from eight Korean HNSCC patients from 2013 to 2015. Next-generation sequencing yielded an average coverage of 94.3× for WES and 35.3× for WGS. In comparative genomic analysis of non-tumor and tumor tissue pairs, we were unable to identify common cancer-associated early mutations and copy number alterations (CNA) except in one pair. Interestingly, in this case, we observed that non-tumor tonsillar crypts adjacent to HPV-positive OPSCC appeared normal under a microscope; however, this tissue also showed weak p16 expression. WGS revealed the infection and integration of high-risk type HPV16 in this tissue as well as in the matched tumor. Furthermore, WES identified shared and tumor-specific genomic alterations for this pair. Clonal analysis enabled us to infer the process by which this transitional crypt epithelium (TrCE) evolved into a tumor; this evolution was accompanied by the subsequent accumulation of genomic alterations, including an ERBB3 mutation and large-scale CNAs, such as 3q27-qter amplification and 9p deletion. We suggest that HPV16-driven OPSCC carcinogenesis is a stepwise evolutionary process that is consistent with a multistep carcinogenesis model. Our results highlight the carcinogenic changes driven by HPV16 infection and provide a basis for the secondary prevention of OPSCC.
참고문헌 (32)
- Fitzmaurice C, "Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: A systematic analysis for the global burden of disease study", JAMA Oncol, 3, pp.524~548 (2016)
- Gooi Z, "The epidemiology of the human papillomavirus related to oropharyngeal head and neck cancer", Laryngoscope, 126, pp.894~900 (2016)
- Chaturvedi K, "Human papillomavirus and rising oropharyngeal cancer incidence in the United States", J Clin Oncol, 29, pp.4294~4301 (2011)
- Chaturvedi K, "Worldwide trends in incidence rates for oral cavity and oropharyngeal cancers", J Clin Oncol, 31, pp.4550~4559 (2013)
- Cancer Genome Atlas Network, "Comprehensive genomic characterization of head and neck squamous cell carcinomas", Nature, 517, pp.576~582 (2015)
- Wentzensen N, "Systematic review of genomic integration sites of human papillomavirus genomes in epithelial dysplasia and invasive cancer of the female lower genital tract", Cancer Res, 64, pp.3878~3884 (2004)
- Vogelstein B, "The multistep nature of cancer", Trends Genet, 9, pp.138~141 (1993)
- Rietbergen M, "No evidence for active human papillomavirus (HPV) in fields surrounding HPV-positive oropharyngeal tumors", J Oral Pathol Med, 43, pp.137~142 (2014)
- Ilmarinen T, "Prevalence of high-risk human papillomavirus infection and cancer gene mutations in nonmalignant tonsils", Oral Oncol, 73, pp.77~82 (2017)
- Palmer E, "Human papillomavirus infection is rare in nonmalignant tonsil tissue in the UK: implications for tonsil cancer precursor lesions", Int J Cancer, 135, pp.2437~2443 (2014)
- Gillison L, "Prevalence of oral HPV infection in the United States, 2009-2010", JAMA, 307, pp.693~703 (2012)
- Alexandrov B, "Signatures of mutational processes in human cancer", Nature, 500, pp.415~421 (2013)
- Tabor P, "Genetically altered fields as origin of locally recurrent head and neck cancer:a retrospective study", Clin Cancer Res, 10, pp.3607~3613 (2004)
- Brennan A, "Molecular assessment of histopathological staging in squamous-cell carcinoma of the head and neck", N Engl J Med, 332, pp.429~435 (1995)
- Wood M, "The clonal relationships between pre-cancer and cancer revealed by ultra-deep sequencing", J Pathol, 237, pp.296~306 (2015)
- Ezaldein H, "Grading of aypia in genital skin lesions: routine microscopic evaluation and use of p16 immunostaining", J Cutan Pathol, 42, pp.519~526 (2015)
- Gultekin E, "P16(INK 4a) and Ki-67 expression in human papilloma virus-related head and neck mucosal lesions", Invest Clin, 56, pp.47~59 (2015)
- Tabrizi N, "Evaluation of p16INK4a immunostaining for the detection of high-grade changes in cervical cytology", Pathology, 47, pp.314~319 (2015)
- Trimble L, "Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2", 3: a randomised, double-blind, placebocontrolled phase 2b trial, 2015, pp.386, 2078~2088
- Marescalco S, "Genome-wide analysis of recurrent copy-number alterations and copy-neutral loss of heterozygosity in head and neck squamous cell carcinoma", J Oral Pathol Med, 43, pp.20~27 (2014)
- Singh B, "Amplification of the 3q26.3 locus is associated with progression to invasive cancer and is a negative prognostic factor in head and neck squamous cell carcinomas", Am J Pathol, 161, pp.365~371 (2002)
- Cancer Genome Atlas Research, "Integrated genomic and molecular characterization of cervical cancer", Nature, 545, pp.378~384 (2017)
- Holsinger C, "Transoral lateral oropharyngectomy for squamous cell carcinoma of the tonsillar region: I. Technique, complications, and functional results", Arch Otolaryngol Head Neck Surg, 131, pp.583~591 (2005)
- Rhie A, "Genomic copy Number Variations Characterize the Prognosis of Both P16-positive and P16-negative oropharyngeal squamous cell carcinoma after curative resection", Medicine (Baltimore), 94, pp.e2187~ (2015)
- Hirsch R, "Epidermal growth factor receptor in non-small-cell lung carcinomas:correlation between gene copy number and protein expression and impact on prognosis", J Clin Oncol, 21, pp.3798~3807 (2003)
- Park WS, "Human papillomavirus in oropharyngeal squamous cell carcinomas in Korea: use of G1 cycle markers as new prognosticators", Head Neck, 34, pp.1408~1417 (2012)
- Li H, "Fast and accurate short read alignment with Burrows-Wheeler transform", Bioinformatics, 25, pp.1754~1760 (2009)
- McKenna A, "The genome analysis toolkit: a mapReduce framework for analyzing next-generation DNA sequencing data", Genome Res, 20, pp.1297~1303 (2010)
- Cibulski K, "Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples", Nat Biotechnol, 31, pp.213~219 (2013)
- Krumm N, "Copy number variation detection and genotyping from exome sequence data", Genome Res, 22, pp.1525~1532 (2012)
- Rosenthal R, "DeconstructSigs: delineating mutational processes in single tumors distinguishes DNA repair deficiencies and patterns of carcinoma evolution", Genome Biol, 17, pp.31~ (2016)
- Larson B, "PurBayes: estimating tumor cellularity and subclonality in next-generation sequencing data", Bioinformatics, 29, pp.1888~1889 (2013)