Human papillomaviruses (HPV) are responsible for the development of almost all cervical cancers. HPV is also found in 85% of anal cancer and in 50% of penile, vulvar, and vaginal cancers, and they are increasingly found in a subset of head and neck cancers, i.e., oropharyngeal squamous cell carcinomas (OPSCC). The model for how HPV causes cancer is derived from several decades of study on cervical cancer, and it is just presumed that this model is not only completely valid for cervical cancer but for all other HPV-driven cancers as well. Next-generation sequencing (NGS) has now provided the necessary tools to characterize genomic alterations in cancer cells and can precisely determine the physical status of HPV in those cells as well. We discuss recent discoveries from different applications of NGS in both cervical cancer and OPSCCs, including whole-genome sequencing and mate-pair NGS. We also discuss what NGS studies have revealed about the different ways that HPV can be involved in cancer formation, specifically comparing cervical cancer and OPSCC.

1.
Adey A, Burton JN, Kitzman JO, Hiatt JB, Lewis AP, et al: The haplotype-resolved genome and epigenome of the aneuploid HeLa cancer cell line. Nature 500:207-211 (2013).
2.
Akagi K, Li J, Broutian TR, Padilla-Nash H, Xiao W, et al: Genome-wide analysis of HPV integration in human cancers reveals recurrent, focal genomic instability. Genome Res 24:185-199 (2014).
3.
Anorlu RI: What is the significance of the HPV epidemic? Can J Urol 15:3860-3965 (2008).
4.
Badaracco G, Venuti A, Sedati A, Marcante ML: HPV16 and HPV18 in genital tumors: significantly different levels of viral integration and correlation to tumor invasiveness. J Med Virol 67:574-582 (2002).
5.
Becker NA, Thorland EC, Denison SR, Phillips LA, Smith DI: Evidence that instability within the FRA3B region extends four megabases. Oncogene 21:8713-8722 (2002).
6.
Brescia RJ, Jenson AB, Lancaster WD, Kurman RJ: The role of human papillomaviruses in the pathogenesis and histologic classification of precancerous lesions of the cervix. Hum Pathol 17:552-559 (1986).
7.
Chaturvedi AK, Engels EA, Pfeiffer RM, Hernandez BY, Xiao W, et al: Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol 29:4294-4301(2011).
8.
Chen J: Signaling pathways in HPV-associated cancers and therapeutic implications. Rev Med Virol 25 Suppl 1:24-53 (2015).
9.
Cullen AP, Reid R, Campion M, Lörincz AT: Analysis of the physical state of different human papillomavirus DNAs in intraepithelial and invasive cervical neoplasm. J Virol 65:606-612 (1991).
10.
Dall KL, Scarpini CG, Roberts I, Winder DM, Stanley MA, et al: Characterization of naturally occurring HPV16 integration sites isolated from cervical keratinocytes under noncompetitive conditions. Cancer Res 68:8249-8259 (2008).
11.
Deng WG, Nishizaki M, Fang B, Roth JA, Ji L: Induction of apoptosis by tumor suppressor FHIT via death receptor signaling pathway in human lung cancer cells. Biochem Biophys Res Commun 355:993-999 (2007).
12.
Deng Z, Hasegawa M, Kiyuna A, Matayoshi S, Uehara T, et al: Viral load, physical status, and E6/E7 mRNA expression of human papillomavirus in head and neck squamous cell carcinoma. Head Neck 35:800-808 (2013).
13.
Deng Z, Hasegawa M, Aoki K, Matayoshi S, Kiyuna A: A comprehensive evaluation of human papillomavirus positive status and p16INK4a overexpression as a prognostic biomarker in head and neck squamous cell carcinoma. Int J Oncol 45:67-76 (2014).
14.
Denison SR, Callahan G, Becker NA, Phillips LA, Smith DI: Characterization of FRA6E and its potential role in autosomal recessive juvenile parkinsonism and ovarian cancer. Genes Chromosomes Cancer 38:40-52 (2003).
15.
DiMaio D, Mattoon D: Mechanisms of cell transformation by papillomavirus E5 proteins. Oncogene 20:7866-7873 (2001).
16.
Dyson N, Howley PM, Münger K, Harlow E: The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 243:934-947 (1989).
17.
Feldman AL, Dogan A, Smith DI, Law ME, Ansell SM, et al: Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively-parallel genomic sequencing. Blood 117:915-919 (2011).
18.
Ferber MJ, Thorland EC, Brink AA, Rapp AK, Phillips LA, et al: Preferential integration of human papillomavirus type 18 near the c-myc locus in cervical carcinoma. Oncogene 22:7233-7242 (2003).
19.
Flaherty A, Kim T, Giuliano A, Magliocco A, Hakky TS, et al: Implications for human papillomavirus in penile cancer. Urol Oncol 53:e1-e8 (2014).
20.
Gao G, Chernock RD, Gay HA, Thorstad WL, Zhang TR, et al: A novel RT-PCR method for quantification of human papillomavirus transcripts in archived tissues and its application in oropharyngeal cancer prognosis. Int J Cancer 132:882-890 (2013).
21.
Gao G, Johnson SH, Kasperbauer JL, Eckloff BW, Tombers NM, et al: Mate pair sequencing of oropharyngeal squamous cell carcinomas reveals that HPV integration occurs much less frequently than in cervical cancer. J Clin Virol 59:195-200 (2014).
22.
Gao G, Johnson SH, Vasmatzis G, Pauley CE, Tombers NM, et al: Common fragile sites (CFS) and extremely large CFS genes are targets for human papillomavirus integrations and chromosome rearrangements in oropharyngeal squamous cell carcinoma. Genes Chromosomes Cancer 56:59-74 (2017).
23.
Giarrè M, Caldeira S, Malanchi I, Ciccolini F, Leão MJ, Tommasino M: Induction of pRb degradation by the human papillomavirus type 16 E7 protein is essential to efficiently overcome p16INK4a-imposed G1 cell cycle arrest. J Virol 75:4705-4712 (2001).
24.
Glover TW, Berger C, Coyle J, Echo B: DNA polymerase alpha inhibition by aphidicolin induces gaps and breaks at common fragile sites in human chromosomes. Hum Genet 67:136-142 (1984).
25.
Hidalgo A, Monroy A, Arana RM, Taja L, Vázquez G, Salcedo M: Chromosomal imbalances in four new uterine cervix carcinoma derived cell lines. BMC Cancer 3:8 (2003).
26.
Hoffmann M, Klose N, Gottschlich S, Görögh T, Fazel A, et al: Detection of human papillomavirus DNA in benign and malignant sinonasal neoplasms. Cancer Lett 239:64-70 (2006).
27.
Hoots BE, Palefsky JM, Pimenta JM, Smith JS: Human papillomavirus type distribution in anal cancer and anal intraepithelial lesions. Int J Cancer 124:2375-2383 (2009).
28.
Hu Z, Zhu D, Wang W, Li W, Jia W, et al: Genome-wide profiling of HPV integration in cervical cancer identifies clustered genomic hot spots and a potential microhomology-mediated integration mechanism. Nat Genet 47:158-163 (2015).
29.
Imai Y, Soda M, Takahashi R: Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity. J Biol Chem 275:35661-35664 (2000).
30.
Jenson AB, Geyer S, Sundberg JP, Ghim S: Human papillomavirus and skin cancer. J Investig Dermatol Symp Proc 6:203-206 (2001).
31.
Joannes A, Grelet S, Duca L, Gilles C, Kileztky C, et al: Fhit regulates EMT targets through an EGFR/Src/ERK/Slug signaling axis in human bronchial cells. Mol Cancer Res 12:775-783 (2014).
32.
Koskinen WJ, Chen RW, Leivo I, Mäkitie A, Bäck L, et al: Prevalence and physical status of human papillomavirus in squamous cell carcinomas of the head and neck. Int J Cancer 107:401-406 (2003).
33.
Kreimer AR, Clifford GM, Boyle P, Franceschi S: Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev 14:467-475 (2005).
34.
Krummel KA, Denison SR, Calhoun E, Phillips LA, Smith DI: The common fragile site FRA16D and its associated gene WWOX are highly conserved in the mouse at Fra8E1. Genes Chromosomes Cancer 34:154-167 (2002).
35.
Kumar N: Cervical cancer; a nightmare for womanhood: review of recent advances. Womens Health Gynecol 2:17 (2016).
36.
Kuroki T, Yendamuri S, Trapasso F, Matsuyama A, Aqeilan RI, et al: The tumor suppressor gene WWOX at FRA16D is involved in pancreatic carcinogenesis. Clin Cancer Res 10:2459-2465 (2004).
37.
Lechner M, Frampton GM, Fenton T, Feber A, Palmer G, et al: Targeted next-generation sequencing of head and neck squamous cell carcinoma identifies novel genetic alterations in HPV+ and HPV- tumors. Genome Med 5:49 (2013).
38.
Licitra L, Bernier J, Grandi C, Merlano M, Bruzzi P, et al: Cancer of the oropharynx. Crit Rev Oncol Hematol 41:107-22 (2002).
39.
Liu X, Schiffman M, Hulbert A, He Z, Shen Z, et al: Association of human papillomavirus 31 DNA load with risk of cervical intraepithelial neoplasia grades 2 and 3. J Clin Microbiol 53:3451-3457 (2015).
40.
Mao L, Lee JS, Kurie JM, Fan YH, Lippman SM, et al: Clonal genetic alterations in the lungs of current and former smokers. J Natl Cancer Inst 89:857-862 (1997).
41.
Marur S, D'Souza G, Westra WH, Forastiere AA: HPV-associated head and neck cancer: a virus-related cancer epidemic. Lancet Oncol 11:781-789 (2010).
42.
Matovina M, Sabol I, Grubisić G, Gasperov NM, Grce M: Identification of human papillomavirus type 16 integration sites in high-grade precancerous cervical lesions. Gynecol Oncol 113:120-127 (2009).
43.
Mellin H, Friesland S, Auer G, Dalianis T, Munck-Wikland E: Human papillomavirus and DNA ploidy in tonsillar cancer-correlation to prognosis. Anticancer Res 23:2821-2828 (2003).
44.
Mooren JJ, Kremer B, Claessen SM, Voogd AC, Bot FJ, et al: Chromosome stability in tonsillar squamous cell carcinoma is associated with HPV16 integration and indicates a favorable prognosis. Int J Cancer 132:1781-1789 (2013).
45.
Näsman A, Attner P, Hammarstedt L, Du J, Eriksson M: Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma? Int J Cancer 125:362-366 (2009).
46.
Ni S, Hu J, Duan Y, Shi S, Li R, et al: Down expression of LRP1B promotes cell migration via RhoA/Cdc42 pathway and actin cytoskeleton remodeling in renal cell cancer. Cancer Sci 104:817-825 (2013).
47.
Ojesina AI, Lichtenstein L, Freeman SS, Pedamallu CS, Imaz-Rosshandler I, et al: Landscape of genomic alterations in cervical carcinomas. Nature 506:371-375 (2014).
48.
Olthof NC, Speel EJ, Kolligs J, Haesevoets A, Henfling M, et al: Comprehensive analysis of HPV16 integration in OSCC reveals no significant impact of physical status on viral oncogene and virally disrupted human gene expression. PLoS One 9:e88718 (2014).
49.
Olthof NC, Huebbers CU, Kolligs J, Henfling M, Ramaekers FC, et al: Viral load, gene expression and mapping of viral integration sites in HPV16-associated HNSCC cell lines. Int J Cancer 136:E207-E218 (2015).
50.
Panwar A, Batra R, Lydiatt WM, Ganti AK: Human papilloma virus positive oropharyngeal squamous cell carcinoma: a growing epidemic. Cancer Treat Rev 40:215-219 (2014).
51.
Parfenov M, Pedamallu CS, Gehlenborg N, Freeman SS, Danilova L, et al: Characterization of HPV and host genome interactions in primary head and neck cancers. Proc Natl Acad Sci USA 111:15544-15549 (2014).
52.
Pirami L, Giachè V, Becciolini A: Analysis of HPV16, 18, 31, and 35 DNA in pre-invasive and invasive lesions of the uterine cervix. J Clin Pathol 50:600-604 (1997).
53.
Rietbergen MM, Leemans CR, Bloemena E, Heideman DA, Braakhuis BJ, et al: Increasing prevalence rates of HPV attributable oropharyngeal squamous cell carcinomas in the Netherlands as assessed by a validated test algorithm. Int J Cancer 132:1565-1571 (2013).
54.
Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM: The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63:1129-1136 (1990).
55.
Scheffner M, Huibregtse JM, Vierstra RD, Howley PM: The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 75:495-505 (1993).
56.
Sozzi G, Pastorino U, Moiraghi L, Tagliabue E, Pezzella F, et al: Loss of FHIT function in lung cancer and preinvasive bronchial lesions. Cancer Res 58:5032-5037 (1998).
57.
Srodon M, Stoler MH, Baber GB, Kurman RJ: The distribution of low and high-risk HPV types in vulvar and vaginal intraepithelial neoplasia (VIN and VaIN). Am J Surg Pathol 30:1513-1518 (2006).
58.
Thorland EC, Myers SL, Gostout BS, Smith DI: Common fragile sites are preferential targets for HPV16 integrations in cervical tumors. Oncogene 22:1225-1237 (2003).
59.
Tommasino M: The human papillomavirus family and its role in carcinogenesis. Semin Cancer Biol 26:13-21 (2014).
60.
Ukpo OC, Moore EJ, Smith DI: Human papillomavirus and oropharyngeal cancer. N Engl J Med 357:1156-1157 (2007).
61.
Vega-Peña A, Illades-Aguiar B, Flores-Alfaro E, López-Bayghen E, Leyva-Vázquez MA, et al: Risk of progression of early cervical lesions is associated with integration and persistence of HPV-16 and expression of E6, Ki-67, and telomerase. J Cytol 30:226-232 (2013).
62.
Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, et al: Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 189:12-19 (1999).
63.
Watson JE, Doggett NA, Albertson DG, Andaya A, Chinnaiyan A, et al: Integration of high-resolution array comparative genomic hybridization analysis of chromosome 16q with expression array data refines common regions of loss at 16q23-qter and identifies underlying candidate tumor suppressor genes in prostate cancer. Oncogene 23:3487-3494 (2004).
64.
zur Hausen H: Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2:342-350 (2002).
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