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ScienceDirect Genetic polymorphisms and HPV infection in oral squamous cell carcinomas Yan Sun1,6, Yang Zhang2,6, Limei Liu3,6, Xicheng Song1 and Guojun Li4,5 Despite declining smoking rates in the United States, the incidence of oral squamous cell carcinomas (OSCC, including oral cavity and oropharynx) is rising in young adults. The reasons have been attributed to changes in sexual behaviors and the increasingly prevalent infection of oncogenic subtypes of human papillomavirus (HPV), principally type16 and occasionally type18. However, only small proportion of individuals who have contracted HPV infection will develop OSCC, suggesting that there is an interindividual variation in susceptibility to HPV infection and related OSCC. Identification of susceptible biomarkers for HPV status would be useful to identify those individuals who are susceptible to HPV infection, to refine the prognostication of HPV associated OSCC, and ultimately to improve prevention efforts for OSCC and potentially other HPVassociated diseases. Our public health OSCC prevention paradigm will need to expand beyond tobacco and alcohol control. Addresses 1 Department of Otorhinolaryngology and Head and Neck Surgery, Yuhuangding Hospital of Qingdao University, Yantai, China 2 Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Key Laboratory of Otolaryngology Head and Neck Surgery, Ministry of Education, Beijing Institute of Otolaryngology, Beijing 100730, China 3 Department of Ophthalmology, Yuhuangding Hospital of Qingdao University, Yantai 264000, China 4 Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA 5 Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA Corresponding authors: Song, Xicheng ([email protected]) and Li, Guojun ([email protected]) 6
These authors contributed equally to this work.
Current Opinion in Virology 2015, 14:1–6 This review comes from a themed issue on Engineering for viral resistance Edited by Albrecht von Brunn
http://dx.doi.org/10.1016/j.coviro.2015.05.004 1879-6257/# Elsevier B.V. All rights reserved.
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Introduction Only small proportion of individuals who have contracted HPV16/18 infection will develop OSCC, suggesting that there is an inter-individual variation in susceptibility to HPV16/18 infection and related OSCC. Given that HPVpositive and HPV-negative OSCC patients appear to have different etiology and prognosis, it is important to identify susceptible markers for both HPV status and HPV-associated outcome among OSCC patients in order to optimize therapeutic management. Therefore, in this paper, we summarize and present our pilot data on genetic polymorphisms of genes in cell cycle/apoptosis and inflammation/immune response pathways which contribute to HPV16/18-associated OSCC. Furthermore, we selected genes in several molecular pathways to assess the combined effects of a panel of polymorphisms within the same pathway, since such combined analysis may amplify the effects of the individual association of each polymorphism with the risk of HPV infection and related outcome among OSCC patients. By knowing the HPV infection status of OSCC patients or other HPV-associated cancer patients, there may be important prognostic implications and potential influences on current and future treatment and prevention strategies for an improved survival and a better quality of life.
Epidemiology of oral squamous cell carcinoma (OSCC) and trends in OSCC incidence OSCC, which constitutes the majority of head and neck cancers, is common worldwide. In the United States, it is estimated that approximately 35 000 new OSCC cases will be diagnosed and 7600 deaths will occur from these cancers in 2008 [1]. The leading known risk factors for these cancers are tobacco use and alcohol consumption. However, despite declining smoking rates in the United States, the overall incidence of OSCC show little change and even is increasing in young adults in the last several decades, and this increasing trend has been related to changes in sexual practices and the increasing prevalence of human papillomavirus (HPV) infection [2,3]. Studies show that oral cavity, laryngeal and hypopharyngeal cancers are ALL in significant declines in incidence which mirror the declines in smoking prevalence in the U.S. [2,4,5]; however, the incidence of oropharyngeal cancer and young oral tongue cancer has been stagnant or increasing for the last three decades [2,4]. This may be due to an increase of HPV infection, which is supported Current Opinion in Virology 2015, 14:1–6
2 Engineering for viral resistance
by rising HPV seroprevalence in Western populations over the last 30 years [6] and changing sexual practices in these populations [7,8]. It is possible that OSCC is evolving from primarily a cancer of middle-aged to elderly smokers and drinkers to one of younger to middle aged nonsmokers who have been exposed to HPV. Understanding susceptibility for and modifying factors of HPV carcinogenic process will facilitate individualized treatment for OSCC. Of the 120 known types of HPV, the high-risk oncogenic HPV16 is the most frequent type, accounting for approximately 90–95% of HPV-positive OSCC [9,10]. Although HPV infection may be a major risk factor for OSCC [9,11], only a small fraction of individuals with a long period of high-risk HPV exposure develop OSCC, implying that host genetic factors may modify the association between HPV infection and risk of OSCC.
associated with a 14.4-fold increased risk of oropharyngeal cancer [21]. A case–control study in Mexican population identified HPV as risk for OSCC (OR = 3.4) after adjustment for other confounding factors including age, smoking, and drinking [22]. The estimate of association of HPV with OSCC (OR = 3.4) in our study [23] was consistent with these results. In addition, other studies also have demonstrated that HPV infection, particularly HPV16, was associated with an increased risk of OSCC, independent of exposure to alcohol and tobacco [20,24]. In a multi-institutional international study of 1670 cases and 1732 controls, Herrero and colleagues found that HPV16 L1, E6, and E7 seropositivity was a significant risk for OSCC [16]. In our matched pair analysis at our institution, we found 40.8% of 120 patients with squamous carcinoma of the head and neck to be HPV-16 seropositive but only 9.2% of matched cancer-free controls (adjusted OR = 6.7, 95% CI = 3.0–14.9) [17].
Prevalence of HPV in OSCC While only 10–25% of SCCHN are associated with highrisk, oncogenic HPV types, these HPV-associated cases represent a distinct subset of tumors, chiefly young oral cavity and oropharyngeal cancer with distinct epidemiologic, clinical, and molecular characteristics. Oropharyngeal cancers were significantly more likely to be HPV positive (35.6%; 95% confidence interval [CI] = 32.6– 38.7) than 23.5% (95% CI = 21.9–25.1) of oral cavity cancers [12]. Almost half of the oral cavity cancers were from Asian studies with particularly high rates of HPV positive tumors (33%) as compared to Western countries where only 16% of oral cavity cancers were HPV positive [12]. With the progress in molecular techniques, oncogenic HPV DNA has been consistently detected in approximately 50% of oropharyngeal cancer and this may be much higher in certain groups of oropharyngeal cancer, such as those lacking significant tobacco exposures [11,13,14]. While the prevalence of detecting HPV in OSCC was 46.5% in a total of 4680 samples from 94 studies [12], we found that among MD Anderson head and neck cancer cases, HPV16 was detected in approximately 25% of the tumors in the oral cavity, and 80% in oropharynx [15]. For HPV-positive tumors, HPV16 has been identified in 90–95% of the tumors followed by HPV31, 33 and 18 [16]. It has been suggested that certain subgroups of OSCC patients are more likely to be HPV16-positive due to effect of potential genetic variants on HPV infection rates.
Association of HPV with risk of OSCC The strongest evidence of an association of HPV16 with risk of oropharyngeal cancer has been, from molecular epidemiologic (HPV16 serologic or tumor DNA status) studies with a case–control design, showing a range of odds ratios from 3 to 60 [11,16,17–21]. A nested case– control study of 292 cases and 1568 controls within a prospective Scandinavian cohort of almost 900 000 subjects found that HPV16 seropositivity was significantly Current Opinion in Virology 2015, 14:1–6
Cell cycle control polymorphisms and HPV infection Cell cycle related genes play a role in modulating cellular DNA repair, cell-cycle control, cell growth and apoptosis to maintain genome stability. p53 and Rb are chief among many critical cell cycle regulatory tumor suppressor genes. Inactivation of both p53 and Rb by E6 and E7 allows the cell to escape normal cell cycle checkpoints, with resulting cell transformation and immortalization [25]. Simultaneous analysis of genetic polymorphism in both p53 and Rb pathways may aid in understanding the distinct mechanisms involved with HPV-associated OSCC. The alteration of genes in the p53 (e.g., MDM2, p73, p21, p27 or p53) and Rb pathways (e.g., Rb, CCND1, E2F, or p16) can lead to loss of appropriate tumor suppressor functions. A common single nucleotide polymorphism (SNP) of p53 at codon 72 in exon 4 results in a substitution of Pro for Arg in the transactivation domain [26]. The common Arg variant allele may alter the susceptibility of p53 to oncogenic HPV E6-mediated degradation [27], and this allele has been associated with oncogenic HPV infection [28,29,30]. Furthermore, in case–control analyses, the homozygous Arg/Arg genotype has been significantly associated with an increased risk of HPV-associated cancer [27,31]. p73, a member of the p53 family, activates the promoters of several p53-responsive genes participating in cell-cycle control, DNA repair, and apoptosis. The two linked non-coding exon 2 polymorphisms of p73 at positions 4 (G > A) and 14 (C > T) are thought to affect p73 function by altering gene expression, perhaps by altering the efficiency of translational initiation [32]. This polymorphism has been reported to significantly modify the risk of HPV-associated OSCC individually or in combination with p53 codon 72 SNP [23]. MDM2 negatively regulates p53 levels by modulating p53 cellular activity [33]. A SNP G2580Tof MDM2, at www.sciencedirect.com
Genetic variants and oral HPV infection Sun et al.
nucleotide 309 in the promoter region has been shown to alter p53 expression levels with subsequent attenuation of the p53 pathway [34]. There also appears to be a strong association between HPV positivity and reduced CCND1 expression in tonsil carcinomas [35]. CCND1 promotes transition through the restriction point in the G1 phase of the cell cycle [36]. A polymorphism of CCND1 exists at codon 242 within the conserved splice donor site of exon 4 modulating the splicing of CCND1 mRNA and causing two transcripts with different half-lives and functional activity [37]. Reduced levels of CCND1 could facilitate the interaction of the HPV16 E7 with Rb. It appears that HPV16 E7 binds to Rb, which in turn results in p16 overexpression. p16 subsequently blocks cell-cycle progression by binding to cyclin-dependent kinase 4 and 6 as well as inhibiting cyclin D [38]. Two adjacent polymorphisms (C43G and C4780T) of p16 have been identified in the 30 untranslated region of exon 3 [39]. Furthermore, the C4780T polymorphism co-segregates with the C74A polymorphism of intron 1 of p16 [39]. Because the C43G polymorphism is associated with low expression of p53 and both polymorphisms have been associated with tumor aggressiveness [39], these two variants may have some functional relevance of HPV infection. Therefore, genetic variants of the cell cycle related genes could affect the inter-individual variations in efficiency of E6 and E7’s impact on these pathways that lead to differences in cell cycle control, resulting in different rates of HPV clearance or HPV oncogenic conversion.
Apoptotic variants and HPV infection During carcinogenesis, tumors have to develop multiple mechanisms to overcome host immune surveillance and intrinsic apoptosis or cell cycle arrest. Individual difference in resistance to apoptosis through the FAS pathway might enable many cancers to escape or counterattack against the immune system [40]. Germline variants in both the extrinsic and intrinsic pathways could affect apoptotic efficiency and resistance to apoptosis, and consequently influence HPV infection. This may be particularly relevant to a viral mechanism which works through both cell cycle and apoptotic mechanisms. Genetic polymorphisms of the FAS and FASL promoters have been suggested to contribute to HPV-associated cancer risk by inducing differential apoptosis of immune cells in responsive to the microenvironmental signals after HPV infection [41,42]. The polymorphism at position 670 of FAS promoter has been found to abolish the binding site for the nuclear transcription element and alter the expression of the FAS gene [43], and the homozygous Pro 72 of p53 polymorphism at codon 72 appears to be an important regulator of apoptosis via the FAS/FASL pathway in OSCC [44].
Polymorphisms of inflammatory and immune response genes and HPV infection While high-risk oncogenic HPVs are well understood as risk factors for OSCC [45,46], investigating genetic host www.sciencedirect.com
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factors in inflammatory and immune responses to HPV infection could help to understand the association between HPV infection and HPV-associated OSCC. It is precisely these responses or the efficiency of immune surveillance which modifies HPV clearance, and persistent infection, leading to HPV infection. Inflammation is a part of host response to either internal or external environmental stimuli, which is promoted by the action of pro-inflammatory cytokines, including IL-1, TNF, INF-g, and IL-6, and is resolved by anti-inflammatory cytokines, such as IL-4, IL-10, IL-13, INF-a, and TGFb. These cytokines may play roles in checking growth of HPV-infected cells and that viral persistence, disease progression, and/or malignant transformation could involve escape from these mechanisms. Therefore, germline variants of these cytokines could modify the efficiency of HPV clearance and HPV infection rates. The failure of HPV to raise effective immune responses may be important in the pathogenesis of HPV-associated cancer, since the etiology of HPV-induced cancer is triggered by a persistent viral infection, which can be minimized by an effective immune response. Polymorphisms of a number of cytokine genes have been implicated in inducing susceptibility or resistance to cancers caused by HPV infection owing to their role in determining host immune response. Therefore, genetic variants of cytokine genes in promoter or coding regions, which are believed to influence the expression levels or functional efficiency of their respective cytokines, may thus be involved in the susceptibility to HPV status of OSCC patients. Considerable evidence has linked polymorphisms in proinflammatory and anti-inflammatory cytokine genes, particularly in regulatory regions, to intra-individual variations in cytokine production and to risk of cancers. The association of cytokine polymorphisms of IFN-g and IL-10 with the risk of cancer has been well documented [47,48] and patients with HPV-positive cervical cancer had a decreased IFN-g transcription and increased IL-10 transcription [49]. IFN-g plays a pivotal role in defense against viruses and intracellular pathogens through the induction of immune-mediated inflammatory responses [50]. The T+874A SNP located at translation start site of IFN-g gene, which coincides with a putative NF-kB binding site, could play a fundamental role in the induction of constitutively high IFN-g production. The +874 alleles T to A with a low (AA), medium (AT) and high (TT) have also been significantly associated with cytokine production [51]. IL10 has a suppressive effect on cell mediated immunity, which may be critical in the elimination of HPV-harboring cells [52]. A number of polymorphisms exist in the IL-10 gene of which the SNP at the 1082 position of the promoter region plays an important role in determining high, medium and low production of IL-10 [53]. The association of G/A SNP at position 1082 has been associated with low (AA), Current Opinion in Virology 2015, 14:1–6
4 Engineering for viral resistance
Table 1 Association of genotypes of selected genes in the cell cycle control pathway with tumor HPV16 infection Genotype
HPV16(+) tumor (n = 121)
p53 (119G > C) GG 53 CG or CC 68 p73 (G4C4 > A4T14) GG 59 GA or AA 62 MDM2 (309T > G) TT 36 GT or GG 85 CCND1 (1G > A) GG 27 GA or AA 94 p16 (43C > G) CC 94 GC or GG 27 p16 (4780C > T) CC 91 CT or TT 30
HPV16() tumor (n = 144)
Adj. ORa, 95% CI
inherited gene mutations, from which common genetic variants can also alter the expression or function of key genes, disrupting the balance of cytokines, and thus affecting cancer risk and outcome.
Conclusion
(43.8) (56.2)
85 (59.0) 59 (41.0)
1.0 1.8 (1.1–3.1)
(48.8) (51.2)
88 (61.1) 56 (38.9)
1.0 1.7 (1.0–2.8)
(29.8) (70.2)
65 (45.1) 79 (54.9)
1.0 2.0 (1.2–3.4)
(22.3) (77.7)
51 (35.4) 93 (64.6)
1.0 2.0 (1.1–3.7)
(77.7) (22.3)
85 (59.0) 59 (41.0)
1.0 0.4 (0.2–0.6)
(75.2) (24.8)
123 (85.4) 21 (14.6)
1.0 2.1 (1.1–4.3)
Genetic polymorphisms may play a significant role in person-to-person variability in HPV infection. The genetic polymorphisms in cell cycle control, apoptosis, and inflammation/immune response pathways may affect their biological function and potential interactions with the HPV E7 and E6 proteins, leading to HPV infection. Thus, these genetic polymorphisms could serve as predictors of risk of HPV infection in OSCC patients as shown in Tables 1–3. Understanding genetic profiling for OSCC is imperative for future cancer prevention efforts and the potential role of the HPV vaccines. Genetic polymorphisms could define individualized molecular profile of HPV OSCC leading to individualized prevention. Such profiles could also potentially optimize patient stratification for clinical trials testing of HPV-targeted
a
Adjusted for sex, age, ethnicity, smoking and alcohol drinking status. Table 3
medium (AG) and high (GG) cytokine production [53]. Polymorphisms in human IL-1b and TNF-a genes have also been reported to influence cytokine expression [54]. TNF-a can directly control HPV infection by induction of apoptosis in HPV-infected cells, such as cervical cancer cells [55]. The perturbation of the balance between proand anti-inflammatory cytokine levels can be caused by Table 2 Association of genotypes of selected genes in the apoptosis pathway with tumor HPV16 infection Genotype
CASP8 (302 G > C) GG GC or CC CASP8 (652 6N del) Ins/Ins Ins/Del or Del/Del FAS (670 A > G) AA AG or GG FASL (124 A > G) AA AG or GG FASL (844 C > T) CC CT or TT FAS (1377 G > A) GG AG or AA
(+)
HPV16 tumor (n = 121)
()
HPV16 tumor (n = 144)
a
Adj. OR , 95% CI
85 (70.3) 36 (29.7)
83 (57.6) 61 (42.4)
1.0 0.6 (0.4–1.0)
25 (20.7) 96 (79.3)
41 (28.5) 103 (71.6)
1.0 1.6 (1.0–2.9)
35 (28.9) 86 (71.1)
55 (38.2) 89 (61.8)
1.0 1.3 (0.7–2.4)
95 (78.5) 26 (21.5)
103 (71.5) 41 (28.5)
1.0 0.8 (0.5–1.6)
55 (45.5) 66 (54.5)
73 (50.7) 71 (49.3)
1.0 1.3 (0.8–2.2)
82 (67.8) 39 (32.2)
117 (81.2) 27 (18.8)
1.0 2.2 (1.2–4.1)
a
Adjusted for sex, age, ethnicity, smoking and alcohol drinking status.
Current Opinion in Virology 2015, 14:1–6
Association of genotypes of selected genes in inflammation/ immune response pathways with tumor HPV16 infection Genotype
HPV16(+) tumor (n = 121)
IL1b (1060T > C) CC 65 CT or TT 56 IL1b (14T > C) CC 78 CT or TT 43 IL1b (580C > T) TT 62 CT or CC 59 IL8 (3470A > T) TT 35 AT or AA 86 TNFa (1431A > G) GG 65 GA or AA 56 PPARg (P12A) CC 106 CG or GG 15 COX2 (1218C > G) GG 90 CG or CC 31 IL4 (588T > C) CC 73 CT or TT 48 IL4 (168T > C) CC 76 CT or TT 45 IL10 (626A > C) CC 74 CA or AA 47
HPV16() tumor (n = 144)
Adj. ORa, 95% CI
(53.7) (46.3)
53 (36.8) 91 (63.2)
1.0 0.5 (0.3–0.8)
(64.5) (35.5)
71 (49.3) 73 (51.7)
1.0 0.6 (0.4–1.0)
(51.2) (48.8)
51 (35.4) 93 (64.6)
1.0 0.6 (0.3-0.9)
(28.9) (71.1)
53 (36.8) 91 (63.2)
1.0 1.5 (1.0–2.6)
(53.7) (46.3)
86 (59.7) 58 (40.3)
1.0 1.2 (0.7–2.1)
(87.6) (22.4)
108 (75.0) 36 (25.0)
1.0 0.4 (0.2-0.8)
(74.4) (25.6)
84 (58.3) 60 (41.7)
1.0 0.5 (0.3–0.9)
(60.3) (39.7)
95 (66.0) 49 (34.0)
1.0 1.4 (0.8–2.4)
(62.8) (37.2)
102 (70.8) 42 (29.2)
1.0 1.6 (1.0–2.8)
(61.2) (38.8)
64 (44.4) 80 (55.6)
1.00 0.60 (0.4–1.0)
a
Adjusted for sex, age, ethnicity, smoking and alcohol drinking status.
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Genetic variants and oral HPV infection Sun et al.
therapies. Exploitation of the association between inherited genetic polymorphisms and HPV status and related outcome using a pathway-based genotyping approach may provide a comprehensive clinical tool for prognosis and prevention of OSCC. Knowing the HPV status of OSCC patients likely has important prognostic implications and may influence future treatment and prevention strategies.
Conflict of interest Nothing declared.
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African American systemic lupus erythematosus patients. J Immunology 2003, 170:132-138. 43. Huang QR, Morris D, Manolios N: Identification and characterization of polymorphisms in the promoter region of the human Apo-1/Fas (CD95) gene. Mol Immunol 1997, 34:577-582. 44. Schneider-Stock R, Mawrin C, Motsch C et al.: Retention of the arginine allele in codon 72 of the p53 gene correlates with poor apoptosis in head and neck cancer. Am J Pathol 2004, 164:233-1241. 45. Bosch FX, Lorincz A, Munoz N et al.: The causal relation between human papillomavirus and cervical cancer. J Clin Pathol 2002, 55:244-265. 46. Santos AM, Sousa H, Catarino R et al.: TP53 codon 72 polymorphism and risk for cervical cancer in Portugal. Cancer Genet Cytogenet 2005, 159:143-147. 47. Kim JW, Roh JW, Park NH et al.: Interferon, alpha (IFN17) Ile184Arg polymorphism and cervical cancer risk. Cancer Lett 2003, 189:183-188. 48. Calhoun ES, McGovern RM, Janney CA et al.: Host genetic polymorphism analysis in cervical cancer. Clin Chem 2002, 48:1218-1224. 49. El-Sherif AM, Seth R, Tighe PJ et al.: Quantitative analysis of IL-10 and IFN-g mRNA levels in normal cervix and human papillomavirus type 16 associated precancer. J Pathol 2001, 195:179-185. 50. Billiau A, Heremans H, Vermeire K et al.: Immunomodulatory properties of interferon-gamma. Ann N Y Acad Sci 1998, 856:22-32. 51. Pravica V, Perrey C, Stevens A et al.: A single nucleotide polymorphism in the first intron of the human IFN-g gene: absolute correlation with a polymorphic CA microsatellite marker of high IFN-g production. Human Immunol 2000, 61:863-866. 52. Zoodsma M, Nolte IM, Schipper M et al.: Interleukin-10 and Fas polymorphisms and susceptibility for (pre)neoplastic cervical disease. Int J Gynecol Cancer 2005, 3:282-290.
39. Sauroja I, Smeds J, Vlaykova T, Kumar R, Talve L, HahkaKemppinen M, Punnonen K, Jansen CT, Hemminki K, Pyrhonen S: Analysis of G(1)/S checkpoint regulators in metastatic melanoma. Genes Chromosomes Cancer 2000, 28:404-414.
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55. Jin L, Sturgis EM, Zhang Y et al.: Association of tumor necrosis factor-alpha promoter variants with risk of HPV-associated oral squamous cell carcinoma. Mol Cancer 2013, 12:80 http:// dx.doi.org/10.1186/1476-4598-12-80. A case–control study showed a strong association of tumor necrosis factor-alpha promoter variants with risk of HPV-associated oral squamous cell carcinoma.
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Current Opinion in Virology 2015, 14:1–6
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ScienceDirect Genetic polymorphisms and HPV infection in oral squamous cell carcinomas Yan Sun1,6, Yang Zhang2,6, Limei Liu3,6, Xicheng Song1 and Guojun Li4,5 Despite declining smoking rates in the United States, the incidence of oral squamous cell carcinomas (OSCC, including oral cavity and oropharynx) is rising in young adults. The reasons have been attributed to changes in sexual behaviors and the increasingly prevalent infection of oncogenic subtypes of human papillomavirus (HPV), principally type16 and occasionally type18. However, only small proportion of individuals who have contracted HPV infection will develop OSCC, suggesting that there is an interindividual variation in susceptibility to HPV infection and related OSCC. Identification of susceptible biomarkers for HPV status would be useful to identify those individuals who are susceptible to HPV infection, to refine the prognostication of HPV associated OSCC, and ultimately to improve prevention efforts for OSCC and potentially other HPVassociated diseases. Our public health OSCC prevention paradigm will need to expand beyond tobacco and alcohol control. Addresses 1 Department of Otorhinolaryngology and Head and Neck Surgery, Yuhuangding Hospital of Qingdao University, Yantai, China 2 Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Key Laboratory of Otolaryngology Head and Neck Surgery, Ministry of Education, Beijing Institute of Otolaryngology, Beijing 100730, China 3 Department of Ophthalmology, Yuhuangding Hospital of Qingdao University, Yantai 264000, China 4 Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA 5 Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA Corresponding authors: Song, Xicheng ([email protected]) and Li, Guojun ([email protected]) 6
These authors contributed equally to this work.
Current Opinion in Virology 2015, 14:1–6 This review comes from a themed issue on Engineering for viral resistance Edited by Albrecht von Brunn
http://dx.doi.org/10.1016/j.coviro.2015.05.004 1879-6257/# Elsevier B.V. All rights reserved.
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Introduction Only small proportion of individuals who have contracted HPV16/18 infection will develop OSCC, suggesting that there is an inter-individual variation in susceptibility to HPV16/18 infection and related OSCC. Given that HPVpositive and HPV-negative OSCC patients appear to have different etiology and prognosis, it is important to identify susceptible markers for both HPV status and HPV-associated outcome among OSCC patients in order to optimize therapeutic management. Therefore, in this paper, we summarize and present our pilot data on genetic polymorphisms of genes in cell cycle/apoptosis and inflammation/immune response pathways which contribute to HPV16/18-associated OSCC. Furthermore, we selected genes in several molecular pathways to assess the combined effects of a panel of polymorphisms within the same pathway, since such combined analysis may amplify the effects of the individual association of each polymorphism with the risk of HPV infection and related outcome among OSCC patients. By knowing the HPV infection status of OSCC patients or other HPV-associated cancer patients, there may be important prognostic implications and potential influences on current and future treatment and prevention strategies for an improved survival and a better quality of life.
Epidemiology of oral squamous cell carcinoma (OSCC) and trends in OSCC incidence OSCC, which constitutes the majority of head and neck cancers, is common worldwide. In the United States, it is estimated that approximately 35 000 new OSCC cases will be diagnosed and 7600 deaths will occur from these cancers in 2008 [1]. The leading known risk factors for these cancers are tobacco use and alcohol consumption. However, despite declining smoking rates in the United States, the overall incidence of OSCC show little change and even is increasing in young adults in the last several decades, and this increasing trend has been related to changes in sexual practices and the increasing prevalence of human papillomavirus (HPV) infection [2,3]. Studies show that oral cavity, laryngeal and hypopharyngeal cancers are ALL in significant declines in incidence which mirror the declines in smoking prevalence in the U.S. [2,4,5]; however, the incidence of oropharyngeal cancer and young oral tongue cancer has been stagnant or increasing for the last three decades [2,4]. This may be due to an increase of HPV infection, which is supported Current Opinion in Virology 2015, 14:1–6
2 Engineering for viral resistance
by rising HPV seroprevalence in Western populations over the last 30 years [6] and changing sexual practices in these populations [7,8]. It is possible that OSCC is evolving from primarily a cancer of middle-aged to elderly smokers and drinkers to one of younger to middle aged nonsmokers who have been exposed to HPV. Understanding susceptibility for and modifying factors of HPV carcinogenic process will facilitate individualized treatment for OSCC. Of the 120 known types of HPV, the high-risk oncogenic HPV16 is the most frequent type, accounting for approximately 90–95% of HPV-positive OSCC [9,10]. Although HPV infection may be a major risk factor for OSCC [9,11], only a small fraction of individuals with a long period of high-risk HPV exposure develop OSCC, implying that host genetic factors may modify the association between HPV infection and risk of OSCC.
associated with a 14.4-fold increased risk of oropharyngeal cancer [21]. A case–control study in Mexican population identified HPV as risk for OSCC (OR = 3.4) after adjustment for other confounding factors including age, smoking, and drinking [22]. The estimate of association of HPV with OSCC (OR = 3.4) in our study [23] was consistent with these results. In addition, other studies also have demonstrated that HPV infection, particularly HPV16, was associated with an increased risk of OSCC, independent of exposure to alcohol and tobacco [20,24]. In a multi-institutional international study of 1670 cases and 1732 controls, Herrero and colleagues found that HPV16 L1, E6, and E7 seropositivity was a significant risk for OSCC [16]. In our matched pair analysis at our institution, we found 40.8% of 120 patients with squamous carcinoma of the head and neck to be HPV-16 seropositive but only 9.2% of matched cancer-free controls (adjusted OR = 6.7, 95% CI = 3.0–14.9) [17].
Prevalence of HPV in OSCC While only 10–25% of SCCHN are associated with highrisk, oncogenic HPV types, these HPV-associated cases represent a distinct subset of tumors, chiefly young oral cavity and oropharyngeal cancer with distinct epidemiologic, clinical, and molecular characteristics. Oropharyngeal cancers were significantly more likely to be HPV positive (35.6%; 95% confidence interval [CI] = 32.6– 38.7) than 23.5% (95% CI = 21.9–25.1) of oral cavity cancers [12]. Almost half of the oral cavity cancers were from Asian studies with particularly high rates of HPV positive tumors (33%) as compared to Western countries where only 16% of oral cavity cancers were HPV positive [12]. With the progress in molecular techniques, oncogenic HPV DNA has been consistently detected in approximately 50% of oropharyngeal cancer and this may be much higher in certain groups of oropharyngeal cancer, such as those lacking significant tobacco exposures [11,13,14]. While the prevalence of detecting HPV in OSCC was 46.5% in a total of 4680 samples from 94 studies [12], we found that among MD Anderson head and neck cancer cases, HPV16 was detected in approximately 25% of the tumors in the oral cavity, and 80% in oropharynx [15]. For HPV-positive tumors, HPV16 has been identified in 90–95% of the tumors followed by HPV31, 33 and 18 [16]. It has been suggested that certain subgroups of OSCC patients are more likely to be HPV16-positive due to effect of potential genetic variants on HPV infection rates.
Association of HPV with risk of OSCC The strongest evidence of an association of HPV16 with risk of oropharyngeal cancer has been, from molecular epidemiologic (HPV16 serologic or tumor DNA status) studies with a case–control design, showing a range of odds ratios from 3 to 60 [11,16,17–21]. A nested case– control study of 292 cases and 1568 controls within a prospective Scandinavian cohort of almost 900 000 subjects found that HPV16 seropositivity was significantly Current Opinion in Virology 2015, 14:1–6
Cell cycle control polymorphisms and HPV infection Cell cycle related genes play a role in modulating cellular DNA repair, cell-cycle control, cell growth and apoptosis to maintain genome stability. p53 and Rb are chief among many critical cell cycle regulatory tumor suppressor genes. Inactivation of both p53 and Rb by E6 and E7 allows the cell to escape normal cell cycle checkpoints, with resulting cell transformation and immortalization [25]. Simultaneous analysis of genetic polymorphism in both p53 and Rb pathways may aid in understanding the distinct mechanisms involved with HPV-associated OSCC. The alteration of genes in the p53 (e.g., MDM2, p73, p21, p27 or p53) and Rb pathways (e.g., Rb, CCND1, E2F, or p16) can lead to loss of appropriate tumor suppressor functions. A common single nucleotide polymorphism (SNP) of p53 at codon 72 in exon 4 results in a substitution of Pro for Arg in the transactivation domain [26]. The common Arg variant allele may alter the susceptibility of p53 to oncogenic HPV E6-mediated degradation [27], and this allele has been associated with oncogenic HPV infection [28,29,30]. Furthermore, in case–control analyses, the homozygous Arg/Arg genotype has been significantly associated with an increased risk of HPV-associated cancer [27,31]. p73, a member of the p53 family, activates the promoters of several p53-responsive genes participating in cell-cycle control, DNA repair, and apoptosis. The two linked non-coding exon 2 polymorphisms of p73 at positions 4 (G > A) and 14 (C > T) are thought to affect p73 function by altering gene expression, perhaps by altering the efficiency of translational initiation [32]. This polymorphism has been reported to significantly modify the risk of HPV-associated OSCC individually or in combination with p53 codon 72 SNP [23]. MDM2 negatively regulates p53 levels by modulating p53 cellular activity [33]. A SNP G2580Tof MDM2, at www.sciencedirect.com
Genetic variants and oral HPV infection Sun et al.
nucleotide 309 in the promoter region has been shown to alter p53 expression levels with subsequent attenuation of the p53 pathway [34]. There also appears to be a strong association between HPV positivity and reduced CCND1 expression in tonsil carcinomas [35]. CCND1 promotes transition through the restriction point in the G1 phase of the cell cycle [36]. A polymorphism of CCND1 exists at codon 242 within the conserved splice donor site of exon 4 modulating the splicing of CCND1 mRNA and causing two transcripts with different half-lives and functional activity [37]. Reduced levels of CCND1 could facilitate the interaction of the HPV16 E7 with Rb. It appears that HPV16 E7 binds to Rb, which in turn results in p16 overexpression. p16 subsequently blocks cell-cycle progression by binding to cyclin-dependent kinase 4 and 6 as well as inhibiting cyclin D [38]. Two adjacent polymorphisms (C43G and C4780T) of p16 have been identified in the 30 untranslated region of exon 3 [39]. Furthermore, the C4780T polymorphism co-segregates with the C74A polymorphism of intron 1 of p16 [39]. Because the C43G polymorphism is associated with low expression of p53 and both polymorphisms have been associated with tumor aggressiveness [39], these two variants may have some functional relevance of HPV infection. Therefore, genetic variants of the cell cycle related genes could affect the inter-individual variations in efficiency of E6 and E7’s impact on these pathways that lead to differences in cell cycle control, resulting in different rates of HPV clearance or HPV oncogenic conversion.
Apoptotic variants and HPV infection During carcinogenesis, tumors have to develop multiple mechanisms to overcome host immune surveillance and intrinsic apoptosis or cell cycle arrest. Individual difference in resistance to apoptosis through the FAS pathway might enable many cancers to escape or counterattack against the immune system [40]. Germline variants in both the extrinsic and intrinsic pathways could affect apoptotic efficiency and resistance to apoptosis, and consequently influence HPV infection. This may be particularly relevant to a viral mechanism which works through both cell cycle and apoptotic mechanisms. Genetic polymorphisms of the FAS and FASL promoters have been suggested to contribute to HPV-associated cancer risk by inducing differential apoptosis of immune cells in responsive to the microenvironmental signals after HPV infection [41,42]. The polymorphism at position 670 of FAS promoter has been found to abolish the binding site for the nuclear transcription element and alter the expression of the FAS gene [43], and the homozygous Pro 72 of p53 polymorphism at codon 72 appears to be an important regulator of apoptosis via the FAS/FASL pathway in OSCC [44].
Polymorphisms of inflammatory and immune response genes and HPV infection While high-risk oncogenic HPVs are well understood as risk factors for OSCC [45,46], investigating genetic host www.sciencedirect.com
3
factors in inflammatory and immune responses to HPV infection could help to understand the association between HPV infection and HPV-associated OSCC. It is precisely these responses or the efficiency of immune surveillance which modifies HPV clearance, and persistent infection, leading to HPV infection. Inflammation is a part of host response to either internal or external environmental stimuli, which is promoted by the action of pro-inflammatory cytokines, including IL-1, TNF, INF-g, and IL-6, and is resolved by anti-inflammatory cytokines, such as IL-4, IL-10, IL-13, INF-a, and TGFb. These cytokines may play roles in checking growth of HPV-infected cells and that viral persistence, disease progression, and/or malignant transformation could involve escape from these mechanisms. Therefore, germline variants of these cytokines could modify the efficiency of HPV clearance and HPV infection rates. The failure of HPV to raise effective immune responses may be important in the pathogenesis of HPV-associated cancer, since the etiology of HPV-induced cancer is triggered by a persistent viral infection, which can be minimized by an effective immune response. Polymorphisms of a number of cytokine genes have been implicated in inducing susceptibility or resistance to cancers caused by HPV infection owing to their role in determining host immune response. Therefore, genetic variants of cytokine genes in promoter or coding regions, which are believed to influence the expression levels or functional efficiency of their respective cytokines, may thus be involved in the susceptibility to HPV status of OSCC patients. Considerable evidence has linked polymorphisms in proinflammatory and anti-inflammatory cytokine genes, particularly in regulatory regions, to intra-individual variations in cytokine production and to risk of cancers. The association of cytokine polymorphisms of IFN-g and IL-10 with the risk of cancer has been well documented [47,48] and patients with HPV-positive cervical cancer had a decreased IFN-g transcription and increased IL-10 transcription [49]. IFN-g plays a pivotal role in defense against viruses and intracellular pathogens through the induction of immune-mediated inflammatory responses [50]. The T+874A SNP located at translation start site of IFN-g gene, which coincides with a putative NF-kB binding site, could play a fundamental role in the induction of constitutively high IFN-g production. The +874 alleles T to A with a low (AA), medium (AT) and high (TT) have also been significantly associated with cytokine production [51]. IL10 has a suppressive effect on cell mediated immunity, which may be critical in the elimination of HPV-harboring cells [52]. A number of polymorphisms exist in the IL-10 gene of which the SNP at the 1082 position of the promoter region plays an important role in determining high, medium and low production of IL-10 [53]. The association of G/A SNP at position 1082 has been associated with low (AA), Current Opinion in Virology 2015, 14:1–6
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Table 1 Association of genotypes of selected genes in the cell cycle control pathway with tumor HPV16 infection Genotype
HPV16(+) tumor (n = 121)
p53 (119G > C) GG 53 CG or CC 68 p73 (G4C4 > A4T14) GG 59 GA or AA 62 MDM2 (309T > G) TT 36 GT or GG 85 CCND1 (1G > A) GG 27 GA or AA 94 p16 (43C > G) CC 94 GC or GG 27 p16 (4780C > T) CC 91 CT or TT 30
HPV16() tumor (n = 144)
Adj. ORa, 95% CI
inherited gene mutations, from which common genetic variants can also alter the expression or function of key genes, disrupting the balance of cytokines, and thus affecting cancer risk and outcome.
Conclusion
(43.8) (56.2)
85 (59.0) 59 (41.0)
1.0 1.8 (1.1–3.1)
(48.8) (51.2)
88 (61.1) 56 (38.9)
1.0 1.7 (1.0–2.8)
(29.8) (70.2)
65 (45.1) 79 (54.9)
1.0 2.0 (1.2–3.4)
(22.3) (77.7)
51 (35.4) 93 (64.6)
1.0 2.0 (1.1–3.7)
(77.7) (22.3)
85 (59.0) 59 (41.0)
1.0 0.4 (0.2–0.6)
(75.2) (24.8)
123 (85.4) 21 (14.6)
1.0 2.1 (1.1–4.3)
Genetic polymorphisms may play a significant role in person-to-person variability in HPV infection. The genetic polymorphisms in cell cycle control, apoptosis, and inflammation/immune response pathways may affect their biological function and potential interactions with the HPV E7 and E6 proteins, leading to HPV infection. Thus, these genetic polymorphisms could serve as predictors of risk of HPV infection in OSCC patients as shown in Tables 1–3. Understanding genetic profiling for OSCC is imperative for future cancer prevention efforts and the potential role of the HPV vaccines. Genetic polymorphisms could define individualized molecular profile of HPV OSCC leading to individualized prevention. Such profiles could also potentially optimize patient stratification for clinical trials testing of HPV-targeted
a
Adjusted for sex, age, ethnicity, smoking and alcohol drinking status. Table 3
medium (AG) and high (GG) cytokine production [53]. Polymorphisms in human IL-1b and TNF-a genes have also been reported to influence cytokine expression [54]. TNF-a can directly control HPV infection by induction of apoptosis in HPV-infected cells, such as cervical cancer cells [55]. The perturbation of the balance between proand anti-inflammatory cytokine levels can be caused by Table 2 Association of genotypes of selected genes in the apoptosis pathway with tumor HPV16 infection Genotype
CASP8 (302 G > C) GG GC or CC CASP8 (652 6N del) Ins/Ins Ins/Del or Del/Del FAS (670 A > G) AA AG or GG FASL (124 A > G) AA AG or GG FASL (844 C > T) CC CT or TT FAS (1377 G > A) GG AG or AA
(+)
HPV16 tumor (n = 121)
()
HPV16 tumor (n = 144)
a
Adj. OR , 95% CI
85 (70.3) 36 (29.7)
83 (57.6) 61 (42.4)
1.0 0.6 (0.4–1.0)
25 (20.7) 96 (79.3)
41 (28.5) 103 (71.6)
1.0 1.6 (1.0–2.9)
35 (28.9) 86 (71.1)
55 (38.2) 89 (61.8)
1.0 1.3 (0.7–2.4)
95 (78.5) 26 (21.5)
103 (71.5) 41 (28.5)
1.0 0.8 (0.5–1.6)
55 (45.5) 66 (54.5)
73 (50.7) 71 (49.3)
1.0 1.3 (0.8–2.2)
82 (67.8) 39 (32.2)
117 (81.2) 27 (18.8)
1.0 2.2 (1.2–4.1)
a
Adjusted for sex, age, ethnicity, smoking and alcohol drinking status.
Current Opinion in Virology 2015, 14:1–6
Association of genotypes of selected genes in inflammation/ immune response pathways with tumor HPV16 infection Genotype
HPV16(+) tumor (n = 121)
IL1b (1060T > C) CC 65 CT or TT 56 IL1b (14T > C) CC 78 CT or TT 43 IL1b (580C > T) TT 62 CT or CC 59 IL8 (3470A > T) TT 35 AT or AA 86 TNFa (1431A > G) GG 65 GA or AA 56 PPARg (P12A) CC 106 CG or GG 15 COX2 (1218C > G) GG 90 CG or CC 31 IL4 (588T > C) CC 73 CT or TT 48 IL4 (168T > C) CC 76 CT or TT 45 IL10 (626A > C) CC 74 CA or AA 47
HPV16() tumor (n = 144)
Adj. ORa, 95% CI
(53.7) (46.3)
53 (36.8) 91 (63.2)
1.0 0.5 (0.3–0.8)
(64.5) (35.5)
71 (49.3) 73 (51.7)
1.0 0.6 (0.4–1.0)
(51.2) (48.8)
51 (35.4) 93 (64.6)
1.0 0.6 (0.3-0.9)
(28.9) (71.1)
53 (36.8) 91 (63.2)
1.0 1.5 (1.0–2.6)
(53.7) (46.3)
86 (59.7) 58 (40.3)
1.0 1.2 (0.7–2.1)
(87.6) (22.4)
108 (75.0) 36 (25.0)
1.0 0.4 (0.2-0.8)
(74.4) (25.6)
84 (58.3) 60 (41.7)
1.0 0.5 (0.3–0.9)
(60.3) (39.7)
95 (66.0) 49 (34.0)
1.0 1.4 (0.8–2.4)
(62.8) (37.2)
102 (70.8) 42 (29.2)
1.0 1.6 (1.0–2.8)
(61.2) (38.8)
64 (44.4) 80 (55.6)
1.00 0.60 (0.4–1.0)
a
Adjusted for sex, age, ethnicity, smoking and alcohol drinking status.
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Genetic variants and oral HPV infection Sun et al.
therapies. Exploitation of the association between inherited genetic polymorphisms and HPV status and related outcome using a pathway-based genotyping approach may provide a comprehensive clinical tool for prognosis and prevention of OSCC. Knowing the HPV status of OSCC patients likely has important prognostic implications and may influence future treatment and prevention strategies.
Conflict of interest Nothing declared.
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