Role of Human Papilloma Virus in Retinoblastoma- A Review
1Assistant Professor, 2Professor and Head, 3Assistant Professor, Department of Microbiology, Kamineni Academy of Medical Sciences and Research Centre, L.B. Nagar, Hyderabad, Telangana, India.
Retinoblastoma (RB) is an intraocular tumor and the primary malignancy occurring in children. The incidence of the RB worldwide is 1 in 16,000 to 18,000 births.1 Review of literature of RB cases in India shows that, 69% cases were unilateral and remaining were bilateral. The median age of the children suffering with RB was around 2.5 years with the male to female ratio of 1.6:1, showing male preponderance. A subset of 10 % of this intraocular tumor leads to the metastasis.2The clinical symptoms include leukocoria, strabismus, hypopyon, orbital cellulitis, hyphema, and exophthalmia.2
Untreated RB can lead to metastasis of the central nervous system, optic nerve, bone marrow and lymphoid systems. A study related to the cause of the specific mortality in long time survivors of RB tumor was done which shows that in hereditary and nonhereditary retinoblastoma survivors, the relative rates of mortality following subsequent malignant neoplasm were higher in those who had undergone radiotherapy treatment.3
Role of Genetic factors in Retinoblastoma
The genetic etiology for retinoblastoma formation is well established, involving the occurrence of the mutations in the RB1 gene.4 Several studies related to the occurrence of the mutations in RB1 gene, leading to loss of its function and the development of the retinoblastoma tumor.5-9 A recent study revealed the correlation between parental intake of diet and development of retinoblastoma. This study has shown that father’s intake of diary associated nutrients and use of calcium supplements associated with the decreased risk and intake of the copper, manganese, and vitamin E were associated with increased risk, while mother’s use of multivitamins close to conception was associated with the decreased risk.10
Role of HPV virus in cancer genesis
There is a strong association of infection or infectious agents and cancer formation. Evan and Muller provided epidemiological guidelines to support the etiologic role of virus as a causative agent of cancer. They hypothesized that geographic distribution of viral infection should coincide with particular cancer; detection of virus or viral markers should be high in tumor cases compared to normal subjects and antiviral treatment should reduce or decrease the tumor incidence. In addition to these other factors included were, virus should have an ability to transform cells in-vitro, viral genome should be demonstrated in the tumor tissue and last but not least, it should be able to induce tumor formation in experimental animals.11
The oncogenic virus such as human papilloma virus (HPV) is known to induce cancer formation, through the interaction of genome of the host cells, alteration in cell cycle regulation, leading to the uncontrolled proliferation and carcinogenesis. HPV is an icosahedral DNA virus and it is very well established fact that it induces the formation of cervical cancer.12 Studies also favored and supported the role of HPV in causation of head and neck squamous cell carcinoma13, oral14 and esophageal cancer.15 The HPV were classified as high risk HPV and low risk HPV, based upon the presence of early proteins E6 and E7 (Figure 1). These E6 and E7 interact and bind with the tumor suppressor genes like p53 and retinoblastoma pRb respectively, leading to their functional degradation and uncontrolled proliferation of cells leading to the carcinogenesis.16
Fig. 1: Genome of Human Papillomavirus
HPV and retinoblastoma
There is a great deal of debate about the role of HPV in retinoblastoma formation. Literature studies supported as well as negated the etiology of HPV in the genesis of retinoblastoma tumor. There is a quite disparity in detection of HPV among different ethnical regions. The presence of the HPV in retinoblastoma tumor was demonstrated in 27.9% of cases in South American region.17 Few Indian studies have shown the causal role of the HPV in retinoblastoma. A study conducted by Mohan et al18 has demonstrated the presence of the HPV in fresh RB tumor samples by nested PCR using appropriate ocular controls and HPV positive controls and demonstrated HPV positivity in 47% of RB cases. Among them HPV16 was detected in 57% of tumors. Anand et al19 has done a detailed study of detection of the HPV in prospective and retrospective cases and found HPV in 24% of RB cases of which 70% cases showed the presence of high risk HPV16, also this study for the first time detected presence of HPV 45,59,68 and 72. This study also showed that reduced expression of pRb, indirectly indicating the inactivation of pRb by the HPV E7 oncoprotein. Normally pRb inhibits the transcription of the cyclin-dependent kinase inhibitor gene p16INK4a, but in this study they proved that the loss of expression of pRb leads to overexpression of p16INK4a. Recently Naru20 and coworkers have detected the presence of HPV16 in non-familial cases of retinoblastoma. Espinoza et al21 has pointed out the presence of HPV6 and concluded that the presence of HPV acts as a cofactor in the progression of the RB through promoting nonrandom additional mutations.
Mode of transmission of human papillomavirus in RB might be A low level of education, lack of barrier contraceptives increases the risk of the cervical HPV infection as well as birth of child with RB tumor. Bhuvaneshwari and coworkers22 in their study showed that 3 RB samples harbored HPV16, HPV16 and 59, HPV16 and 73 correlated with the HPV16 in the respective mothers cervical brushing samples. This study clearly demonstrated the possible association of the HPV in RB formation as an alternative mechanism other than the mutations in RB1 gene. Similar study was done by Shetty et al23 demonstrated the presence of high risk HPV virus in 69.7% of RB cases (n=76), and in 50% of the cases (n=10) had similar HPV status along with the corresponding maternal cervical cytology smear.
Orjuela et al24 in RB tumor samples found increase presence of HPV 18 than HPV16 and this may be due to an increased oncogenic potential of HPV18 in retinal tissue. They also hypothesized that initial perinatal transmission of HPV was seen high in mothers infected with HPV18 compared to women infected with HPV16.
Another mechanism which might allow the HPV to the retinal cells is the presence of HPV in the paternal sperm cells. A study conducted by the Chan et al25 demonstrated the presence of HPV sequences in the Percoll washed sperm cells. 64% of sperm specimens showed the presence of high risk HPV16 and 18 and suggested the possible role of sperm as a vector for HPV, similar results are echoed by the Lai et al26 and they suggested that certain HPV genes are expressed actively in infected sperm cells and these virus infected sperm cells behave as vectors for transmission of HPV. Chan et al27 demonstrated the transmission of the HPV DNA from the sperm cells to the uterus and embryo.
Several other studies from different parts of the world demonstrated the presence of HPV in retinoblastoma. Hector et al28 demonstrated that not only high risk HPV are found in the RB cases, but also low risk HPV6 is found to be associated with the RB formation.
Contrary to the above results, several studies ruled out the role of HPV in the RB formation. A study conducted by Antoneli had demonstrated the prevalence of HPV DNA in RB cases was 4.6% and in normal control it was 9.1%, indicating low prevalence of HPV and they were unable to conclude the role of HPV in RB formation29 Howard and coworkers studied the role of DNA oncogenic viruses in the formation of RB but could not demonstrate the association.30 A similar study was done by Gillison et al to correlate the role of DNA viruses including HPV, adenovirus and polyomavirus in the genesis of RB, but was not able find any pRb inactivating viruses in the RB tissue.31 Ryoo et al from Korea screened for the presence of HPV16 in RB and found no causal relationship with retinoblastoma.32
Human Papillomavirus is termed as oncogenic virus and is one of the most commonly sexually transmitted infection. It has already proven its role in genesis of cervical tumor and other squamous cell carcinomas such a penile cancer. RB origin till now is known to be caused due to the mutations mainly in the RB1 gene. However recent studies have shown a profound relationship between the infectious agents and genesis of the cancer. Studies have shown the role as well negated the role of HPV in the genesis of the RB tumor formation. The presence or absence of HPV in RB mainly depends upon the epidemiology of HPV in that particular region, socio-economic conditions.
This review lays out a platform to evaluate alternative strategies to prevent retinoblastoma formation including the use FDA approved vaccines against HPV as studies have shown that RB tumor can be acquired from infected parents. We also propose that screening for HPV has to be done for both the partners who have suspicious lesions for the same to prevent the child from tumor formation. We emphasize that the role of HPV in the genesis of the retinoblastoma tumor has to be further investigated with appropriate control population.
- Houston SK, Murray TG, Wolfe SQ, Fernandes CE. Current update on retinoblastoma. Int Ophthalmol Clin. 2011 Winter;51(1):77-91
- Bakhshi S, Gupta S, Gogia V, Ravindranath Y. Compliance in retinoblastoma. Indian J Pediatr 2010;77:535-40
- Yu CL, Tucker MA, Abramson DH, Furukawa K, Seddon JM, Stovall M, Fraumeni JF Jr, Kleinerman RA. Cause- specific mortality in long-term survivors of retinoblastoma. J Natl Cancer Inst. 2009 Apr 15;101(8):581-91
- Ali MJ, Parsam VL, Honavar SG, Kannabiran C, Vemuganti GK, Reddy VA. RB1 gene mutations in retinoblastoma and its clinical correlation. Saudi J Ophthalmol.2010
- Macias M, Dean M, Atkinson A, Jimenez-Morales S, Garcia-Vazquez FJ, Saldaña-Alvarez Y, Ramirez-Bello J, Chavez M, Orozco L. Spectrum of RB1 gene mutations and loss of heterozygosity in Mexican patients with retinoblastoma: identification of six novel mutations. Cancer Biomark. 2008;4(2):93-9
- Choy KW, Pang CP, Yu CB, Wong HL, Ng JS, Fan DS, Lo KW, Chai JT, Wang J, Fu W, Lam DS. Loss of heterozygosity and mutations are the major mechanisms of RB1 gene inactivation in Chinese with sporadic retinoblastoma. Hum Mutat. 2002 Nov;20(5):408
- Price EA, Price K, Kolkiewicz K, Hack S, Reddy MA, Hungerford JL, Kingston JE, Onadim Z. Spectrum of RB1 mutations identified in 403 retinoblastoma patients. J Med Genet. 2014 Mar;51(3):208-14
- Lohmann DR, Gerick M, Brandt B, Oelschläger U, Lorenz B, Passarge E, Horsthemke B. Constitutional RB1-gene mutations in patients with isolated unilateral retinoblastoma. Am J Hum Genet. 1997 Aug; 61(2):282- 94.
- Ata-ur-Rasheed M, Vemuganti Gk, Honavar Sg, Ahmed N, Hasnain Se, Kannabiran C. Mutational analysis of the RB1 gene in Indian patients with retinoblastoma. Ophthalmic Genet. 2002 Jun;23(2):121-8
- Bunin GR, Li Y, Ganguly A, Meadows AT, Tseng M. Parental nutrient intake and risk of retinoblastoma resulting from new germline RB1 mutation. Cancer Causes Control.
- Evans AS, Muller NE. Viruses and cancer; causal associations. Ann Epidemiol. 1990;1:71-92
- Haedicke J, Iftner T. Human papillomaviruses and cancer. Radiother Oncol. 2013 Jul 3
- Seiwert T. Accurate HPV testing: a requirement for precision medicine for head and neck cancer. Ann Oncol. 2013 Nov;24(11):2711-3
- Walline HM, Komarck C, McHugh JB, Byrd SA, Spector ME, et al. High-Risk Human Papillomavirus Detection in Oropharyngeal, Nasopharyngeal, and Oral Cavity Cancers: Comparison of Multiple Methods. JAMA Otolaryngol Head Neck Surg. 2013 Oct 31
- Feng B, Awuti I, Deng Y, Li D, Niyazi M, Aniwar J, Sheyhidin I, Lu G, Li G,Zhang L. Human papillomavirus promotes esophageal squamous cell carcinoma by regulating DNA methylation and expression of HLA-DQB1. Asia Pac J Clin Oncol.2013 Oct 22
- Münger K, Scheffner M, Huibregtse JM, Howley PM. Interactions of HPV E6 and E7 oncoproteins with tumour suppressor gene products. Cancer Surv. 1992; 12:197-
- Palazzi MA, Yunes JA, Cardinalli IA, Stangenhaus GP, Brandalise SR, Ferreira SA, Sobrinho JS, Villa LL. Detection of oncogenic human papillomavirus in sporadic retinoblastoma. Acta Ophthalmol Scand. 2003
- Mohan A, Venkatesan N, Kandalam M, Pasricha G, Acharya P, Khetan V, Gopal L, Sharma T, Biswas J, Krishnakumar S. Detection of human papillomavirus DNA in retinoblastoma samples: a preliminary study. J Pediatr Hematol Oncol. 2009 Jan;31(1):8-13
- Anand B, Ramesh C, Appaji L, Kumari BS, Shenoy AM, Nanjundappa, Jayshree RS, Kumar RV. Prevalence of high-risk human papillomavirus genotypes in retinoblastoma. Br J Ophthalmol. 2011 Jul;95(7):1014-8
- 20. Naru J, Aggarwal R, Singh U, Kakkar N, Bansal D. HPV- 16 Detected in One-Fourth Eyes With Retinoblastoma: A Prospective Case-control Study From North India. J Pediatr Hematol Oncol. 2016 Jul; 38(5):367-71.
- Espinoza JP, Cardenas Vj, Luna CA, Fuentes HM, Comacho GV et al. Loss of 10p material in a child with human papillomavirus-positive disseminated bilateral retinoblastoma. Cancer Genet Cytogenet. 2005; 161:146- 50
- Bhuvaneswari A, Pallavi VR, Jayshree RS, Kumar RV. Maternal transmission of human papillomavirus in retinoblastoma: A possible route of transfer. Indian J Med Paediatr Oncol. 2012 Oct;33(4):210-5
- Shetty OA, Naresh KN, Banavali SD, Shet T, Joshi R, Qureshi S, Mulherkar R, Borges A, Desai SB. Evidence for the presence of high risk human papillomavirus in retinoblastoma tissue from nonfamilial retinoblastoma in developing countries. Pediatr Blood Cancer. 2012 Feb;58(2):185-90
- Orjuela M. Castaneda VP, Ridaura C, Lecona E, Leal C et al. Presence of human papillomavirus in tumor tissue from children with retinoblastoma: an alternative mechanism for tumor development. Clin Cancer Res. 2000;6:4010-6
- Chan PJ, Su BC, Kalugdan T, Seraj IM, Tredway DR, King A. Human papillomavirus gene sequences in washed human sperm deoxyribonucleic acid. Fertil Steril. 1994 May;61(5):982-5
- Lai YM, Yang FP, Pao CC. Human papillomavirus deoxyribonucleic acid and ribonucleic acid in seminal plasma and sperm cells. Fertil Steril. 1996 May;65(5):1026- 30
- Chan PJ, Seraj IM, Kalugdan TH, King A. Evidence for ease of transmission of human papillomavirus DNA from sperm to cells of the uterus and embryo. J Assist Reprod Genet. 1996 Jul;13(6):516-9
- Montoya-Fuentes H, de la Paz Ramirez-Munoz M, Villar-Calvo V, Suarez-Rincon AE, Ornelas-Aguirre JM, Vazquez-Camacho G, Orbach-Arbouys S, Bravo-Cuellar A,Sanchez-Corona J. Identification of DNA sequences and viral proteins of 6 human papillomavirus types in retinoblastoma tissue. Anticancer Res. 2003 May- Jun;23(3C):2853-62
- Antoneli CB, Ribeiro KB, Sredni ST, Arias VE, Andreoli MA, de Camargo B, Sobrinho JS, Prado JC, Soares FA, Villa LL. Low prevalence of HPV in Brazilian children with retinoblastoma. J Med Virol. 2011 Jan;83(1):115-8
- Howard E, Marcus D, O'Brien J, Albert D, Bernards R. Five DNA tumor viruses undetectable in human retinoblastomas. Invest Ophthalmol Vis Sci. 1992
- Gillison ML, Chen R, Goshu E, Rushlow D, Chen N, Banister C, Creek KE, Gallie BL. Human retinoblastoma is not caused by known pRb-inactivating human DNA tumor viruses. Int J Cancer. 2007 Apr 1; 120(7):1482-90.
- Ryoo NK, Kim JE, Choung HK, Kim N, Lee MJ, Khwarg SI. Human papilloma virus in retinoblastoma tissues from Korean patients. Korean J Ophthalmol. 2013