Epstein Barr Virus (EBV) is a gamma-1 herpes virus that is restricted to primate hosts and usually acts as a latent infection in host B lymphocytes. Although an EBV infection is typically asymptomatic, the virus has the potential inducing oncogenesis to form a wide array of tumors [6] [7] . The most common kinds of cancer caused by EBV include: Hodgkin Lymphoma, Burkitt Lymphoma, diffuse large B cell lymphoma (DLBCL), pyrothorax lymphoma, nasopharyngeal carcinoma, gastric carcinoma, and leiomyosarcoma of the immunocompromised [8] . However, healthy individuals with a typically asymptomatic EBV infection have an immune system that contains the virus via antigen specific memory CD8 T lymphocytes [9] .

Oncogenes encoded by EBV include latent membrane protein 1 (LMP1) and LMP2A where LMP1 induces growth promoting signals while mimicking CD40 signaling pathways while LMP2A acts like a B cell receptor that activates AKT, NF-kB, NOTCH, and phosphatidylinositol 3 kinase [10] [11] . EBV nuclear antigen (EVBN- A) 3A/C silences tumor suppressor as a mechanism associated with oncogenesis [12] [13] .

Hepatocellular carcinoma (HCC) accounts for approximately 70% - 85% of all types of liver cancer [14] . Liver

cancer is the third leading cause of deaths associated with cancer in addition to being the sixth most common cancer [15] . The likelihood of developing HCC while infected with hepatitis B virus (HBV) is between a 2500% - 3700% increase compared to patients without HBV [16] [17] . Elevated risk of HCC is correlated with a high viral load of HBV [18] . HBV is likely to cause liver cirrhosis and inflammation which is found in 80% - 90% of cases of HCC [18] . The regulation of HBV proliferation in the liver involves both natural killer cells and CD8+ T cells that actively fight the HBV infection [19] .

HCC has three molecular mechanisms associated with an infection of HBV [20] . The first is cell proliferation and variability from the expression of viral protein HBX [2] . The second mechanism is related to HBV DNA integration which changes the expression of endogenous genes in addition to destabilizing the chromosome of the host genome [2] . The destabilization of the host chromosome is more common in HBV infections than it is in hepatitis C viral (HCV) infections. The third involves the accumulation of DNA damage caused by inflammation and hepatocyte division [2] .

130 - 170 million people world-wide are infected with HCV [21] . HCV infections are associated with some degree of liver fibrosis in addition to 15% - 25% of patients developing cirrhosis after 10 - 40 years of infection [22] . Patients with chronic hepatitis C (CHC), in addition to cirrhosis of the liver, increase the risk of liver failure and the formation of HCC [23] . Chronic infections are correlated to low NK cells titers despite the fact that NK cells usually high in the liver [24] . However, NK cells are activated and kill HCV-infected hepatocytes releasing antigens that prime specific CD8 and CD4 response [25] .

Oncogenesis associated with oxidative stress has been examined in several mouse models including mice deficient in copper/zinc superoxide dismutase and mice with erythroid-2-related transcription factor-1 (Nrf1) knockout [26] [27] . Continued exposure to H₂O₂ can increase the activity of methylation of oligos, including the down regulation of catalase by affecting its promoter region [28] [29] . Increased methylation in HCC cells also respectively increases the expression of Snail [28] [30] . This methylation silences the expression of E-cadherin by a mechanism that first involves methylating the E-cadherin promoter via histone deacetylase 1 and DNA (cystosine-5)-methyltransferase 1, which increases expression of Snail [28] . The reduction of E-Cadherin is an early biomarker for both HCC and HCV-related cirrhosis [30] .

HBV and HCV have similar mechanisms with regard to their effect on the host chromosomes. While these oncogenes are common in HBV and HCV infections, the likelihood of developing HCC depends on the insertion of the viral genes in addition to altered bases and changes in the epigenetic profiles of the host chromosome. Common genes effected by aberrant bases in HCC during an HBV and HCV infection include TP53, CTNNB1, and AXIN. Deletions and silencing of CDKN2A in HCC tissue is also common in HBV and HCV infected patients. Mutations in tumor suppressor genes including TP53, ARID1A, AXIN1, and CDKN2A and an oncogene known as ARID1A are common in 10% of HCC tumors [31] .

Human Herpes Virus 6 (HHV-6) is associated with encephalitis in immunocompetent individuals, maternal fetal infections, hematological malignancies, and digestive problems in immunocompromised individuals [32] - [34] . The virus is known to infect oligodendrocytes and astrocytes in samples in vivo and in vitro in addition to being detected in brain tumors of both adult and children patients via PCR, immunohistochemistry, and in situ hybridization [35] [36] . The mechanism for oncogenesis may involve the expression of viral protein ORF-1, which can form a dimer and deactivate p53, and U95, which can bind and deactivate NF-kB [34] [37] . HHV-6 is best known for its ability to infect CD4+ T cells which may increase the immunological effect from HIV in AIDS patients [38] . The ability for HHV-6 to evade the immune system is largely due to its ability to remain dormant though the life cycle in the cell. However, the expression of viral proteins is known to alter the immunomodulation associated with the engagement of CD46 receptors as well as alter the expression of cell surface receptor in T cells [39] .

At the time, presence of Human Herpes Virus 8 (HHV-8) or Kaposi’s sarcoma-associated herpes virus (KSHV) was found in virtually all Kaposi’s sarcoma (KS) tissue for both immune competent and incompetent patients and appeared to be specific of the virus since it was yet to be found present in nearly any other tissue or diseases [40] - [42] . HHV-8 is also found in primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD) [43] . HHV-8 viral proteins contribute to the pathogenesis and can be found in both latent and lytic phases [44] . The ability for HHV-8 to evade the immune systems comprises of many factors which include evasion of NK and T cell response, blockage of apoptotic pathways, interference of interferon signaling, and host chemokine network alterations [45] .

KS is a vascular tumor that forms nodular lesions on skin and mucosa before it becomes a more aggressive form of cancer found in multicentric lesions of lymph nodes [46] . The mechanism of oncogenesis remains unclear since much of the potential oncogenes are only present in the lytic phase where the KS samples collected suggest that the HHV8 is still in latent phase [47] . These genes include K1, vIRF, and cIL8R [47] . The mechanism of HHV8 in KS is still not understood and likely involves a multistep process of oncogenesis.

The worldwide leading cause of morbidity and mortality for women is cervical cancer [48] [49] . Even though human Papillomavirus (HPV) plays a very important part in the etiology of cervical cancer, the virus itself is not completely sufficient for cancer prognosis [50] [51] . With more than 120 HPV types, there are at least 15 HPV types with oncogenic potential when there is a persistent infection [52] [53] . Although NK cells have the capacity of recognizing and killing virus-infected transformed cells by granule-dependent cytotoxicity and apoptotic pathways, the tumor cells associated with HPV infections evade attacks by NK cells [54] . Dendritic cells are not able to promote T-cell immune response during a HPV infection which significantly attenuates the humoral immune response [55] [56] . Many of the biomarkers associated with oncogenesis include various surface proteins of HPV [57] [58] . The most notable oncoproteins, E5, E6, and E7, initiate continuous proliferation without genetic proofreading which causes mutations that can lead to cancer [4] [5] . The regulation of HPV genome post infection likely involves gene regulation from miRNA of the host [59] [60] .

Human T-cell Leukemia virus type 1 (HTLV-1) is one of the oldest retroviruses and the first human retrovirus to be discovered [61] . Its discovery followed an epidemiological study of Adult T-cell leukemia/lymphoma (ATLL) where the cancer appeared to have been spreading like a pathogen in Japan [62] . ATLL is an aggressive lymphoproliferative disease that can be contracted from asymptomatic individuals [63] [64] . ATLL oncogenesis involves the HTLV-1 protein Tax to quell apoptosis, initiate a cascade reaction that leads to cellular inflammation, and inhibition of p53 in a cascade associated with DNA repair respectively [65] - [68] . The reason for HTLV-1 persistence in a manner that does not trigger an innate immune response still remains a mystery. The ability to detect HTLV-1 in serum is very difficult since an infection requires the transfer from infected cells [69] . Hypothesis of HTLV-1 spreading by mitosis of infected cells is a likely reason for its ability to evade the immune system [70] .

Merkel cell Polyomavirus (MCPyV) can be found in 80% of all Merkel cell carcinomas [71] [72] . A recent study showed a small presence of MCPyV in extrapulmonary small cell carcinomas [73] . The frequency of MCPyV, in the general population, is 80% of people who are over the age of 50 years [74] . The virus is also present in over 85% of homo- and bisexual HIV positive young men [74] . The incidence of developing MCC is very rare for immunocompetent individuals, the tumor is much more likely to occur in AIDS patients and those with chronic lymphocytic leukemia [75] [76] . Complete remission of an MCC tumor is possible for those immunosuppressed individuals who become immunocompetent [77] . MCPyV-positive tumors have up regulated CD3G, CD3D, ZAP70, and IGHM; however, the biological significance in oncogenesis remains unknown [78] . Although there is evidence of a link between ultraviolet (UV) radiation and specific mutations in TP53 and Ha-RAS, the mechanism associated with UV radiation in oncogenesis associated with MCPyV has yet to be determined [79] .

Borrelia burgdorferi (Bb) is a spirochete that causes the zoonotic tick borne infection known as Lyme disease [80] . Erythema chronicum migrans (ECM), lymphocytoma cutis, and acrodermatitis chronica atrophicans (ACA) are a few of the cutaneous disorders associated with Bb infection [81] - [83] . Primary cutaneous B-cell lymphoma (PCBCL), in skin affected by ACA and patients with serology associated with previous exposure to Bb, shows evidence that PCBCL may be caused by Bb [84] - [86] . Bb can also be found in skin lesions of patients with PCBCL [87] - [89] . Borrilia induces a strong immunological response but has the ability to stave off the immune system despite dendritic cell (DC) activation and recognition of Bb surface lipoproteins [90] . The DC response is coupled with various effector T-cells.

Chlamydia pneumoniae is an intracellular parasite, gram negative bacillus, and causes infection in 50% of adults exposed to the pathogen [91] [92] . The bacteria are transmitted through aerosol and respiratory secretions [91] [93] . An infection with C. pneumoniae can cause pneumonia, bronchitis, rhinitis, sinusitis, COPD or an asymptomatic infection. C. pneumoniae has the ability to evade innate immunity involving type 1 IFN by restricting the phosphorylation and nuclear translocation of IRF3 [94] .

Although the mechanism for C. pneumoniae to cause lung cancer is unknown, there are a few possible mechanism associated with its oncogenisis. One possible mechanism involves mediators associated with inflammation [95] . Inflammation can cause damage of DNA through reactive oxygenated species. Inflammation can also damage cells including the cells ability to repair itself in addition to increasing the rate of cellular division [96] . C. pneumoniae can localize and infect preferentially to the lungs of smokers [97] . Monocytes secretion of IL-1β, IL-8, superoxide oxygen radicals, and tumor necrosis factor act as mediators of inflammation and can also cause damage to lung tissue and DNA which can result in carcinogenesis [98] .

Helicobacter pylori chronic infections are associated with peptic ulcerations and atrophic gastritis in addition to being associated with the development of gastric carcinoma, which is the second leading cause of deaths related to cancer in the world [99] [100] . Most H. pylori infected individuals are asymptomatic and never develop neoplasms even though H pylori infection is very prevalent in patients with gastric cancer [101] . It is important to note that there are an abundant amount of H. Pylori strains and many individuals harbor more than one strain [102] - [104] . H. Pylori induces a robust immune response associated with an increase in IL-1, IL-8, and IL-6 concentration [105] . An increase in the number of CD4 and CD8 T-cells of infected individuals as compared to pre-infected individuals is also common [106] .

The mechanism for oncogenesis associated with gastric carcinoma is unknown. However, H pylori’s association with chronic inflammation, which leads to aberrant methylation genes including tumor suppressor genes, suggest a potential epigenetic mechanism is involved [107] [108] . Human gastric mucosae have high levels of methylation in the presence of H. pylori [109] [110] .

Mycoplasma is the smallest self-replicating prokaryote and acts as a parasite that infects vertebrates. An infection of Mycoplasma can alter the cellular metabolism and physiology of a host and can act as an opportunistic pathogen under rare circumstances [111] [112] . Chronic Mycoplasma infections have the capacity to induce genetic instability and malignant transformation [113] - [118] . The metastasis of tumor cells can be influenced by the presence of Mycoplasma in vivo in addition to being a factor in increasing the invasiveness of tumors in vitro [114] [116] [118] . P53 suppression and NF-kB activation are influenced by an infection of Mycoplasma [119] . Although there are studies that begin to correlate the effect of Mycoplasma to various cancers, the results remain in conjecture.

The presence of cholangiocarcinoma is common Southeast Asia, Japan, Chile, Bolivia, and northern India [120] - [124] . Cholangiocarcinoma is of greater risk if the patient has gallstones [125] [126] . However, patients that are chronic typhoid are 167 times more likely to develop cholangiocarcinoma [127] .

There are several potential mechanisms associated with the development of cholangiocarcinoma from Salmonella typhi. The first mechanism is associated with cholangiocarcinoma formation involves the deconjugation of conjugated toxins and bile acid to form carcinogenic biproducts by the enzyme β-glucuronidase of the bacteria [128] [129] . These byproducts of glucuronidase are mutagens that bind to DNA and create the opportunity for oncogenesis [3] . Chronic typhoid carriers that are not treated by antibiotics have an increased concentration of free radicals, which are known to promote oncogenesis [130] . The site of the infection of S. typhi-1 is known to cause inflammation [131] . It is also important to note that S. typhi-1 infection has the capacity to survive macrophage phagocytosis [132] . The lifetime of the S. typhi-1 and its overall effect on macrophages remains unclear.

Streptococcus bovis is a bacteria that is commonly associated with colorectal cancer. Although there is some discrepancy on the prevalence of S. bovis and the rate of colorectal tumors, there is evidence that 25% - 80% of those infected with S. bovis have colorectal tumors with 18% - 62% having colonic neoplasia [133] -[139] . The etiology of the development of cancer associated with a bacterial infection usually involves chronic inflammation and the production of carcinogenic metabolites [140] . Many cancers associated with bacterial infections originate at the sight of the infection, causing chronic irritation, and inflammation [141] . Finding the proper metabolite in the microbiome, where there is a lot of competing floras, is very difficult but there remains a potential for the bacteria to create a microclimate that allows mutagens to flourish [140] .

Clonorchis sinensis is a hermaphroditic trematonde liver fluke found primarily in Southeast Asia. C. sinensis was reported to have infected 7 million people in southern China, Korea, Taiwan, and Vietnam [142] . The liver fluke is commonly transmitted by consuming the muscle and connective tissue of undercooked fresh water fish in the endemic region. The matured worms begin to attach to intrahepatic bile ducts and sometimes even the gall-bladder and pancreatic duct [143] . C. sinensis is known to cause biliary tree inflammation, epithelial cell hyperplasia, mucin-producing cells in the mucosa mataplasia, and periductal fibrosis [144] - [148] . The second most prevalent liver cancer is cholangiocarcinoma behind only hepatocellular carcinoma. C. sinensis can cause an inflammatory response that induces the likelihood of forming cholangiocarcinoma [149] . Although rats are resistant to C. sinensis, the resistance is not from specific immunity and instead involves primarily local inflammation [150] .

Opsithorchis viverrini is a food borne trematode that transmits by ingesting the fins, skin, or musculature of raw or undercooked fish. The liver fluke is endemic in Thailand, Vietnam, Cambodia, and Lao [151] [152] . O. viverrini is associated with conditions including obstructive jaundice, periductal fibrosis, cholelithiasis, cholangitis, and hepatomegaly [153] . O. Viverrini is linked with the etiology of cholangiocarcinoma (CCA), as studied by epidemiological and experimental evidence [152] [154] - [156] . The leading cause of cancer mortality in Southeast Asia is CCA. There are multiple mechanisms for oncogenesis associated with an O. viverrini which include mechanical injury of epithelial cells, immunopathology associated with infection related inflammation, and the toxic excretory/secretory (ES) molecules from the parasite [157] .

Schistosomiasis is the second leading cause of morbidity and mortality of a parasitic disease after malaria [158] . The disease affects 10% of the world’s population and is usually picked up by drinking water contaminated with Schitosoma haematobium in sub-Saharan Africa [159] [160] . The geographic areas that are endemic to S. haematobium have elevated numbers of bladder carcinomas. S. haematobium has both the ability to evade host immunity in addition to being able to effect the hormonal microenvironment in a way that suits its reproduction and growth [156] .

The potential mechanisms of oncogenesis bladder carcinomas involve either environmental factors or the N-nitroso compounds associated with bladder inflammation [157] - [162] . The environmental factors including pesticides and cigarette smoke have the potential to work synergistically with S. haematobium infection by increasing the likelihood of bladder carcinoma [162] [163] . N-nitroso compounds are found in excess in the urine of infected individuals [164] - [167] . These compounds have been hypothesized to have come from endogenous

and exogenous sources. A potential endogenous source might be associated with the inflammatory response of the bladder while an exogenous source might come from the diet of the individual [166] [167] .