Papillomaviridae is a family of non-enveloped viruses with double-stranded DNA genomes [67]. Members infectious to humans, HPV, have been linked to various cancers, most significantly cervical cancer [11,12,13]. However, only a subset of the ~150 types of HPV, the so-called high-risk types such as HPV-16 and-18, are typically linked to cancer [68]. The main proposed mechanism of contribution of high-risk HPV to cervical cancer is through integration of the viral DNA into the host genome and expression of viral oncogenes. It has been shown, for example, that the E6 and E7 early oncogenes degrade tumor suppressors p53 and retinoblastoma protein (pRb), which among other effects cause the cell to arrest in the S-phase, leading to genomic instability, aneuploidy, DNA damage and, consequently, carcinogenesis [69,70] (see Figure 2 for details). It is thought that a similar mechanism is also at work in other HPV-associated cancers such as colorectal cancer [71]. HPV is the most frequently sexually transmitted infectious agent in the United States, and vaccines against HPV are recommended for all girls aged 11 to 12 years, aiming to reduce the burden of cervical cancer [72]. HPV has also been identified as a potential risk factor for various other cancer types, including anal [9,10], bladder [11] colorectal [14,15] esophageal [17,18,19], head and neck [11,20,21], oral [23], prostate [24], renal [25], skin/mucosal [26,27,28] and vulvar cancer [29]. In most of these cases, however, the association with HPV is not as strong as for cervical cancer, or is only seen in subsets of patients, and consequently there is also conflicting data. For example, a study from 2014 found no link between HPV infection and colorectal cancer [16]. In addition, there is an established correlation between HPV infection and head and neck cancer [11,20,21], but also data indicating that the presence of HPV in head and neck tumors predicts better long-term clinical outcome [22]. Moreover, merely associating the presence of specific viral sequences with cancer status does not necessarily indicate a causal role of the virus.

Viruses of the Herpesviridae family are enveloped dsDNA viruses infecting mammals, birds and reptiles [73]. Various members have been implicated in cancer formation, including cytomegalovirus (CMV, also known as human herpesvirus 5, HHV5), Epstein–Barr virus (EBV or HHV4), herpes simplex virus (HSV or HHV1/2) and HHV6 and HHV7 (Table 1). The strongest association with cancer has been reported for EBV, which has been linked to colorectal carcinoma (CRC) [33] (although a later study found no association [16]), esophageal [34] and gastric cancer [35] (interestingly, however, patients with EBV-positive gastric cancer had a better response to chemotherapy and better survival [36]), hepatocellular carcinoma [37], lymphoma (Burkitt lymphoma, diffuse large B-cell lymphoma and peripheral T-cell lymphoma) [38,39,40], oral [41], as well as skin and mucosa associated cancers [26]. Therefore, it has been proposed that vaccination against EBV might be a viable means to prevent EBV-associated cancers [74]. Various EBV vaccine candidates are currently in preclinical or clinical development.

CMV has been linked to colorectal cancer [30], however, in non-elderly patients CMV-positive tumors have been associated with increased disease-free survival rate [31]). HHV6 was found to be connected to malignant melanoma [26] and B-cell lymphoma [39], HHV7 to bladder and oral cancer as well as to T-cell lymphoma [26], and HSV has been associated with oral cancer [41].

In HIV-infected individuals, Kaposi sarcoma-associated herpesvirus (KSHV) infection is associated with Kaposi sarcoma [42].

Mechanistically, herpesviruses such as CMV and HSV and others are known to induce DNA synthesis and counteract apoptosis via activation of the rat sarcoma (Ras)/rat fibrosarcoma (Raf)/meiosis-specific kinase (MEK)/extracellular signal-related kinase (ERK) pathway [71,75] (see Figure 3 for details). In addition, KSHV has been shown to inhibit tumor suppressor protein p53 [76].

Two members of the Polyomaviridae family (non-enveloped double-stranded DNA (dsDNA) viruses), namely BKV and JCV, have been linked to CRC [43,44,46,47,48,49]. However, other studies have challenged this notion and found no link [16,45]. There is also a possible association of BKV with bladder cancer [26]. The clearest evidence, however, has been obtained for Merkel cell polyomavirus (MCV) that has been identified as a major causative factor for Merkel cell carcinoma [50,51]. Consequently, it has been proposed that an anti-MCV vaccine might help to prevent Merkel cell carcinoma [77,78].

It has been hypothesized that MCV contributes to oncogenesis in two steps: integration of the viral genome into the host genome followed by mutational truncation of the large T antigen gene [79]. The truncated T antigen promotes cell cycle progression. The T antigen likely also plays a role in oncogenic transformation mediated by other polyomaviruses such as BKV and JCV. It has been shown to interact with various host proteins, thereby altering the processes of DNA repair, cell cycle regulation and proliferation [80] (see Figure 4 for details).

The retroviruses human immunodeficiency virus (HIV) and human T-lymphotropic virus type 1 (HTLV-1) have both been associated with cancer. Three HIV-associated cancers are known, cervical cancer, aggressive B cell non-Hodgkin lymphoma and Kaposi sarcoma [55,56]. In addition, HIV infection has been linked to an increased risk for anal cancer [52,53] and worse overall colostomy-free survival rates [54]. The effect of HIV infection is likely indirect; the virus weakens the immune system and renders infected individuals more susceptible to infections by other viruses, such as Kaposi sarcoma-associated herpesvirus (KSHV), which has been linked to Kaposi sarcoma [42]. For HTLV-1, oncogenesis is thought to involve multiple mechanisms [6,81]. These include: (1) the establishment of a persistent infection that results in chronic inflammation, which attracts phagocytes that release reactive oxygen species, contributing to DNA damage, (2) the genomic integration and expression of viral oncogenes, such as the Tax-1 protein that, among other functions, inhibits tumor suppressor p53, and (3) the suppression of host immune responses. A summary of the functions of Tax-1 is shown in Figure 5.

Various other viruses have been linked to cancer. Among these are the hepatitis viruses HBV and HCV. HBV (family Hepadnaviridae with a partially double-stranded DNA genome and an envelope) infects the liver and has been linked to liver cancer [11] but may also be a risk factor for cancers of the bile duct [59], the colon [60] and the pancreas [61,62]. HCV (an enveloped ssRNA virus of the Flaviviridae family) also infects the liver and has been associated with liver and bile duct cancer [11,59]. Liver carcinogenesis by HBV and HCV is multifactorial and has been linked, amongst others, to virus-induced changes in signaling pathways, the inflammatory status and to elevated production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) [82,83,84] (see Figure 6 for details). Anelloviruses (circular single-stranded DNA (ssDNA) viruses) including torque teno virus (TTV) have been associated with hepatic [63] and mucosal [26] cancer as well as leukemias [26]. Human bocavirus (HBoV) and other members of the Parvoviridae family (ssDNA viruses) have been linked to various cancers, including colorectal and lung cancer [64], squamous cell carcinoma [65] and skin cancer [26]. The ssRNA orthobunyaviruses may be linked to colorectal cancer [66]. The mechanisms of oncogenesis of anelloviruses, parvoviruses and orthobunyaviruses remain largely unknown.