Viral Oncogenesis

Question 1

What are the viruses known to cause human cancers? What cancers do they cause?

Answer 1

• Epstein-Barr virus (EBV)
  
  • Burkitt and Hodgkin lymphoma, B cell lymphomas in immunodeficient individuals, nasopharyngeal carcinoma, and gastric carcinoma
• Kaposi Sarcoma Herpesvirus (KSHV) and Human Herpesvirus 8 (HHV8)
  
  • Kaposi’s sarcoma
  • Primary Effusion Lymphoma (PEL) - typically also infected with EBV
• Human T-cell lymphotropic virus (HTLV)
  
  • Adult T cell lymphoma
• Hepatitis B virus (HBV) and Hepatitis C virus (HCV)
  
  • Primary hepatocellular carcinoma
• Human Papillomavirus (HPV)
  
  • Some carcinomas, especially cervical and other genital carcinomas
• Merkel cell polyomavirus (MCV)
  
  • Merkel cell carcinoma - primary neuroendocrine carcinoma of the skin

Question 2

What cancers result from EBV, and what is the mechanism?

Answer 2

• EBV is prevalent in the human population with over 90% of the population being seropositive for virus infection
  
  • The prevalence of KSHV can be quite low depending on the population studied
• Both KSHV and EBV have large linear DNA genomes encoding about 100 genes
• Like all herpeviruses, EBV and KSHV establish lifelong latency in humans in certain cell types
• For EBV, latency, in which few or any viral genes are expressed, is mediated by two virally encoded latent membrane proteins (LMPs) that drive B cells into the memory B cell compartment
  
  • LMP1 mimics a CD40 receptor signal whereas LMP2A mimics a B cell receptor signal – two signals that are key for survival, growth, and differentiation of B cells
• Along with EBNA1 (important for viral genome maintenance), there are number of other viral proteins associated with EBV latency they are expressed in the nucleus of infected cells (EBNA – Epstein-Barr virus nuclear antigen)
  
  • All of these proteins, since they alter normal cellular functions and are important for maintaining the viral genome and viral gene expression, and are thought to contribute to the ability of EBV to contribute to cancer
• Like all herpesviruses, EBV and KSHV are transmitted via close physical contact such as saliva
• EBV was the first virus found to be associated with human cancer by Denis Burkitt studying the occurrence of a lymphoma in Africa in the late 1950s
  
  • This lymphoma bears his name – Burkitt Lymphoma
• EBV is now known to be associated with Hodgkin lymphoma, nasopharyngeal carcinoma, gastric carcinoma, and other B cell lymphoproliferative disorders with a high incidence in immune suppressed individuals such as transplant patients and HIV/AIDS patients

Question 3

What cancers arise from KSHV, and what is the mechanism?

Answer 3

• Virus is found in Karposi sarcoma lesions found in HIV/AIDS patients
  
  • With the onset of the HIV/AIDS epidemic in the early 1980s, there was a sudden occurence of KS affecting primarily gay and bisexual HIV/AIDS patients with up to 50% of reported AIDS patients having this tumor—an extraordinary rate of cancer predisposition
• The advent of HAART and the improvement of immune function in HIV/AIDS patients has largely reduced this cancer
• Primary effusion lymphomas, also seen in HIV/AIDS patients are also infected with KSHV and in most cases also EBV
• Castleman’s disease (giant or angiofollicular lymph node hyperplasia, lymphoid hamartoma, angiofollicular lymph node hyperplasia) is an uncommon lymphoproliferative disorder also associated with KSHV infection

Question 4

What cancers arise from hepatitis B, and what is the mechanism?

Answer 4

• Hepadnavirus - hepa (liver) and dna because it is a DNA virus
• HBV has a circular genome of partially double-stranded DNA
• The virus replicates through an RNA intermediate form by reverse transcription
  
  • Replication takes place in the liver and the virus spreads to the blood where viral proteins and antibodies against them are found in infected people
• HBV infections causes epidemics in Asia and Africa and is endemic in China
  
  • It thought about a third of the world population has been infected at one point in their lives with 350 million being chronic carriers
  • National and regional prevalence ranges from over 10% in Asia to under 0.5% in the United States and northern Europe
  • The virus is transmitted by exposure to infectious blood or body fluid
• The acute illness causes liver inflammation, vomiting, jaundice, and in rare instances death
  
  • Chronic hepatitis B infection eventually can cause cirrhosis and liver cancer - a disease with poor treatment response due to limited therapies
• An effective subunit vaccine is made in yeast and is in use and contains one of the viral envelope proteins, hepatitis B surface antigen (HBsAg)
  
  • It prevents both infection and disease including cancer
  • Viral DNA is integrated in tumors with limited viral gene expression
• One potential protein has been identified in tumors – the X protein or HBx
  
  • ​Multiple functions have been ascribed to the protein, but the role of HBx in malignancy is controversial
• Occurrence of cancer may be due to chronic liver damage, immune response, and enhanced mutation frequency with or without a role for a particular viral gene

Question 5

What are the cancers that arise from hepatitis C, and what is the mechanism?

Answer 5

• HCV belongs to the genus Hepacivirus a member of the family Flaviviridae
• HCV contains a positive sense single-stranded RNA genome
  
  • The genome consists of a single open reading frame that is about 9,600 nucleotides long
  • This single open reading frame is translated to produce a single protein product, which is then further processed to produce smaller active proteins
• The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years
  
  • In some cases, those with cirrhosis will go on to develop liver failure, liver cancer or life-threatening esophageal and gastric varices
• HCV is spread primarily by blood-to-blood contact associated with intravenous drug use, poorly sterilized medical equipment and transfusions
• An estimated 150–200 million people worldwide are infected with hepatitis C
• No vaccine against hepatitis C is available
• The virus persists in the liver in about 85% of those infected
• This persistent infection can be treated
  
  • Previously the standard therapy was a combination of pegylated interferon and ribavirin, with either boceprevir or telaprevir added in some cases
• The HCV genotype is clinically important in determining potential response to interferon-based therapy and the required duration of such therapy
  
  • Genotypes 1 and 4 are less responsive to interferon-based treatment than are the other genotypes (2, 3, 5 and 6)
• More promising therapies that over better cure rates (50–80%) have been developed
  
  • Sofosbuvir for use against chronic hepatitis C infection was just approved by the FDA in December 2013
    
    • It is the first drug that has demonstrated safety and efficacy without the need for interferon treatment
  • It inhibits the viral polymerase requite for HCV replication
  • Sofosbuvir will cost $84,000 for 12 weeks of treatment and $168,000 for the 24 weeks
  • It is appears to have a much better overall cure rate
• Patients who develop cirrhosis or liver cancer may require a liver transplant
  
  • Hepatitis C is the leading reason for liver transplantation
• Similar to HBV, the role of HCV in liver cancer is not entirely understood, but is likely similar as that for HBV except since the HCV genome never exists as DNA, it is not integrated in the host genome
  
  • The occurrence of cancer may be due to chronic liver damage, immune response, and enhanced mutation frequency rather than expression of a particular viral gene in the tumor cells

Question 6

What cancers arise from MCV, and what is the mechanism?

Answer 6

• MCV is thought to cause Merkel cell carcinoma, a rare but aggressive form of skin cancer
  
  • Approximately 80% of Merkel cell carcinoma (MCC) biopsies are infected with MCV
• MCV appears to be a common pathogen with almost universal infection of older children and adults
• MCV is detected in respiratory secretions also from healthy skin, and in gastrointestinal tract tissues and elsewhere, and so its precise mode of transmission is not clear
• The virally encoded T antigen appears to be important for this cancer

Question 7

What are the cancers that arise from HPV, and what is the mechanism?

Answer 7

• HPV is a DNA virus from the papillomavirus family
• HPV establish productive infections in keratinocytes of the skin or of mucous membranes
• While the majority of the known types of HPV cause no symptoms in most people, some types can cause warts or squamous cell papilloma
• There is close to two hundred different types of HPV that infect humans
  
  • Of these, about a dozen including types 16, 18, 31, and 45 are considered high-risk types since they associated with cervical cancer, as well as anal cancer, vulvar cancer, vaginal cancer, and penile cancer
  • Several types of HPV, in particular type 16, have also been found to be associated with HPV-positive oropharyngeal cancer (OSCC), a form of head and neck cancer
• HPV-induced cancers often have viral sequences integrated into the cellular DNA and express two HPV early genes (E6 and E7) that act as oncoproteins by disabling two important tumor suppressors – p53 and Rb
• HPV infection is a cause of nearly all cases of cervical cancer
  
  • ​This being said – most infections do not cause cancer
  • Most HPV infections in young women are temporary and have little long-term significance
  • Seventy percent of infections are gone in one year and ninety percent in two years
• However, when the infection persists (less than 10% of the time), there is risk of developing precancerous lesions of the cervix, which can progress to invasive cancer
  
  • This process usually takes 10–15 years, providing many opportunities for detection and treatment of the pre-cancerous lesion
• The Papanicolaou (Pap) test or liquid-based cytology is used to detect abnormal cells that may develop into cancer and the lesion can be removed
  
  • Pap smears have reduced the incidence and fatalities of cervical cancer in the developed world, but even so there were 11,000 cases and 3,900 deaths in the U.S. in 2008
• Cervical cancer has substantial mortality in resource-poor areas; worldwide, there are an estimated 490,000 cases and 270,000 deaths each year
• Two vaccines are in current use - Cervarix and Gardasil, which prevent infection with the HPV types (16 and 18) that cause 70% of cervical cancer
  
  • It is expected that wide spread use of these vaccines will reduce HPV-associated cancer
  • The vaccine consists “virus-like” particles that are made either in insect cells or yeast

Question 8

What is HTLV, and how is it transmitted?

Answer 8

• HTLV-1 is important in a variety of diseases including HTLV-1-associated myelopathy and cancer
• Between one in twenty and one in twenty-five infected individuals may develop cancer as a result of being infected with HTLV-1
• It was the first identified human retrovirus – HIV was identified shortly after HTLV-1
  
  • Infection with HTLV-1, like infection with other retroviruses, probably occurs for life and can be inferred when antibodies against HTLV-1 are detected in the serum
• HTLV-1 has an interesting geographical distribution pattern with a virtually exclusive concentration in southwestern Japan, the Caribbean islands, regions of South America, and tropical Africa
• There are a number of modes of transmission
  
  • HTLV-infected T cells readily pass from mother to child in breast milk
    
    • The risk of HTLV-1 transmission reaches 20% and is affected by the duration of breastfeeding, the proviral load, and the quantity of maternal antibodies
  • Intrauterine infection is less common, about 5%
  • Increased exposure and increased proviral load increase the risk of sexual transmission of both HTLV-1
  • As would be expected, transfusion, transplantation, and intravenous drug use are modes of HTLV-1 transmission
• The risk of seroconversion due to contaminated blood transfusion has been reported to be 40%-60% and increases in immunosuppressed recipients
  
  • Transmission of the virus via transfusion has virtually been eliminated since the implementation of viral screening of donated blood in 1986
  • Transmission today is mostly confined to the mother-to-infant and sexual routes
• Carriers of the virus are readily identified by screening for the anti-HTLV-1 antibodies and the most effective measure for the prevention of mother-to-infant transmission is to not breast feed

Question 9

What cancers arise from HTLV, and what is the mechanism?

Answer 9

• The cancer associated with HTLV-1 infection, Adult T-cell leukemia/lymphoma (ATL), overall is a fairly rare cancer of T-cells
  
  • The time between infection and onset of cancer can be quite variable – ranging from 40 to 60 years after infection
• The cancer is thought to be due to the pro-oncogenic effect of viral DNA incorporated into host lymphocyte DNA
  
  • Chronic stimulation of the lymphocytes at the cytokine level may play a role in the development of the malignancy
  • The lymphoma ranges from a very indolent and slowly progressive type to a very aggressive and nearly uniformly lethal proliferative type
  • Standard chemotherapeutic approaches are used targeting cells and not the virus
  • The HTLV-1 Tax – a cellular activator is thought to play a key role in the development of cancer
  • As well as cancer, HTLV-1 infection is associated with a progressive demyelinating upper motor neuron disease known as HAM/TSP, an abbreviation for HTLV-1 associated myelopathy/Tropical Spastic Paraparesis
    
    • It is characterized by sensory and motor deficits, particularly of the lower extremities, incontinence and impotence
    • Less than 2% of infected individuals develop HAM/TSP, but can vary depending on the population studied

Question 10

What are the different types of HTLVs?

Answer 10

• Four HTLVs have been identified
  
  • HTLV-1 and HTLV-2 are both involved in actively spreading epidemics, affecting 15-20 million people worldwide
    
    • HTLV-1 is the more clinically significant of the two, as it has been proven to be the etiologic agent of multiple disorders
    • At least 500,000 of the individuals infected with HTLV-1 eventually develop an often rapidly fatal leukemia, while others will develop a debilitative myelopathy, and yet others will experience uveitis, infectious dermatitis, or other inflammatory disorders
    • HTLV-2 is associated with milder neurologic disorders and chronic pulmonary infections
  • The novel HTLV-3 and HTLV-4 have been isolated only in a few cases
    
    • no specific illnesses have yet been associated with these viruses
    • In the United States, HTLV-I/II seroprevalence rates among volunteer blood donors average 0.016 percent