Infections as Hidden Drivers of Cancer

It is estimated that infections are responsible for 12 to 15% of the global cancer burden. These infections can trigger changes in the cells, leading to a condition known as dysplasia (precancerous cells). If left untreated, these cells may become cancerous over time, allowing them to grow and spread into surrounding tissues.

Helicobacter pylori (H. pylori)

Approximately half of the world’s population is infected with H. pylori, with higher prevalence in developing countries, although most do not exhibit any symptoms. H. pylori can spread through direct contact with saliva, vomit and faecal matter from an infected person, or by consuming contaminated food or water. Most infections occur during childhood and can last a lifetime unless treated, suggesting that the host’s own immune system is not effective in clearing this infection. H. pylori can cause chronic irritation, swelling and inflammation of the inner lining of the stomach (gastritis) and stomach ulcers, which can promote cancer. The bacteria also produce toxins, which can cause mutations in the DNA of stomach cells. In individuals infected with H. pylori, around 10% will develop peptic ulcer disease, 1 to 3% will develop gastric cancer, and less than 0.1% will develop mucosa-associated lymphoid tissue (MALT), a rare type of non-Hodgkin lymphoma. Infection with H. pylori is the strongest known risk factor for gastric cancer, and it is now considered the most common etiological agent of infection-associated cancers. Routine testing for H. pylori, which can be done by blood test, breath test or stool test, but is usually not recommended for general population unless the individual is exhibiting symptoms (such as stomach pain, bloating, nausea or vomiting), or with a history of peptic ulcer disease. H. pylori infection can be treated using a combination of antibiotics and medicines to help reduce acid in the stomach, which can cure the infection in 80 to 90% of people. Good personal hygiene, having clean drinking water and properly cooked food can help to prevent H. pylori infection.

Human Papillomavirus (HPV)

Persistent infection with HPV, a sexually transmitted disease, accounts for up to 95% of cervical cancer cases. Among the more than 200 types of HPVs, high-risk HPV 16 and 18 are responsible for 70% of HPV-infected cervical cancers, and HPV 31, 33, 45, 52 and 58 accounts for the additional 10 to 20% cases. Besides cervical cancer, HPV infection is also associated with other cancers such as head and neck, anal, penile, vaginal and vulvar cancers. Most individuals will be infected with HPV at some point in their lives, although the majority of these infections resolve naturally without symptoms. Following infection, HPV-derived E6 and E7 oncoproteins inactivate the tumor suppressor p53 and pRb, respectively, triggering growth and proliferation of abnormal cells. In some cases, HPV can also integrate its genome into the host’s genome, resulting in sustained expression of E6 and E7 oncoproteins, amplification of oncogenes, chromosomal rearrangements, and chromosomal instability. HPV vaccination (Cervarix, Cecolin, Walrinvax, Cervavac, Gardasil, and Gardasil-9) is a highly effective intervention measure to protect against HPV infection. Since it usually takes around 10 to 20 years following HPV infection to progress into cancer, routine screening can help to detect early signs of cancer, when it is easier to treat.

Hepatitis B and C (HBV and HCV)

Hepatocellular carcinoma (HCC) is the most common form of liver cancer, accounting for up to 90% of cases. Around 80% of HCC is due to infection with HBV and HCV, with Asia Pacific region having the highest rates of HBV and HCV infections in the world. Both viruses can be transmitted through infected blood, needle sharing, and contaminated equipment during invasive procedures. HBV is also more common than HCV to be spread through unprotected sex and during childbirth. These viruses can cause chronic inflammation in the liver, leading to cirrhosis (buildup of scar tissues in the liver), which increases the risk of developing HCC (greater risk of developing HCC if co-infected with both viruses). HBV can integrate its DNA into the host’s genome, resulting in mutations and genomic instability. Unlike HBV, HCV does not integrate into host’s genome, but it can still induce genomic instability. Infection with HBV is more likely to cause symptoms such as flu-like illness and jaundice, while infection with HCV is less likely to cause symptoms but more likely to cause chronic infection. Infections with these viruses also increase the risk of developing other cancers like bile duct cancer and non-Hodgkin lymphoma. The Hepatitis B vaccine can help to protect against HBV infection and is recommended for all children and adults, but there is no vaccine against HCV currently. A simple blood test can easily detect the presence of these viruses, and antiviral drugs can help to control the viral load of both viruses and lower the risk of developing HCC.

Epstein-Barr Virus (EBV)

EBV is a member of the herpesvirus family and is primarily transmitted through bodily fluids, especially saliva. Humans are the only known natural host of EBV, and it is estimated that over 90% of the world’s population are infected with EBV. EBV infection is life-long, and most people infected with EBV experienced mild flu-like symptoms or no symptoms. EBV primarily infects B cells, which plays a key role in the immune system, resulting in weakened immune systems. After primary infection, EBV can cause the production of memory B cells, which can harbor the virus in a latent manner by evading immune system detection. Because of this, dormant EBV can be reactivated under certain conditions such as during stress or when the immune system is compromised. Although not everyone infected with EBV will develop cancer, EBV infection is associated with nasopharyngeal carcinoma, Burkitt lymphoma, Hodgkin lymphoma and stomach cancer. EBV-related cancers are more common in South Asia, Middle East and Africa. Studies have shown that EBV promotes unregulated tumor growth by down-regulating tumor suppressor genes, inactivating DNA repair genes and inducing genomic instability. EBV infection can be detected through a blood-based antibody test. There is currently no vaccine to prevent EBV infection, nor treatment to cure EBV.

Human herpes virus 8 (HHV-8)

HHV-8, also known as Kaposi sarcoma-associated herpesvirus (KSHV), has been detected in nearly all tumors of patients diagnosed with Kaposi sarcoma. It is a rare cancer that affects the blood vessels and causes the proliferation of abnormal growth. The lesions often appear as purple, red, or brown spots on the skin. Other notable cancers associated with HHV-8 are primary effusion lymphoma (rare and aggressive type of lymphoma, occurs when HHV-8 infects B cells, leading to the uncontrolled proliferation of these cells), and multicentric Castleman disease (characterized by the overgrowth of lymphatic tissues, and if left untreated often develops into large B cell lymphoma). The virus primarily infects endothelial cells, which line the blood vessels. HHV-8 also produces oncoproteins that can mimic normal signaling pathways to promote uncontrolled cell proliferation and angiogenesis. Like EBV, this virus can also establish lifetime latency in B cells and endothelial cells and can be reactivated under certain conditions such as when the immune system becomes compromised. The likelihood of HHV-8 associated cancers is significantly higher among individuals living with HIV. Saliva is thought to be the most important conduit for HHV-8 transmission, which can be exchanged through activities like kissing or sharing of utensils. HHV-8 is thought to be endemic in sub-Saharan Africa, whereby prevalence can be >90% in some populations. Outside of this region, the prevalence is around 20 to 30% in the Mediterranean, and <10% in northern Europe, Asia and USA.

Human T-cell Leukemia Virus Type 1 (HTLV-1)

HTLV-1, also called human T-lymphotrophic virus, is linked to adult T-cell leukemia/lymphoma (ATLL). HTLV-1 infection can also cause a progressive disease of the nervous system called HTLV-1 associated myelopathy (HAM) or tropical spastic paraparesis (TSP). HTLV-1 primarily infects CD4+ T lymphocytes (which harbors 90% of the viral load), but it can also infect CD8+ T cells, B cells, monocytes and dendritic cells. The Tax oncoprotein produced by HTLV-1 is the primary driver of cancer development following infection. Tax oncoprotein interacts with host cellular proteins to regulate viral gene expression and promote aberrant activation of signaling pathways to drive clonal proliferation and survival of T-cells bearing the HTLV-1 provirus. HTLV-1 infection is predominantly found in specific geographic regions, including southern Japan, sub-Saharan Africa, the Caribbean, parts of South America (notably Brazil, Colombia, Chile, and Peru), certain areas of the Middle East (such as Iran), and Australia. Although most people infected with HTLV-1 remain asymptomatic, 2 to 5% of infected individuals develop ATLL 20 to 60 years after infection. It is spread through infected semen, vaginal fluids, infected blood, needle sharing and breast milk. There is currently no vaccine and specific treatment for HTLV-1 infection, although treatment is available to manage its associated conditions.

Human Immunodeficiency Virus (HIV)

Although HIV infection does not cause cancer directly, it impairs the immune system and increases susceptibility to cancers, particularly those attributable to other infections such as cervical cancer, Kaposi sarcoma and non-Hodgkin lymphoma. Viruses like HPV, HBV and HCV are also more likely to infect people living with HIV due to suppressed immune system. HIV can be transmitted through semen, vaginal fluids, anal mucus, infected blood, needle sharing and breast milk. While there is no cure for HIV infection, antiretroviral therapy can help to control the viral load and maintain a good immune system. There is currently no vaccine to protect against HIV infection. The main infectious agents contributing to the global cancer burden are H. pylori, HPV, HBV, and HCV, which together account for 90% of all infection-attributable cancers worldwide. Persistent infection by these agents can cause chronic inflammation, introduce mutations or induce genomic instability, leading to increased risk of developing site-specific diseases. Although not everyone infected with these infectious agents will develop cancer, preventive measures such as vaccination, regular screening, practicing safe sex, adopting good personal hygiene and healthy lifestyle, ensuring clean water and properly cooked food, can help to reduce the risk of developing cancers associated with infections.