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Genes and the Environment

Genes and the Environment. Viruses and Cancer. Environmental Exposure and Cancer. Carcinogenesis. What Causes Cancer?. Carcinogens  Age  genetic make up  immune system  diet  day-to-day environment  Viruses. Age. Diet. Factors in Carcinogenesis. Chromosomes/DNA.

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Genes and the Environment

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  1. Genes and the Environment Viruses and Cancer. Environmental Exposure and Cancer.

  2. Carcinogenesis

  3. What Causes Cancer? • Carcinogens  • Age  • genetic make up  • immune system  • diet  • day-to-day environment  • Viruses

  4. Age

  5. Diet

  6. Factors in Carcinogenesis Chromosomes/DNA

  7. In addition to chemicals and radiation, a few viruses also can trigger the development of cancer. In general, viruses are small infectious agents that cannot reproduce on their own, but instead enter into living cells and cause the infected cell to produce more copies of the virus. Like cells, viruses store their genetic instructions in large molecules called nucleic acids. In the case of cancer viruses, some of the viral genetic information carried in these nucleic acids is inserted into the chromosomes of the infected cell, and this causes the cell to become malignant.

  8. Viruses Viruses contribute to development of some cancers.  Typically, the virus can cause genetic changes in cells that make them more likely to become transformed. These cancers and viruses are linked • Cervical cancer and the genital wart virus, HPV • Primary liver cancer and the Hepatitis B virus  • T cell leukaemia in adults and the Human T cell leukaemia virus

  9. HTLV-1 • naturally infects CD4+ T lymphocytes and can be transmitted between close contacts through blood transfer or from mother to infant through cells in breast milk. • In most cases the infection is harmless. However, as many as 1 in 20 infected individuals eventually develop a type of adult T cell leukaemia in which every tumour cell carries a clonally integrated HTLV1 provirus. • HTLV1 differs from the standard 'chronically oncogenic' and 'acutely oncogenic' retroviruses in its mechanism of action; • it appears to drive cell growth through expression of a particular viral protein, Tax, in latently-infected cells

  10. HTLV retrovirus and adult T-cell leukaemia

  11. Mode of action • Tax can transactivate expression of a number of key cellular genes that enhance cell growth. • The best examples are the genes encoding • interleukin 2 (a T cell growth factor) and • the interleukin 2 receptor (a molecule that allows cells to respond to the growth factor). • As a consequence, the infected cells not only make their own growth signals, but also respond to them

  12. Mode of action • HTLV1 induces a weak growth transformation of T cells in the laboratory but, in the body, is probably never sufficiently strong to induce T cell leukaemia on its own. • BUT, a virally infected cell in which growth controls have even partly broken down, is more susceptible to further genetic accidents. • During persistent infection a gradual build-up of HTLV1-positive T cells which have accumulated additional genetic changes may occur. • Eventually this can lead to selection and outgrowth of a fully malignant, HTLV1-positive clone • At this stage malignant cell growth can occur in the absence of tax gene expression.

  13. Epstein Barr Virus • Epstein-Barr virus (EBV), also called Human herpesvirus 4 (HHV-4), is a virus of the herpes family (which includes Herpes simplex virus and Cytomegalovirus), • one of the most common viruses in humans. • Most people become infected with EBV, • often asymptomatic • but commonly causes infectious mononucleosis. • It is named after Michael Epstein and Yvonne Barr, who together with Bert Achong discovered the virus in 1964.

  14. On infecting the B-lymphocyte, the linear virus genome circularises and the virus subsequently persists within the cell as an episome. • The virus can execute several distinct programmes of virally-encoded gene expression • broadly categorised as being lytic cycle or latent cycle. • The lytic cycle or productive infection results in staged expression of a host of viral proteins with the ultimate objective of producing infectious virions. Formally, this phase of infection does not inevitably lead to lysis of the host cell as EBV virions are produced by budding from the infected cell. • The latent cycle programmes are those that do not result in production of virions.

  15. EBV-associated malignancies • The strongest evidence linking EBV and cancer formation is found in Burkitt's lymphoma and Nasopharyngeal carcinoma

  16. Burkitts Lymphoma • a type of Non-Hodgkin's lymphoma • most common in equatorial Africa • co-existent with the presence of malaria. • Malaria infection causes reduced immune surveillance of EBV immortalised B cells, so allowing their proliferation. This proliferation increases the chance of a mutation to occur. Repeated mutations can lead to the B cells escaping the body's cell-cycle control, allowing the cells to proliferate unchecked, resulting in the formation of Burkitt's lymphoma. Burkitt's lymphoma commonly affects the jaw bone, forming a huge tumour mass. It responds quickly to chemotherapy treatment, namely cyclophosphamide, but recurrence is common. • Other B cell lymphomas arise in immunocompromised patients such as those with AIDS or who have undergone organ transplantation with associated immunosuppression. • Smooth muscle tumours are also associated with the virus.

  17. Nasopharyngeal carcinoma • found in the upper respiratory tract, most commonly in the nasopharynx, and is linked to the EBV virus. • It is found predominantly in Southern China and Africa, due to both genetic and environmental factors. It is much more common in people of Chinese ancestry (genetic), but is also linked to the Chinese diet of a high amount of smoked fish, which contain nitrosamines, well known carcinogens (environmental).

  18. Kaposi's sarcoma • form of skin cancer that can involve internal organs. It most often is found in patients with acquired immunodeficiency syndrome (AIDS), and can be fatal.

  19. K.S. • Kaposi's sarcoma (KS) was once a very rare form of cancer, primarily affecting elderly men of Mediterranean and eastern European background (tumours on lower legs), until the 1980s, when it began to appear among AIDS patients. • AIDS-related KS, emerged as one of the first illnesses observed among those with AIDS. Unlike classic KS, AIDS-related KS tumours generally appear on the upper body, including the head, neck, and back. The tumours also can appear on the soft palate and gum areas of the mouth, and in more advanced cases, they can be found in the stomach and intestines, the lymph nodes, and the lungs.

  20. Kaposi Sarcoma and HHV8 • Studies in 2000 showed that HHV-8 was the culprit behind KS. • It does not work alone. • In combination with a patient's altered response to cytokines (regulatory proteins produced by the immune system) and the HIV-1 transactivating protein Tat which promotes the growth of endothelial cells, HHV-8 can then encode interleukin 6 viral proteins, specific cytokines that stimulate cell growth in the skin. • This becomes KS.

  21. HHV-8 • HHV-8 destroys the immune system further by directing a cell to remove the major histocompatibility complex (MHC-1) proteins that protect it from invasion. • These proteins are then transferred to the interior of the cell and are destroyed. • This leaves the cell unguarded and vulnerable to invaders which would normally be targeted for attack by the immune system.

  22. The natural history of HPV infection and cervical cancer

  23. Cervical Screening

  24. Genomic Map of HPV (von Knebel Doberitz/European Journal of Cancer 2002; 38: 2229-2242).

  25. The interacting worlds of HPV and p16

  26. The Hepatitis B Virus (HBV) • HBV is a mostly double-stranded DNA virus in the Hepadnaviridae family. • HBV causes hepatitis in human. • The HBV genome has four genes: pol, env, pre-core and X that respectively encode the viral DNA-polymerase, envelope protein, pre-core protein (which is processed to viral capsid) and protein X. • The function of protein X is not clear but it may be involved in the activation of host cell genes and the development of cancer.

  27. Consequences of HBV Infection • HBV causes acute and chronic hepatitis. • The chances of becoming chronically infected depends upon age. • About 90% of infected neonates and 50% of infected young children will become chronically infected. • In contrast, only about 5% to 10% of immunocompetent adults infected with HBV develop chronic hepatitis B.

  28. Hepatocellular carcinoma • cancer that arises from hepatocytes, the major cell type of the liver. • Hepatocellular carcinoma is one of the major cancer killers. • It affects patients with chronic liver disease who have established cirrhosis, and currently is the most frequent cause of death in these patients. • The main risk factors for its development are hepatitis B and C virus infection, alcoholism and aflatoxin intake.

  29. integrated HBV can generate chromosomal instability • it has been suggested that viral DNA sequences encompassing the encapsidation signal may exhibit intrinsic recombinogenic activity via binding to a putative ‘recombinogenic’ cellular protein

  30. Genes and the Environment –Thyroid Disease

  31. The thyroid gland is a small gland located at the front and sides of the neck. • It is made up of right and left lobes connected by a bridge called the isthmus and weighs between 20 and 30 grams. • It is slightly heavier in females and becomes enlarged during menstruation and pregnancy.

  32. The thyroid gland produces three hormones called thyroxine (T4), tri-iodothronine (T3) and calcitonin. These hormones help to regulate the body's metabolism.

  33. Iodine is essential for the production of the thyroid hormones. • Good sources of iodine include fish such as cod, sea bass and haddock. • Dairy products and plants grown in soil that is rich in iodine are also good sources.

  34. The thyroid participates in these processes by producing thyroid hormones, principally thyroxine (T4) and triiodothyronine (T3). • These hormones regulate the rate of metabolism and affect the growth and rate of function of many other systems in the body. • Iodine is an essential component of both T3 and T4. • The thyroid also produces the hormone calcitonin, which plays a role in calcium homeostasis.

  35. Physiology • The primary function of the thyroid is production of the hormones thyroxine (T4), triiodothyronine (T3), and calcitonin. • Up to 80% of the T4 is converted to T3 by peripheral organs such as the liver, kidney and spleen. • T3 is about ten times more active than T4.

  36. The function of the thyroid gland is to take iodine, found in many foods, and convert it into thyroid hormones:thyroxine (T4) and triiodothyronine (T3). • Thyroid cells are the only cells in the body which can absorb iodine. • These cells combine iodine and the amino acid tyrosine to make T3 and T4.

  37. T3 and T4 are then released into the blood stream and are transported throughout the body where they control metabolism (conversion of oxygen and calories to energy). • Every cell in the body depends upon thyroid hormones for regulation of their metabolism. • The normal thyroid gland produces about 80% T4 and about 20% T3, however, T3 possesses about four times the hormone "strength" as T4.

  38. The thyroid gland is under the control of the pituitary gland, a small gland at the base of the brain. • When the level of thyroid hormones (T3 & T4) drops too low, the pituitary gland produces Thyroid Stimulating Hormone (TSH) which stimulates the thyroid gland to produce more hormones. • Under the influence of TSH, the thyroid will manufacture and secrete T3 and T4 thereby raising their blood levels.

  39. The thyroid gland is invested by a thin capsule of connective tissue, which projects into its substance and imperfectly divides it into masses of irregular form and size. • Cut surface reveals a number of closed vesicles, containing a yellow fluid, and separated from each other by intermediate connective tissue

  40. Significance of iodine • In areas of the world where iodine (essential for the production of thyroxine, which contains four iodine atoms) is lacking in the diet, the thyroid gland can be considerably enlarged, resulting in the swollen necks of endemic goitre.

  41. Significance of iodine • Because of the thyroid's selective uptake and concentration of what is a fairly rare element, it is sensitive to the effects of various radioactive isotopes of iodine produced by nuclear fission. • In the event of large accidental releases of such material into the environment, the uptake of radioactive iodine isotopes by the thyroid can, in theory, be blocked by saturating the uptake mechanism with a large surplus of non-radioactive iodine, taken in the form of potassium iodide tablets.

  42. Significance of iodine • While biological researchers making compounds labelled with iodine isotopes do this, in the wider world such preventive measures are usually not stockpiled before an accident, nor are they distributed adequately afterward. • One consequence of the Chernobyl disaster was an increase in thyroid cancers in children in the years following the accident.

  43. Chernobyl • On April 26, 1986, the fourth reactor of the Chernobyl Nuclear Power Plant, exploded at 01:23 AM local time. All permanent residents of Chernobyl and Zone of alienation were evacuated because radiation levels in the area had become unsafe.

  44. Chernobyl

  45. Chernobyl

  46. Chernobyl

  47. Identifying molecular mechanisms that revealunderlying pathobiology in Thyroid Neoplasia

  48. Background • Thyroid Cancer • most frequently occurring endocrine malignancy, • sub-divided into a number of diagnostic /morphological categories. • Papillary thyroid carcinoma (PTC) • Most common thyroid malignancy • Ireland<100 cases/yr, U.S.~24,000 cases/yr • Incidence on the rise - global estimate 0.5 million new cases this year • Fastest growing cancer in women worldwide

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