Lecture 2.Molecular Basis of Cancer I.pdf

Molecular Basis of Cancer I Instructors : Professor Amein Al-Ali email: [email protected] Department of Clinical Biochemistry Thursday, January 18, 2024 Learning objectives After participating successfully in this session and related activities, students should be able to • Understand the most...

Molecular Basis of Cancer I Instructors : Professor Amein Al-Ali email: [email protected] Department of Clinical Biochemistry Thursday, January 18, 2024 Learning objectives After participating successfully in this session and related activities, students should be able to • Understand the most important causes of cancer, and their relevance to prevention of cancer. Thursday, January 18, 2024 Presentation title DNA damage causes Cancer • Cancer develops due to damage to the cells DNA • DNA damage can be: ➢ Inherited (germ line errors) • Makes up 10% cancers • In inherited cases every cell in the body carries one copy of DNA with that genetic defect (germ-line mutations) Thursday, January 18, 2024 Presentation title DNA Damage Causes Cancer ➢ Acquired (somatic) errors• As a person gets older the number of DNA • • mutations increases therefore increased risk of cancer Acquired mutations in a cell may eventually lead to cancer in that tissue For somatic mutations, only the cancer cells carry the DNA mutation/error, not the normal cells Thursday, January 18, 2024 Presentation title Somatic Mutations are not Passed on to Offspring Fig 13.9 Lewin et al. Thursday, January 18, 2024 Presentation title Cancer: Causes Acquired DNA damage can be induced by the following environmental exposures ➢ ➢ ➢ ➢ ➢ ➢ ➢ ➢ Thursday, January 18, 2024 Radiation Viruses Bacteria Chemical carcinogenesis Age Diet UV light Other? Presentation title The Incidence of Cancer Increases with Age Fig 13.15 Lewin et al. Thursday, January 18, 2024 Presentation title Effects of Ionizing Radiation on Normal and Cancer Cells Normal Cancer Thursday, January 18, 2024 Presentation title DNA Damage Leads to Cancer • Obesity predisposes to some forms of cancer • Chronic inflammation predisposes to cancer • Chemicals, Carcinogens compounds or chemicals produce cancer • Spontaneous are that mutations arise because of chemical changes in nucleotides Thursday, January 18, 2024 Presentation title DNA Damage Leads to Cancer - chemicals Thousands of chemicals are present in food • “Natural” carcinogens in food may account for up to 80% of carcinogens that we are exposed to in our diet. meat preservatives, hydrazine (Mashrooms), Heterocyclic amines (Meat cooked well), Aflatoxins (nuts), High fat and low fiber diet predisposes to cancer • Chemical Carcinogens include tobacco smoke (benzopyrene),Organic dyes( acridine or ethedium bromide) Thursday, January 18, 2024 Presentation title Cells Susceptible to DNA Damage • Rapidly dividing cells are particularly susceptible to genetic damage and cancer • Examples of somatic cells that divide frequently such as bone marrow, gut cells, skin cells etc Thursday, January 18, 2024 Presentation title Cells Susceptible to DNA Damage • DNA repair enzymes correct these errors, however if there are: ➢ ➢ ➢ ➢ • Substantial mutations Loss of DNA repair enzymes Less time for the DNA repair mechanisms Accumulation of DNA mutations occurs Cancer cells tend to have a more rapid cell cycle and gradually accumulate more and more genetic damage Thursday, January 18, 2024 Presentation title Cells That are Dividing are More Susceptible to Genetic Damage Figure 17-14 : Dividing Cells are Especially Susceptible to Genetic Damage and Cancer Purves et al. Life The Science of Biology 7th Edition Thursday, January 18, 2024 Presentation title • Some Cancers are Caused by Viruses Substantial evidence that infectious agents such as viruses are causal agents in a variety of cancers • May account for 15% of cases of cancer • Viral infections that cause cancer are often “latent” ie present for a long time in the cell and may not always be clinically apparent • The virus genes persist in the host DNA in a subset of infected cells • Periodically the virus genes will replicate and will produce new virus particles Thursday, January 18, 2024 Presentation title 17-1 : Human Cancers Known to be Caused by Viruses CANCER ASSOCIATED VIRUS Liver Cancer nasopharyngeal cancer T cell leukemia Anogenital cancers Kaposi’s sarcoma Lymphoma Hepatitis B virus Epstein-Barr virus Human T cell lymphotropic Virus HTLV Papillomavirus Kaposi’s sarcoma herpes virus HIV virus Purves et al Life 7th Ed Thursday, January 18, 2024 Presentation title How Can A Virus Cause Cancer? • RNA virus or retrovirus (e.g. HIV virus) can transform a cell by altering critical genes that regulate cell growth • The virus gene can be inserted upstream of the gene or within the coding sequence of the gene leading to over expression of a protein, or expression of a more active protein e.g. HIV virus causes lymphoma • DNA tumor viruses activate the host cells DNA replication machinery e.g., papilloma virus causes carcinoma of the cervix Thursday, January 18, 2024 Presentation title Inherited Cancer Predisposition Syndromes • About 10% of all cancers result from inheritance of a mutated gene that predisposes the individual to cancer • it has been shown that some cancers appear to aggregate in families • Familial aggregation occurs in virtually every type of human cancer including breast, colon, sarcomas etc Thursday, January 18, 2024 Presentation title Inherited Cancer Predisposition Syndromes • Some familial aggregation is due to: Shared Exposure To Carcinogens ✓ Genetic Predisposition ✓ Combination Of Both ✓ • Person who has a parent or sibling who develops cancer at a young age has 2 times the risk of developing the same cancer Thursday, January 18, 2024 Presentation title Table 1. Selected human cancers associated with Mendelian syndromes Cancers Selected Syndromes Dominant Breast and/or Ovarian Cancers Breast/ovarian cancer syndrome Colon cancer Endocrine Tumours Melanoma Prostate cancer Renal cancer Retinoblastoma Wilms’ tumour Basal cell skin cancers Recessive Acute leukemia and non-Hodgkin’s lymphomas Skin cancers X-Linked Lymphomas Thursday, January 18, 2024 Li-Fraumeni syndrome Cowden syndrome Hereditary non-polyposis colon cancer Familian adenomatous polyposis Juvenile polyposis Peutz-Jeghers syndrome Multiple endocrine neoplasias Dysplastic nevus syndrome Hereditary prostate cancer von Hippel-Lindau syndrome Papillary renal carcinoma syndrome Hereditary retinoblastoma Hereditary Wilms’ tumour syndromes Nevoid basal cell carcinoma syndrome Ataxia telagiectasia Fanconi anemia Bloom syndrome Xeroderma pigmentosum X-linked lymphoproliferative syndrome Presentation title Features Suggestive of an Inherited Cancer Susceptibility Syndrome • • • • • • Several close or first degree relatives with a common cancer Several close or first degree relatives with related cancers i.e. breast and ovary Two members of the same family with the same rare cancer Early age of onset of cancer Bilateral cancers in paired organs Tumors in two different organs in one individual Thursday, January 18, 2024 Presentation title Cancer and Inherited Predisposition • • • As about 10% of all cancers appear to run in families this has important consequences: ✓ Routine screening for cancers ie breast and bowel cancer prone families ✓ Colon cancer family members may need regular colonoscopy ✓ Genetic counselling Treatment and prognosis may change (may need more aggressive treatment or different types of treatment) Identification of the molecular mechanisms of cancer formationdesign of potential novel therapies Thursday, January 18, 2024 Presentation title Genes that Cause Inherited Cancer Predisposition Syndromes • The identification of inherited cancer susceptibility genes is in early stages • Potent single gene defects that are highly predictive of cancer account for less than 10% of cases • However, in many cases the genetic predisposition must include the appropriate environmental stimulus •A defined dose of carcinogen may have different effects on the individual depending on their genetic make up, i.e. UV light exposure in people with different skin colour Thursday, January 18, 2024 Presentation title Cancer susceptibility genes • Familial susceptibility to cancer can occur as: ✓ Inherited cancer susceptibility for a single type of cancer e.g. Colon cancer ✓ Number of different types of cancer as part of a familial cancer predisposing syndrome e.g. Multiple endocrine neoplasias • In some instances genes implicated to play a role in familial cancer are also implicated in sporadic cancer e.g. colon cancers Thursday, January 18, 2024 Presentation title The identification of an individual at risk from a genetic predisposition to cancer must take into account the following: • Some cancers are common, ie 1 in 10 women get breast cancer • Penetrance is variable ie the percentage of individuals with a specific genetic defect who will get the disease may vary depending on the gene For example – some colon cancer syndromes – 100% - inherited breast cancer syndromes – 40-70% • This is important for cancer screening and family counselling Thursday, January 18, 2024 Presentation title Figure 1 : Nonpenetrance, anticipation, and phenocopies in dominant syndromes. Abbreviations: Br, Breast cancer; Ov, Ovarian cancer; Pr, Prostate cancer Reprinted from Clinical Cancer Genetics, 1998 (ISBN 0471-14655-2) by K. Offit with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc. Thursday, January 18, 2024 Presentation title Cancer: Genetic Events • Cancer in general apart from rare syndromes does not arise from a mutation or error in only one gene • Cancer arises from a series of cumulative genetic errors which result in a growth advantage • By the time a patient presents with cancer if we examine the DNA of the cancer there may be over 7 significant mutations in specific genes in the cancer cell DNA Thursday, January 18, 2024 Presentation title Figure 17-18 : Multiple Mutations Transform a Normal Colon Epithelial Cell into a Cancerous Cell Purves et al. Life The Science of Biology 7th Edition DCC- Deleted in Colorectal Carcinoma Thursday, January 18, 2024 Colon of FAP Coli Patient Compared To Normal Colon Thursday, January 18, 2024 Presentation title Breast Cancer: Family History • Up to 10% of breast cancer is due to a genetic predisposition Hereditary breast cancer genes include BRCA1 17q BRCA2 13q • Many families affected by breast cancer show an excess of ovarian, colon, prostatic and other cancers attributable to the same inherited mutation • Most women, due to an inherited genetic mutation, get breast cancer before the age of 65 Thursday, January 18, 2024 Presentation title Inherited Breast Cancer Syndromes • Life time risk for sporadic breast cancer in the community is 11% • Earlier age onset of inherited forms of breast cancer51% for BRCA1 and 28% for BRCA2 –by the age of 50 compared to general population • Life time risk of breast cancer- BRCA1 and BRCA2 83-88% by age of 70 • Life time risk of ovarian cancer in this group of patients with hereditary breast and ovarian cancer syndromes is 16-60% Thursday, January 18, 2024 Presentation title Features that Indicate Increased Likelihood of an Individual having BRCA Mutations • • • • • • Multiple cases of early onset breast cancer in the family Ovarian cancer (with a family history of breast or ovarian cancer) Breast and ovarian cancer in the same woman Bilateral breast cancer Ashkenazi Jewish heritage Male breast cancer Thursday, January 18, 2024 Presentation title Requirements for a Screening Test for a person at risk for a familial cancer syndrome • Prevention or early detection is the ultimate goal in the management of any patient with a familial cancer syndrome • Screening includes gene testing and looking for early evidence of the clinical phenotype ie. colonic polyps or breast lumps • Benefits of screening long term need to be weighed against cost both physical and emotional for the patient Thursday, January 18, 2024 Presentation title Testing and Screening Strategies for Breast Cancer Families • BRCA1 and BRCA2 mutations are thought to be the most common cause of autosomal dominant highly penetrant breast cancer susceptibility syndromes • Testing became available in 1996 Testing for mutations • The optimal testing strategy is to initiate testing on the youngest affected family member Thursday, January 18, 2024 Presentation title Testing for Mutations • Affected family members may not be alive to test. Proceed only with thorough counselling of the limitations and benefits of genetic testing • Genetic testing should result in early identification of at risk individuals and therefore increased detection and survival advantage for the patient • Unless there is a highly suggestive family history, cancer susceptibility testing is not considered appropriate for screening unaffected individuals (except specific ethnic groups where specific mutations are more common) Thursday, January 18, 2024 Presentation title Problems With Testing • • Only 50% of the family will have the mutation • • Mutations can occur in almost any position > 500 mutations have been reported and majority of mutations result in a truncated protein No simple test to screen for the specific mutation Thursday, January 18, 2024 Presentation title Problems with testing • Molecular screening to detect a mutation for the first time in an affected individual or family is very technically demanding- sequence gene or look for truncation mutants • Only positive test is informative i.e. detection of known or likely deleterious mutation • It is a common disease therefore there is the problem of phenocopies Thursday, January 18, 2024 Presentation title Carcinoma of the breast Karp 3rd Ed Thursday, January 18, 2024 Presentation title Objectives: You should now be able to understand the most important causes of cancer, and their relevance to prevention of cancer Content synopsis: • • • • • • cancer is a disease of DNA genetic errors may be inherited or acquired that predispose to cancer cancer increases with age correlating with increased DNA errors cancer results from the accumulation of multiple DNA errors/mutations genetic predisposition to cancer can be identified acquired DNA errors can cause cancer such as that induced by mutagens: UV sunlight, chemical carcinogens, and ionizing radiation and viruses Thursday, January 18, 2024 Presentation title