Neoplasia 3 PDF

NEOPLASIA III DR. NADA HAMZA SHAREEF Learning objectives: -Epidemiology of cancer. -Molecular Basis of Cancer. -The genes changes which occur in neoplasia. -The inheritance of certain tumors in families. -Stages in carcinogenesis. -Geographical variations in the incidence of malignant tumor. -Env...

NEOPLASIA III DR. NADA HAMZA SHAREEF Learning objectives: -Epidemiology of cancer. -Molecular Basis of Cancer. -The genes changes which occur in neoplasia. -The inheritance of certain tumors in families. -Stages in carcinogenesis. -Geographical variations in the incidence of malignant tumor. -Environmental factors and its effects. EPIDEMIOLOGY OF CANCER : Cancer epidemiology provides tools and methods to understand the cancer problem in any given population from the local level up to global level Cancer epidemiology can help us to know about the origin of cancer , identify and develop improved treatments. Dietary Western processed world Colon Cigarette Lung meat low fiber cancer smoking cancer content Cancer epidemiology information uses to applies a plan to control cancer and prevention guide by screening and early detection programs.  - Geographic and environmental factors - Those give us ideas about that environmental factors are the predominant cause of the most common sporadic cancers ex: Breast cancer – Death rates 4-5x higher in US and Europe than in Japan Stomach cancer – Death rates 7x higher in Japan than in the US Hepatocellular carcinoma – Uncommon in US, one of the most common and lethal cancers in some African populations. - Most geographic patterns related to environmental exposures - Age Frequency of cancer increases with age with peak between ages of 55 and 75 Increased accumulation of somatic mutations - Heredity 5-10% of cancers - Acquired preneoplastic disorders Dysplasia, colonic adenoma-  Environmental influences causes of cancer can be racial (possibly hereditary), influences obtained by epidemiologic studies cultural influences Molecular Basis of Cancer Genetic origins of cancer is a complex matter, but certain “genomic basis ” have emerged that are likely relevant to every cancer. Nonlethal genetic damage lies at the heart of carcinogenesis. The initial damage (or mutation) may be caused by environmental exposures(as virus or chemicals ), may be inherited in the germline, or may be spontaneous. A tumor is formed by the clonal expansion of a single precursor cell that Under go genetic damage (i.e., tumors are clonal). Alterations in DNA are heritable, being passed to daughter cells, so all tumor cells share the same set of mutations. As occur in point mutations or chromosomal translocations.  Four classes of normal regulatory genes are the principle targets of cancer causing mutations : Growth promoting proto-oncogenes Growth-inhibiting tumor suppressor genes Genes that regulate programmed cell death (apoptosis) Genes involved in DNA repair Mutations that activate proto-oncogenes generally cause an increase in normal functions of the encoded gene product, or even completely new function on the affected gene product that is oncogenic. Because these mutations cause a “gain-of-function,” despite the presence of a normal copy of the same gene. i.e. act in a dominant fashion. Mutations that affect tumor suppressor genes : cause a “loss of-function,” and in most instances both alleles must be damaged before transformation can occur. So this gene behave in a recessive fashion. Apoptosis-regulating genes : Abnormalities in those genes result in less death and, therefore, enhanced survival of the cells. These abnormalities include gain of-function mutations in genes whose products suppress apoptosis and loss-of-function mutations in genes whose products promote cell death. Carcinogenesis results from the accumulation of complementary mutations in a stepwise fashion over time.  Normal Proto-oncogenes + Cell growth and Tumor suppressor genes - proliferation Cancer Mutated or “activated” ++ oncogenes Malignant transformation Loss or mutation of Tumor suppressor genes 10 accumulation of complementary mutations Genes involved in DNA repair The Genes Changes which occur in Neoplasia ❖ Oncogenes : Genes that promote autonomous cell growth in cancer cells are called oncogenes,and their unmutated cellular counterparts are called proto-oncogenes. Oncogenes encode proteins called oncoproteins that have the ability to promote cell growth in the absence of normal growth-promoting signals. Oncoproteins resemble the normal products of proto-oncogenes but bear mutations that are often inactivate internal regulatory elements; consequently, Cells expressing oncoproteins are thus freed from the normal checkpoints in cell cycle and controls that limit growth, and as a result proliferate excessively. ❖ Tumor suppressor genes are genes that normally prevent uncontrolled growth and, when mutated or lost from a cell, uncontrolled growth lead to cancer. ❖ DNA repair genes These are genes that ensure each strand of genetic information is accurately copied during cell division of the cell cycle. Mutations in DNA repair genes lead to an increase in the frequency of mutations in other genes, such as proto-oncogenes and tumor suppressor genes. Molecular Defects will be in form of : Gene amplification: increases the expression of oncogenes. Deletions: missing base pairs frequently affect tumor suppressor genes Most (and possibly all) human cancers have molecular defects that affect one or more components of these pathways: Growth Factors: Normal cells require stimulation by growth factors to proliferate. Most soluble growth factors are made by one cell type and act on a neighboring cell to stimulate proliferation (paracrine action). Some cancer cells, however, acquire the ability to synthesize the same growth factors to which they are responsive, creating an autocrine loop. In tumors in which an autocrine loop is an important pathogenic element, the growth factor gene itself is usually not altered or mutated. More commonly, signals transduced by other oncoproteins cause overexpression and increased secretion of growth factors , thereby initiating and amplifying the autocrine loop. Growth Factor Receptors: A large number of oncogenes encode growth factor receptors, of which receptor tyrosine kinases are the most important in cancer.. Receptor tyrosine kinases can be activated in tumors by multiple mechanisms, including point mutations, gene rearrangements, and gene amplifications. : examples : ERBB1 encodes the epidermal growth factor receptor (EGFR) which is involved by point mutations in a subset of lung adenocarcinomas. These mutations result in activation of the EGFR tyrosine kinase. ERBB2 (HER2). This gene is amplified in certain breast carcinomas, leading to overexpression of the HER2 receptor and constitutive tyrosine kinase activity. Gene rearrangements: Such as ALK. For example, a deletion on chromosome 5 fuses part of the ALK gene with part of another gene called EML4(fusion gene) in a subset of lung Why these are important to us to understand those mutations ?? For example, breast cancers with ERBB2 amplification and overexpression of HER2 generally respond to treatment with antibodies or drugs that block HER2 activity (Herceptin),These inhibitors not only cause the cessation of tumor growth but also induce apoptosis and tumor regression, reflecting the ability of receptor tyrosine kinase signaling to augment cell survival as well as proliferation. RAS Mutations. Point mutations of RAS family genes constitute the most common type of abnormality involving proto-oncogenes in human tumors(15% to 20% ). For example, 90% of pancreatic adenocarcinomas and cholangiocarcinomas, about 50% of colon, endometrial, and thyroid cancers and about 30% of lung adenocarcinomas and myeloid leukemias. The RAS genes, of which there are three in humans (HRAS, KRAS, NRAS). RAS most commonly is activated by point mutations RAS is trapped in its active state and the cell is forced into a continuously proliferating state. Transcription Factors: Proteins that help turn specific genes on or of by binding to near by DNA ex: MYC proto- oncogenes. MYC Oncogene: ❑ MYC primarily functions by activating the transcription of other genes ❑ Amplification (over expression) in neuroblastoma, breast cancer. ❑ Translocation 8,14 in Burkitt’s lymphoma. Insensitivity to Growth Inhibitory Signals : Tumor Suppressor Genes Whereas oncogenes encode proteins that promote cell growth, the products of tumor suppressor genes apply brakes to cell proliferation. Mutation of such genes renders cells refractory to growth inhibition and mimics the growth- promoting effects of oncogenes. Retinoblastoma gene (RB) The function of the RB protein is to regulate the G1/S checkpoint (just before DNA replication ) located on chromosome 13. Retinoblastoma: a childhood tumor. 60% of retinoblastomas are sporadic, while the remaining ones are familial, it had inherited as an autosomal dominant trait (one intact RB gene is all that is needed for normal function). To account for the sporadic and familial occurrence explained by two-hit hypothesis, which means : Two mutations (hits) are required to produce retinoblastoma; (Both of the normal alleles of the RB locus must be inactivated (hence the two hits) for the development of retinoblastoma ). In familial cases, children inherit one defective copy of the RB gene in the germ line; the other copy is normal In the sporadic form, both RB mutations in the tumor cells are acquired. TP53: Guardian of the Genome(i.e: With loss of normal p53 function, DNA damage goes unrepaired, mutations become fixed in dividing cells) Located on chromosome 17p.more than 70% of human cancers have a defect in this gene. ❑ Gene encodes a nuclear protein which binds to and modulates expression of genes important for DNA repair, cell division and cell death by apoptosis. Other Tumor Suppressor Genes. APC:. Adenomatous polyposis coli (APC) Gatekeeper of Colonic Neoplasia is a tumor suppressor gene that function by downregulating growth promoting signaling pathways. Germline loss-of-function mutations involving the APC are associated with familial adenomatous polyposis.. As with other tumor suppressor genes, both copies of the APC gene must be lost for an adenoma to arise. Then several additional mutations must occur for adenomas to progress to cancers. In addition to these hereditary forms of colon cancer, 70% to 80% of nonfamilial colorectal carcinomas and sporadic adenomas also show acquired defects involving both APC genes, So APC loss of function in the pathogenesis of colonic tumors. DNA REPAIR GENES These are genes that ensure each strand of genetic information is accurately copied during cell division of the cell cycle. Mutations in DNA repair genes lead to an increase in the frequency of mutations in other genes, such as proto-oncogenes and tumor suppressor genes. Their mutation will cause tumorigenesis.  Defects in DNA repair mechanisms(Inheritance ): Xeroderma Pigmentosum. Individuals with inherited disorder of DNA repair, xeroderma pigmentosum, are at increased risk for the development of cancers of the skin particularly following exposure to the UV light contained in sun rays.. Ataxia-telangiectasia the gene mutated in ataxiatelangiectasia, ATM, is important in recognizing and responding to DNA damage caused by ionizing radiation ,characterized by oculocutanous telangiectasia , chorea (involuntary movement ) with slurred speech and neuropathy with increase risk of leukemia and lymphoma. Familial Breast Cancer Mutations in two genes, BRCA1 and BRCA2, account for 25% of cases of familial breast cancer, (mutations in the BRCA2 gene increase the risk of breast cancer in both men and women ). Also higher risk of epithelial ovarian cancers, and men have a slightly higher risk of prostate cancer. Stages in Carcinogenesis Long period of time elapses between exposure to stimulus and the emergence of clinical cancer Initiation Promotion Progression  Initiation ❑ Can occur after a single exposure to chemical or physical carcinogen; ❑ Involves genetic mutation. ❑ Promotion ❑ It is a slow and gradual process; usually takes years ❑ hormones, local tissue responses, immune responses ❑ Progression: ❑ Requires continuous clonal proliferation of altered cells, Allows progressive growth to clinically detectable tumor. ❑ It is irreversible due to pronounced changes in the genome. Environmental(EXTRINSIC) Factors and itsEffect The incidence of cancer varies with age (at any age, but is mostly older adults), geographic factors, and genetic background. The geographic variation in cancer incidence results mostly from different environmental exposures. Environmental extrinsic factors implicated in carcinogenesis include infectious agents, smoking, alcohol, diet, obesity, reproductive history, and exposure to carcinogens. Cancer risk rises in certain tissues in the setting of increased cellular proliferation caused by chronic inflammation or hormonal stimulation, those changes in epithelial cell referred as precancerous lesion.  Radiation Radiant energy, in the form of the UV rays of sunlight or as ionizing radiation, is carcinogenic. Ultraviolet Rays Exposure to UV rays derived from the sun, particularly in fair-skinned individuals, is associated with an increased incidence of squamous cell carcinoma, basal cell carcinoma, and melanoma of the skin. Evidence – ❑ skin cancer in radiologists 1920s ❑ Unprotected miners exposed to ionizing radiation – 10 folds increase risk of lung cancer. ❑ Radiotherapy for head and neck increase the risk of thyroid carcinoma particularly in children. ❑ Hiroshima – early – leukemia and lymphoma.. Later-thyroid, breast, lung and colon cancer. ❑ Chernobyl-high cancer incidence in the surrounding areas. ❑ Intense intermittent exposure to UV light – malignant melanoma of skin. *Radiation causes a wide range of different types of damage to DNA. - Single and double stranded breaks. - Base damage Effect depend on quality of radiation and dose. - High dose ionizing radiation breaks DS DNA, translocations and less important point mutations. - Low dose (therapeutic dose) – genomic instability. DNA repair mechanisms important Incorrect repair of DNA damage–mutation Chemical carcinogens Chemicals carcinogen interact with DNA e.g. cause specific base damage. single stranded breaks. can be divided into direct and indirect : Indirect-Acting Carcinogens Are chemicals that require metabolic conversion to become active carcinogens (ultimate carcinogens ) Ex , Polycyclic hydrocarbons ❑ Created with burning of coal tar, plant, and animal material. ❑ benzopyrene and other carcinogens formed by hydroxylation during the burning of tobacco are implicated in the causation of lung and bladder cancer..  Aromatic amines B-naphthylamine was responsible for a 50-fold increased incidence of bladder cancers in heavily exposed workers in the aniline dye and rubber industries. Nitrosamines Conversion of dietary nitrates/nitrites to nitrosamines by gut bacteria lead to gastrointestinal cancer. Direct-Acting Agents Require no metabolic conversion to become carcinogenic like cyclophosphomide and chlorombucil.. They are typically weak carcinogens but are important because some of them are cancer chemotherapy drugs (e.g., alkylating agents) used in regimens that may cure certain types of cancer (e.g., Hodgkin lymphoma), only to evoke a subsequent, second form of cancer, usually leukemia. Microbial Carcinogenesis Oncogenic RNA Viruses Human T-Cell Leukemia Virus Type 1. HTLV-1 causes adult T-cell leukemia/lymphoma (ATLL). Oncogenic DNA Viruses HPV At least 70 genetically distinct types of HPV have been identified. Some types (e.g., 1, 2, 4, and 7) cause benign squamous papillomas (warts) in humans. In contrast, high-risk HPVs (e.g., types 16 and 18) have been implicated in the genesis of squamous cell carcinomas of the cervix, Epstein-Barr Virus. Has important role in the pathogenesis of several human tumors: the African form of Burkitt lymphoma , nasopharyngeal carcinoma. Hepatitis B and C Viruses It is estimated that 70% to 85% of hepatocellular carcinomas worldwide are caused by infection with hepatitis B virus (HBV) or hepatitis C virus (HCV ). Aflatoxins(produce by Aspergillus flavus fungi ) Aspergillus grows on improperly stored grains and nuts – liver cancer(Hepatocellular carcinoma). Schistosoma hematobium (parasite)– urinary bladder cancer. Helicobacter (bacteria ) – gastric cancer and lymphoma. Hormones – estrogens, combined menopausal hormone therapy (estrogen plus progestin), causing breast cancer, endometrial cancer. - androgens cause liver cancers. Occupations associated with the development of tumors: Agents or Groups of Agents type of cancers may develop Arsenic and arsenic compounds Lung carcinoma, skin carcinoma Asbestos Lung cancer and Mesothelioma Benzene AML Cadmium and cadmium compounds Prostate carcinoma Nickel compounds Lung and oropharyngeal carcinoma Radon and its decay products Lung carcinoma Vinyl chloride Hepatic carcinoma Predisposing conditions ❑ Ulcerative colitis – colorectal carcinoma. ❑ Liver cirrhosis – liver cancer. ❑ Adenoma of large intestine – adenocarcinoma. ❑ Hashimoto’s thyroiditis – Papillary thyroid carcinoma Acquired Preneoplastic Lesions A brief listing of some of the chief precursor lesions follows: Squamous metaplasia and dysplasia of the bronchial mucosa, seen in habitual smoker →→→ lung cancer Endometrial hyperplasia and dysplasia, because of unopposed estrogenic stimulation →→→ endometrial carcinoma Leukoplakia of the oral cavity, vulva, or penis, →→→ squamous cell carcinoma Villous adenomas of the colon, →→→ colorectal carcinoma “ Thank You