Predisposing Factors for Cancer PDF

28 PREDISPOSING FACTORS FOR CANCER ILOs By the end of this lecture, students will be able to 1. Categorize predisposing factors to malignancy into hereditary and acquired 2. Delineate the impact of cellular interactions to radiation, chemical & biological carcinogenic agents to types of...

28 PREDISPOSING FACTORS FOR CANCER ILOs By the end of this lecture, students will be able to 1. Categorize predisposing factors to malignancy into hereditary and acquired 2. Delineate the impact of cellular interactions to radiation, chemical & biological carcinogenic agents to types of cancer Predisposing factors of cancer: These can be either hereditary or acquired. I. Hereditary factors include: 1. Age Most cancer occurs in individuals older than 55 due to accumulation of somatic mutations and decline in immune surveillance. However, certain cancers are particularly common in children. These malignancies are not typically carcinomas but rather leukemia, lymphoma, CNS tumors, and sarcomas. 2. Genetic factors: Approximately 95% of malignancies arise sporadically (i.e., do not have an apparent inherited familial basis). However, germline mutations that increase cancer risk—often in tumor suppressor genes—do occur. Hereditary Cancer: Only 5% to 10% of all cancers are hereditary. Hereditary cancers develop due to heritable mutations in specific genes. There is usually a recognizable pattern of cancer on one side of the family. There are several clues which suggest that there is hereditary cancer in a family include: - Age of diagnosis is usually younger than in sporadic forms of cancer (often younger than 50). - Multiple family members have the same or related types of cancer. - Cancer is more likely to develop in more than one site in the body. - Rare cancers may occur, for example, male breast cancer. Genetic testing using blood or saliva can help detect gene mutations that cause hereditary forms of cancer because they are inherited in the germ line and are therefore present in every cell in the body. Examples: - Hereditary breast and ovarian cancers originate from autosomal dominant inherited mutations in the TSGs: BRCA1 and/or BRCA2. It is characterized by earlier age of onset, bilaterality, and significantly increased risk of developing breast, ovarian, prostate and other types of cancer in other family members. - Hereditary Coloraectal Carcinoma (CRC) has two well-described forms: a. Familial adenomatous polyposis (FAP): caused by mutations in the APC gene. People with FAP develop hundreds to thousands of polyps in their colon, which is 100% precancerous and associated with a very high risk of developing CRC. People Page 1 of 4  with a first-degree relative (a parent, sibling, or child) with FAP have a 50% chance of having inherited the familial APC genetic mutation. b. Hereditary nonpolyposis colorectal cancer (Lynch Syndrome): which is caused by germline mutations in the DNA mismatch repair genes (eg: MLH1) and result in genomic instability and increased risk of colorectal cancer. - Li- Fraumeni syndrome: Multiple cancers due to mutations in TP53 gene. - Skin cancer: Xeroderma pigmentosum with inherited defects in genes responsible for DNA repair. II. Acquired Predisposing Conditions 1. Environmental Factors: Established environmental risk factors include the following: 1) Infectious agents are either directly or indirectly causal in 15% of cancers worldwide. 2) Smoking is implicated in oropharyngeal, laryngeal, esophageal, pancreatic, and bladder cancers and in 90% of lung cancer deaths. 3) Alcohol increases the risk of oropharyngeal malignancies and by causing alcoholic cirrhosis that contributes to hepatocellular carcinoma. 4) Dietary factors are associated with colorectal, prostate, and breast cancers. 5) Obesity is linked to 14% of cancer deaths in men and 20% of those in women. 6) Estrogen exposure, particularly if unopposed by progesterone, increases the risk of breast and endometrial cancer. Agents or Groups of Type of cancer Typical Use or Occurrence Agents Arsenic Lung and skin cancer Component of electrical and semiconductor devices. Benzene Acute myeloid leukemia Component of light oil Radon Lung carcinoma From decay of minerals containing uranium Vinyl chloride Hepatic angiosarcoma Refrigerant; adhesive for plastics 2. Chronic Inflammation: tissue injury will induce compensatory cell proliferation in an environment of genotoxic reactive oxygen species and inflammatory mediators that can promote cell survival in the face of genetic damage. When inflammation persists over years, cells with potentially oncogenic mutations can survive and expand. Pathological condition Associated neoplasm Etiological agent Asbestosis, silicosis Mesothelioma Asbestos fibers Lung cancer Silica particles Inflammatory bowel Colorectal cancer disease Pancreatitis Pancreatic carcinoma Alcoholism Chronic cholecystitis Gall bladder cancer Bile acids, bacteria, stones 3. Precursor Lesions: Defined as local morphologic changes that are associated with increased risk of malignant transformation, these include: Page 2 of 4  Metaplasia is defined as the replacement of one mature cell type with another mature cell type, often associated with tissue damage, repair, and regeneration. Unfortunately, the metaplastic epithelium is prone to malignant transformation. Examples: Barrett esophagus, gastroesophageal reflux damages the squamous epithelium of the esophagus, leading to its replacement by glandular (gastric or intestinal) epithelium better suited to an acidic environment that develop adenocarcinoma. Squamous metaplasia of the bronchial epithelium in chronic smokers, and in the uterine cervix epithelium in human papilloma virus infection, often leads to the development of lung and cervix squamous cell carcinoma respectively. Dysplasia means “disordered growth” with loss of cellular uniformity and architectural organization, and a loss of orderly differentiation. It can range from mild, moderate to severe. Dysplasia can occur adjacent to frank malignancy and in many cases antedates the development of cancer. However, dysplasia does not equate to malignancy, and do not necessarily progress to cancer. Removal of the inciting stimulus from dysplastic epithelium (e.g., chronic irritation) can result in reversion to complete normalcy. Carcinoma in situ \ intraepithelial neoplasia occurs when dysplastic changes are marked and involve the entire thickness of an epithelium, but the lesion does not penetrate the basement membrane, the lesion is considered a preinvasive neoplasm. This lesion can persist for years before it becomes invasive carcinoma. Examples; intraepithelial neoplasia of skin, breast, uterine cervix, and urinary bladder. Hyperplasia (e.g., endometrial hyperplasia due to prolonged unopposed estrogens) Certain benign neoplasms (e.g., colonic villous adenoma may progress to cancer in approximately half of cases). 4. Immunodeficiency States: Immune compromise—particularly related to deficits in T- cell immunity—increases the risk of malignancy, especially those caused by oncogenic viruses (e.g., lymphomas associated with Epstein-Barr virus [EBV]). Carcinogenic Agents and Their Cellular Interactions Environmental agents that cause genetic damage and induce neoplastic transformation include the following: Chemical carcinogens Radiant energy Oncogenic viruses and other microbes A. Steps Involved in Chemical Carcinogenesis Neoplastic transformation brought about by chemicals is broadly divided into two stages: Initiation refers to the induction of certain irreversible changes (mutations) in the genome. All initiating chemical carcinogens target DNA, RNA, and proteins, inflicting nonlethal damage that cannot be adequately repaired. Mutated cells can then pass on the DNA changes to daughter cells. Initiated cells are not transformed cells; they do not have growth autonomy or unique phenotypic characteristics. However, in contrast to normal cells, they give rise to tumors when appropriately stimulated by promoting agents. Initiators fall in two categories: Page 3 of 4  Direct-acting agents require no metabolic conversion to become carcinogenic (e.g., many alkylating agents used for chemotherapy). Indirect-acting agents require metabolic conversion; examples of such indirect-acting agents are polycyclic hydrocarbons and benzo[a]pyrene. Promotion refers to the process of tumor induction in previously initiated cells. This occurs by enhancing the proliferation of initiated cells. The effect of promoters is relatively short- lived and reversible; promoters do not affect DNA and are nontumorigenic by themselves. Promotors include: Various drugs, phenols, and phorbol esters. Unopposed estrogenic stimulation of endometrium and breast. Chronic inflammatory processes associated with ongoing tissue repair (e.g., chronic hepatitis and inflammatory bowel disease). B. Radiation Carcinogenesis: Radiant energy, in the form of UV rays or ionizing radiation, is carcinogenic. o Ultraviolet Rays: Sun-derived UV radiation, especially UVB, can cause skin cancer, particularly in fair-skinned people. o Ionizing Radiation: electromagnetic (e.g., x-rays) and particulate (e.g., α and β particles or neutrons) sources are all carcinogenic by inducing DNA mutations; either directly or indirectly by the generation of free radicals from water or oxygen. Radiation-induced neoplasms are mainly myeloid leukemias, followed by thyroid cancer in children. C. Microbial Carcinogenesis 1. Viruses: a. Oncogenic RNA Viruses: Human T-lymphotropic virus 1 (HTLV-1) is a retrovirus causing a T-cell leukemia and/or lymphoma that is endemic in Japan. b. Oncogenic DNA Viruses: Oncogenic DNA viruses integrate into the host cell genome forming a stable association. Human Papillomavirus: Cervical squamous cell cancers contain HPV types 16 or 18 in more than 90% of cases. Epstein-Barr Virus: It infects B cells and oropharyngeal epithelium. EBV is associated with multiple human cancers: o Lymphoma: particularly Burkitt lymphoma and Hodgkin lymphoma. o Nasopharyngeal carcinoma 2. Hepatitis B and C Viruses: 70% - 85% of hepatocellular carcinomas are due to hepatitis B virus (HBV) or hepatitis C virus (HCV) infections. 3. Helicobacter Pylori: Infection can lead to gastric carcinoma or gastric lymphomas. References: 1. Kumar, Abbas, Aster. Robbins Basic Pathology, 10th ed. Elsevier. 2. Mitchell, Kumar, Abbas, Aster. Pocket Companion to Robbins and Cotran Pathologic Basis of Disease, 9th ed. Elsevier. Page 4 of 4