Epidemiology of Cancer PDF

 EPIDEMIOLOGY Epidemiology of Cancer Incidence: Increasing globally. WHO data (2012): 14.1 million new cases worldwide. Prediction for 2035: 24 million new cases Environmental Factors...

 EPIDEMIOLOGY Epidemiology of Cancer Incidence: Increasing globally. WHO data (2012): 14.1 million new cases worldwide. Prediction for 2035: 24 million new cases Environmental Factors and Cancer Environmental exposures are dominant risk factors for many cancers, making them potentially preventable. Geographic variations highlight differences in cancer types: Breast Cancer: Stomach Cancer: Liver Cancer: Death rates 4-5 times 7 times higher in Common in Africa higher in the U.S. and Japan than in but rare in the U.S. Europe than Japan. the U.S. Major environmental factors: Obesity linked to Prolonged estrogen exposure Infectious Responsible for 15% of Diet Reproductive increases breast and endometrial cancers globally. increased cancer risk. History cancer risk. Agents 90% of lung cancer deaths attributed to Independent risk for oropharynx, liver, and Smoking smoking; associated with cancers of the Alcohol esophagus cancers. Alcohol combined with mouth, esophagus, pancreas, and bladder. smoking increases risk of cancer in upper airways and upper digestive tract Age and Cancer Frequency increases with age (55-75 years) Childhood Cancer: Accounts for 10% of deaths under Causes: age 15 1. Accumulation of mutations. Common lethal types: Leukemias, CNS tumors, 2. Declining immune competence. lymphomas, Soft-tissue Familial Cancers Common cancers (breast, ovarian, pancreatic, colon) have familial forms. The transmission pattern of familial cancers is not clear Segregation analysis of large families usually reveals that predisposition to the tumors is dominant but multifactorial inheritance cannot be easily ruled out. Certain familial cancers can be linked to the inheritance of mutant genes Features of Familial Cancers: Familial cancers are not associated with specific marker phenotypes. E.g Tumors in Multiple or In contrast to the familial Early onset close bilateral adenomatous polyposis relatives tumors syndrome, familial colonic cancers do not arise in preexisting benign polyps. In general siblings have a Acquired Cancer relative risk between 2-3X. Predisposing Conditions Include: 1. Disorders 2. associated with Immunodeficiency chronic states inflammation 3. Precursor lesions Tumors arising in the context of chronic inflammation are mostly Examples carcinomas but also include Squamous metaplasia and dysplasia of bronchial mesothelioma of lymphoma. mucosa,seen in in habitual smokers—a risk factor for lung Immunodeficiency states mainly carcinoma predispose to virus-induced cancers Endometrial hyperplasia and dysplasia, seen in women including specific types of lymphoma with unopposed estrogenic stimulation—a risk factorfor and carcinoma and some sarcoma- endometrial carcinoma like lesions Leukoplakia of the oral cavity, vulva, and penis, which Molecular analyses have shown that may progress to squamous cell carcinoma precursor lesions often possess some Villous adenoma of the colon, associated with a high risk of the genetic lesions found in their for progression to colorectal carcinoma associated cancers Interactions Between Environmental andGenetic Factors Inherited trait versus Acquired factors  CANCER GENES Are genes that are recurrently affected by genetic aberrations in cancers presumably because they contribute directly to the malignant behavior of cancer cells Causative mutations that give rise to cancer genes: 1 may be acquired by the action of environmental agents as chemicals, radiation, or viruses 2 may occur spontaneously 3 may be inherited in the germ line Functional classes of cancer genes: Are genes that induce a transformed phenotype when expressed in cells by 1. Oncogenes promoting increased cell growth. Oncogenes are mutated or overexpressed versions of normal cellular genes, which are called proto-oncogenes. Most oncogenes encode transcription factors, factors that participate in pro-growth signaling pathways, or factors that enhance cell survival. Oncogenes are considered dominant genes because a mutation involving a single allele is sufficient to produce a pro-oncogenic effect They enhance cell survival of cells 2. Genes that Genes of this class protect against apoptosis are often overexpressed in cancer cells regulate apoptosis Genes that promote apoptosis tend to be underexpressed or functionally inactivated by mutations in cancer cells are genes that normally prevent uncontrolled growth and, when mutated or lost from 3. Tumor a Cell allow the transformed phenotype to develop. suppressor genes both normal alleles of tumor suppressor genes must be damaged for transformation to occur (recessive genes) Tumor suppressor genes can be placed into two general groups: 1. “Governors”that act as important brakes on cellular proliferation 2. “Guardians” that are responsible for sensing genomic damage Some guardian genes initiate “damage control response” that leads to the cessation of proliferation or, if the damage is too great to be repaired, may induce apoptosis GENETIC LESIONS IN CANCER The genetic changes found in cancers vary from point mutations involving single nucleotides to abnormalities large enough to produce gross changes in chromosome structure. In certain neoplasms, genetic abnormalities are non random and highly characteristic. Specific chromosomal abnormalities have been identified in most leukemias and lymphomas and in an increasing number of nonhematopoietic tumors Other tumors are characterized by particular point mutations.  Driver mutations Passenger mutations Driver mutations are mutations that alter Passenger mutations are acquired the function of cancer genes and thereby mutations Do not affect cellular behavior directly contribute to the development or They occur at random Passenger progression of a given cancer. Gene mutations mutations are sprinkled throughout the They are usually acquired but in cancer genome occasionally inherited Passenger mutations related to cancers Driver mutations tend to be tightly caused by carcinogen exposure, such as clustered within cancer genes melanoma and smoking-related lung cancer Types of gene mutations in cancer Point Mutations Aneuploidy Point mutations can either activate or inactivate It is defined as a number of chromosomes that is not the protein products of the affected genes a multiple of the haploid state i.e a chromosome Point mutations that convert proto-oncogenes number that is not a multiple of 23. into oncogenes generally produce a gainof-function Aneuploidy is remarkably common in carcinomas A cardinal example is point mutations that convert Aneuploidy tends to increase the copy number of the RAS gene into a cancer gene, one of the most key oncogenes and decrease the copy number of comment events in human cancers. potent tumor suppressors. The tumor suppressor gene that is most commonly Examples 1. Chr.8 carrying MYC oncogene is present in increased copies in tumor cells affected by point mutations in cancer is TP53 2. Portions of chr.17 carrying TP53 gene are often lost in tumor cells Deletions Gene Amplifications Proto-oncogenes may be converted to oncogenes Deletion of specific regions of chromosomes may by gene amplification with consequent result in the loss of particular tumor suppressor overexpression and hyperactivity of otherwise genes normal proteins. Examples Examples 1. RB gene deletions are associated with 1. NMYC gene amplification in 20-35% of retinoblastoma neuroblastoma 2. Deletion of 17p is associated with loss of TP53 2. HER2 (also known as ERBB2) amplification occurs in about 20% of breast cancers Gene Rearrangements Gene rearrangements may be produced by chromosomal translocations or inversions. Highly associated with Leeukemias and sarcomas Gene rearrangements can activate proto- 1. Some gene rearrangements result in overexpression of 2. Oncogenic gene rearrangements create fusion genes oncogenes in two ways: proto- oncogenes by removing them from their normal encoding novel chimeric proteins regulatory elements and placing them under control of an Example inappropriate, highly active promoter or enhancer Philadelphia (Ph) chromosome in chronic myeloid examples leukemia Burkitt lymphoma: Myc gene translocation from chr.8 to Consists of balanced reciprocal translocation between 14 chr. 9 and 22 leading to fusion of ABL oncogene(chr 9) with follicular lymphoma: a reciprocal translocation between BCR locus chr.14 and 18 leads to overexpression of the anti-apoptotic ABL-BCR hybrid gene results in activation of growth gene BCL2 on chr.18 factor signaling pathways