University:
Franklin University
Course:
BIO-406 | Genetics
Academic year:

2020
Views:

335

Pages:

40
Author:

6AstralAdventurer

Introduction • Cancer is one of the most common and serious diseases seen in clinical medicine. • There are 14 million new cases of cancer diagnosed each year and over 8 millions deaths from the disease worldwide Neoplasia • Cancer is the name used to describe the more virulent forms of neoplasia • a disease process characterized by uncontrolled cellular proliferation leading to a mass or tumor (neoplasm) Neoplasia • For a neoplasm to be a cancer, however, it must also be malignant, which means that not only is its growth uncontrolled, it is also capable of invading neighboring tissues that surround the original site (the primary site) and can spread (metastasize) to more distant sites • Tumors that do not invade or metastasize are not cancerous but are referred to as benign tumors • There are three main classes of cancer: • Sarcomas, in which the tumor has arisen in mesenchymal tissue, such as bone, muscle, or connective tissue, or in nervous system tissue; • Carcinomas, which originate in epithelial tissue, such as the cells lining the intestine, bronchi, or mammary ducts • Hematopoietic and lymphoid malignant neoplasms, such as leukemia and lymphoma, which spread throughout the bone marrow, lymphatic system, and peripheral blood. Types of Genetic Alterations in Cancer • Subtle alterations Small deletions Insertions Single base pair substitutions (Point mutations) • Chromosome number changes • Chromosomal translocation • Amplifications multiplication of a chromosomal segment to produce regions with many copies of the same gene • Exogenous sequences Cancer causing genes • Oncogenes: – Genes that normally trigger cell division or growth • Tumor Suppressors (TSGs): – Genes that normally suppress cell division – Or cause cells to die off when appropriate Oncogenes • proto-oncogenes are normal genes that, when mutated in very particular ways lead to excessive levels of activity. Once mutated, these genes are referred to as activated oncogenes Oncogenes • Oncogenes encode proteins such as the following: • Proteins in signaling pathways for cell proliferation • Transcription factors that control the expression of growth promoting genes • Inhibitors of programmed cell death machinery Oncogenes • proteins encoded by proto-oncogenes promote cancer when activated or overexpressed Tumor suppressor genes (TSGs) • To drive oncogenesis, loss of function of a TSG typically requires mutations at both alleles: – missense, – nonsense, – frame-shift mutations – gene deletions – loss of a part or even an entire chromosome. – epigenomic transcriptional silencing Tumor suppressor genes (TSGs) • TSGs encode proteins involved in many aspects of cellular function: • maintenance of correct chromosome number and structure, • DNA repair proteins, • proteins involved in regulating the cell cycle, cellular proliferation, or contact inhibition, Cellular Heterogeneity within Individual Tumors Cancer types • Sporadic • Cancers in families – Familial – Hereditary Cancers in families • forms of cancer have a higher incidence in relatives of patients than in the general population – Hereditary: • single mutant gene • mendelian patterns of inheritance • less than 5% of all patients – Familial: • shared environment and one or more genetic variants that increase susceptibility and are therefore classified as multifactorial, with complex inheritance • increased predisposition to cancer Two-Hit Theory Two-Hit Theory • many hereditary cancers – Retinoblastoma – familial polyposis coli – familial breast cancer – neurofibromatosis type 1 (NF1), – Lynch syndrome – Li-Fraumeni syndrome Retinoblastoma • rare malignant tumor of the retina in infants • Incidence: approximately 1 in 20,000 births Retinoblastoma • smaller tumors, diagnosed at an early stage, can be treated by local therapy • must usually be followed by removal of the affected eye, • Approximately 40% of cases of retinoblastoma are of the heritable form, • Dominant • rapid rate of proliferation…somatic mutation will occur as a second hit…more than one cell (multifocal tumors)…in one or both eyes Familial Breast Cancer due to Mutations in BRCA1 and BRCA2 • BRCA1 and BRCA2 • Mutations in BRCA1 and BRCA2 are also associated with a significant increase in the risk for ovarian and fallopian duct cancer in female heterozygotes • mutations in BRCA2 and to a lesser extent, BRCA1, also account for 10% to 20% of all male breast cancer Familial Breast Cancer due to Mutations in BRCA1 and BRCA2 • ≈3% to 5%…highly penetrant dominantly inherited mendelian predisposition that increases the risk for female breast cancer (12% lifetime risk observed in the general female population) • Characteristics: – – – – Multiple affected individuals in a family, earlier age at onset, frequent multifocal, bilateral disease or second independent primary breast tumor, – and second primary cancers in other tissues such Hereditary Colon Cancer • Colorectal cancer, a malignancy of the epithelial cells of the colon and rectum, is one of the most common forms of cancer. • Most cases are sporadic, but a small proportion of colon cancer cases are familial, • Two autosomal dominant: • familial adenomatous polyposis (FAP) • Lynch syndrome (LS) Familial Adenomatous Polyposis (FAP) • Subvariant Gardner syndrome • In FAP heterozygotes, benign adenomatous polyps numbering in the many hundreds develop in the colon during the first two decades of life. In almost all cases, one or more of the polyps becomes malignant. Surgical removal of the colon (colectomy) prevents the development of malignancy. Familial Adenomatous Polyposis • Because this disorder is inherited as an autosomal dominant trait, relatives of affected persons must be examined periodically by colonoscopy. • FAP is caused by loss-of-function mutations in a TSG known as the APC gene. Familial Adenomatous Polyposis (FAP) • Gardner syndrome …APC and is therefore allelic to FAP. • Gardner syndrome have, in addition to the adenomatous polyps with malignant transformation seen in FAP, other extracolonic anomalies, including osteomas of the jaw and desmoids, which are tumors arising in the muscle of the abdominal wall. Testing for Germline Mutations Causing Hereditary Cancer • BRCA1 and BRCA2 testing • Colorectal Cancer Germline Mutation Testing BRCA1 and BRCA2 testing • whole-genome sequencing to screen for germline mutations • a woman found to carry a BRCA1 mutation: – removal of the cancer – prophylactic mastectomy on the unaffected breast – bilateral oophorectomy SPORADIC CANCER • Activation of Oncogenes – Point Mutation – Chromosome Translocation – Telomerase as an Oncogene • Loss of Tumor Suppressor Gene in – TP53 and RB1 in Sporadic Cancers Activation of Oncogenes by Point Mutation • RAS gene derived from a bladder carcinoma cell line. • RAS encodes one of a large family of small guanosine triphosphate (GTP)–binding proteins (so-called G proteins) that serve as molecular “on-off” switches to activate or inhibit downstream molecules. Activation of Oncogenes by Point Mutation • the activated oncogene and its normal counterpart proto-oncogene differed at only a single nucleotide • abnormal Ras protein that was able to signal continuously, thus stimulating cell division and changing it into a tumor Activation of Oncogenes by Chromosome Translocation • chromosomes 9 and 22, the so-called Philadelphia chromosome that is seen in chronic myelogenous leukemia (CML) • The translocation moves the proto oncogene ABL1, a tyrosine kinase, from its normal position on chromosome 9q to a gene of unknown function, BCR, on chromosome 22q • As cells differentiate, telomerase activity declines in all somatic tissues; as telomerase function is lost, telomeres shorten…apoptosis telomerase activity results from chromosome or genome mutations that directly up-regulate the telomerase gene; indirectly, telomerase may be only one of many genes whose expression is altered by a transforming oncogene