Cancer Genetics
Cancer • Disease characterized by uncontrolled cell growth • This causes tumors • Tumors may be benign or malignant • Benign tumors grow in size but do not invade and destroy surrounding tissue • These may still be deadly • Laryngeal papillomas for example can occlude the airway and cause asphyxiation • Cancer usually means malignant • Malignancy means a cell is invasive • Invasion destroys • The internal cellular order of a tissue • Membranes and barriers that define organs
Malignancy • Invasion is prerequisite to malignancy • Malignancy defined as the tendency to become worse, or to progress in virulence • Cells which are invasive tend to spread • This is metastasis • However an invasive tumor is not automatically metastatic • Metastatic cells may migrate to other sites within the same organ • Cells or groups of cells may travel through the vasculature or reticuloendothelial system to distant sites
The steps in invasion • Initial mutation (initiation) alters genes resulting in growth • Progressive growth (influenced by tumor promoters) creates more cells, each with a certain probability of mutating to more virulent state • Rapidly growing cells more prone to mutation than quiescent cells • Mutations may occur in DNA repair enzymes making other mutations more likely • Mutations may also lead to genomic instability, fragmenting the genome • Each break means another mutation • Mutant cells arise within the population of growing cells that are able to break through into surrounding tissues
Effects of mutations • Up regulation of positive signals for growth • Down regulation of negative signals that suppress growth • Elimination of signals that might stimulate immunological attack or apoptosis (programmed cell death) • Interference with the normal process of cell-cell binding • Production of proteins that result in degradation of surrounding tissues
Tumor cell properties which may change during tumor progression • antigenicity • growth rate • response to hormones • response to cytotoxic drugs • karyotypic abnormalities • capacity for invasion and metastasis
Germline versus somatic mutations that result in cancer • Germline • Mutations in certain genes • The mutation must not be so severe that it results in fetal death • Heritable • Variable penetrance depending on mutation • Somatic • Wider array of target genes • Mutations that wouldn’t be tolerated during development can occur in somatic cells • Sporadic appearance • Non-heritable
Environmental factors • Experimentation and epidemiology indicate that cancer is caused by mutagens • Most mutagens are carcinogens and most carcinogens are mutagens • Exceptions include tumor promoters such as TPA • This stimulates cell division without mutagenizing • Identification of any particular agent is difficult
Unidentified environmental influences • Japanese colon cancer rates rise and stomach cancer rates fall when Japanese move to America • Stomach cancer • Helicobacter pylori? • Stress? • Colon cancer? • Lifestyle – sedentary in US • Environmental exposures? • Overall risk dependent on both exposure and genetic predisposition
Carcinogens • Mutagens = carcinogens generally • Works against specific genetic background • Two step experimental induction of cancer • Initiation = mutagenesis • Promotion = mitogenesis
Carcinogens(and UV, ionizing radiation, …) • Common carcinogens act as both initiators and promoters • Polycyclic aromatic hydrocarbons – cigarette smoke; soot; tobacco • Alkylating agents – mustard gas • Industrial agents – benzene; vinyl chloride; asbestos • Metals – arsenic • Drugs – cyclophosophamide; DES • Food additives – Nitrosamines • Natural substances – Aflatoxin B1 • Promoters • Are not mutagens but provoke cell division by activating positive growth signals • TPA (PMA)
Human tumor viruses • These are an uncommon cause of cancer • HTLV I and II – STD’s • Retroviruses found in patients leukemia • HTLV I Adult T-Cell leukemia/lymphoma • HTLV II Hairy Cell leukemia • Infection only rarely results in disease • Rare forms of leukemia • These are integrative viruses • It’s genome inserts into chromosomal DNA as a necessary step in viral replication • The integration site is therefore mutated • Promoters on the virus can up-regulate transcription from proximal host genes
Viruses II • Hepatitis B virus – may be STD’s • Chronic form may result in hepatocellular carcinoma • Herpes virus – may be STD’s • EBV provokes unregulated growth in people chronically infected with Plasmodium • Burkitt’s lymphoma • Kaposi’s sarcoma results from KSHV
Human papillomavirus • HPV 16 and 18 – STD’s • Cervical cancer • Unregulated expression of oncogenes E6 and E7 provoke tumors • De-regulation is a result of integration of the virus such that molecules that regulate expression of E6 and E7 are destroyed • Other HPV • Eg HPV-1 common warts; HPV-11 laryngeal warts • Exist as episomes – not integrated • Benign tumors (warts) that may regress or be recurrent • Almost never progress to malignancy
Types of Cancer • Epithelial tissue • Carcinoma • Most common form of solid tumor in humans • Stem or basal cells are mutated • Not as common among animals • Connective tissue • Sarcoma • These are more common in animals and are often virally caused in them • Others named for the cell type of origin • Glial cells – glioma • Melanocytes– melanoma • Neuroblastoma (from sympathetic nervous tissue – most common in children), etc.
Leukemia • Abnormal proliferation and development of hematopoietic cells in bone marrow and blood • This results in the expansion of cells that circulate in the vasculature • Often in the form of blast cells, or undifferentiated cells of hematopoietic origin • Classification • Acute or chronic • Lymphogenous or myelogenous • Suffixes -cyticverus -blastic refers to the maturity of the proliferating cell • A blast is a more immature form of a cell • Leukemic or aleukemic • Aleukemic means there is no abnormal increase of cells in the blood
Lymphoma • Cancer of the lymphoid tissue • Usually malignant • Named according to the predominant cell type within the tumor or the discoverer • Burkitt’s lymphoma • A B-cell proliferation confined to the lymphoid tissues • Also properly described as a "B-Cell lymphoma"
Types of cancer genes
Cancer is a genetic disease • Cell division accomplishes replacement of dead or sloughed cells • Most cells are programmed to die as a result of normal terminal differentiation • Apoptosis • Sloughing • Genes affecting growth control may either turn cell division off or turn it on • Germline mutations may result in predisposition • Often are Tumor suppressor genes • These are negative controls on cell growth • Restrict cell division • Provoke apoptosis • Somatic mutations may result in uncontrolled growth • Oncogenes • These are positive signals to grow or inhibitory signals against apoptosis • Viral oncogenes interact with cellular cancer genes
Cell cycle • In G0 a cell imposes control on cell growth • Restriction points on DNA synthesis also exist in G1, S and G2 phases • In order to enter S, a positive signal to divide must be received • Negative effects on growth are thereby relieved
Families • How positive signals changed? • Hormone – autocrine loop • Cell overproduces a signal that tells itself to grow • Sis – Platelet Derived Growth Factor beta subunit – Stomach cancer • HST – FGF – Glioma • Growth Factor Receptors • RET – Rearranged during Transfection – Multiple Endocrine Neoplasia (MEN) • Erb B – (First identified in avian erythroblastosis virus) • ERBB1 – EGFR homolog – glioblastoma – but viral oncogene • ERBB2 – (NEU) EGFR family – responsiveness to chemotherapy in breast cancer – amplified in 20-30% breast cancers - over expression confers taxol resistance in breast cancer • B3/B4 – no cancer connections
Positive acting Cancer Genes – Growth factor receptors • Cells grow and differentiate under control of external signals • Why would a cell divide? • It receives an external signal • It responds to that signal with division • The signal is a growth factor • E.g. Epidermal Growth Factor • Must have a specific receptor to respond • Epidermal Growth Factor Receptor
Nuclear • N-myc • related to v-myc and c-myc • Avian myelocytomatosis virus • DNA binding protein • amplification in neuroblastomas • Myb • related to v-myb • Avian myeloblastosis viral oncogene • DNA binding protein • malignant melanoma, lymphoma, leukemia • Fos • related to v-fos • Finkelmurineosteosarcoma • transcription factor of AP-1 complex • Human osteosarcoma
DNA repair enzymes • These are not oncogenes per se • They do not participate in cellular proliferative signals • Instead they act to enhance the mutability of the genome • This in turn increases the chances for mutagenesis of cancer genes
Family History Flags of Hereditary Cancer • Cancer in 2 or more relatives • Early age of diagnosis • Multiple primary tumors • Bilateral or multiple rare tumors • Existing mutation predisposes to cancer
Multistep evolution in cancer
Proto-oncogenes • Induce telomerase activity • Block apoptosis • Stimulate proliferation • Increase blood supply
Tumor Suppresor Genes • Gatekeepers: regulation of cell cycle; growth inhibition by cell-to-cell contact • Caretakers: Repair DNA damage • Maintain genome integrity
Oncogene-caused cancer exemples - Amplification of the same gene as a cause of oncogene-caused cancer (can be diagnosed by FISH) • Chromosomal translocations as a cause of oncogene-caused cancer (Brc/Abl novel fusion gene that confers growth and survival advantage to Chronic Multiple Myeloma is a result of translocation) • Common idea – overexpression or gain-of-function of oncogenes in cancer
Hereditary Syndromes of Oncogenes • MEN2 – predisposition to thyroid cancer, GOF germline mutations • Different mutations in RET gene (cell surface receptor tyrosine kinase) • Different outcomes so genetic testing is important
Loss of second allele in cancer
Knudson hypothesis
Hereditary Syndromes of Tumor Suppresor Genes • Retinoblastoma – Rb1 (gate-keeper gene) • Familial AdenomatousPolyposis (FAP) • Hereditary Nonpolyposis Colorectal Cancer Syndrome • Hereditary Breast/Ovarian Cancer Syndrome
Knudsen two hit model for Retinoblastoma • Model for heritable cancer • Rb-1 travels in families • Single hit in germline predisposes for Retinoblastoma • results in heterozygosity for all cells • Second hit in Rb necessary to lose cell cycle control • This results in a Loss of Heterozygosity • Specific mechanisms for the second hit
Knudsen two hit model • Rb travels in families • Leukocoria is initial presentation • Usual red reflection in an eye on photography is white • Disease can be treated in bilateral form by removal of eyes • Radiation and chemotherapy can eliminate tumors without loss of eyesight • Cancer will reemerge in other tissues later in life • Notably as osteosarcoma
Normal Colon and FAP colon
Normal function of APC protein
Specific FAP phenotypes associated with specific APC mutations • FAP is caused by germline LOF mutations in APC gene
Colorectal tumor DNA sample gel electrophoresis with microsatellite instability
Cell signaling in TGFbeta (defective in some cancers)
Hereditary Breast/Ovarian Cancer • BRCA 1 / 2 genes • Associated with defective DNA repair complex that repairs breaks and cross-links in DNA
