5-14 Things That Cause Cancer Flashcards
A mutation in the proto-oncogene ERBB1 (EGFR) creates what?
Adenocarcinoma of the lung
- mutation activation
A mutation in the proto-oncogene ERRB2 (HER) creates what?
Breast carcinoma
- amplification mode of activation
A mutation in the proto-oncogene RET creates what?
multiple endocrine neoplasia 2A and B
Familial medullary thyroid carcinomas
A mutation in the proto-oncogene PDGFRB creates what?
Gliomas & leukemias
Overexpression and translocation mode of activation
A mutation in the proto-oncogene KIT creates what?
Gastrointestinal stromal tumors
- seminomas, certain leukemias
Point mutation mode of activation
A mutation in the proto-oncogene ALK creates what?
Adenocarcinoma of the lung
- certain lymphomas, neuroblastoma
Translocation, fusion gene mode of activation
A mutation in the proto-oncogene KRAS creates what?
Colon, lung and pancreatic tumors
- activated via a point mutation
A mutation in the proto-oncogene NRAS creates what?
Melanomas, hematologic malignancies
A mutation in the proto-oncogene GNAS creates what?
pituitary adenoma, other endocrine tumors
- activation via a point mutation
A mutation in the proto-oncogene BRAF creates what?
Melanomas
- also leukemias, colon carcinoma, etc.
- BRAF* is a RAS signal transduction
A mutation in the proto-oncogene ABL creates what?
Chronic myeloid leukemia, acute lymphoblastic leukemia
- activated via a translocation, or a point mutation
A mutation in the proto-oncogene C-MYC creates what?
Burkitt Lymphoma
- via translocation activation
A mutation in the proto-oncogene N-MYC creates what?
Neuroblastoma
- small cell carcinoma of the lung
- activated via an amplification
A mutation in the proto-oncogene L-MYC creates what?
Small-cell carcinoma of the lung
- activated via amplification
A mutation in the proto-oncogene CCND1 (Cyclin D) creates what?
Mantle cell lymphoma
- also multiple myeloma
- activation via a translocation mechanism
Breast and esophageal cancers too
- activation via an amplification mechanism
A mutation in PAX8 gene can make it act like a proto-oncogene and cause what?
Renal carcinoma
A mutation in PAX5 gene can make it act like a proto-oncogene and cause what?
Non-Hodgkin Lymphoma
Lymphocytic leukemia
A mutation in PAX3 and PAX7 genes can make it act like a proto-oncogene and cause what?
Embryonic rhabdomyosarcoma
Chronic myelogenous leukemia is caused by translocation activation of what genes?
ABL 9q34/BCR 22q11
Acute myeloid leukemia is caused by which translocation activation of what genes?
AML1 8q22/ETO 21q22**
PML 15q22/RARA 17q12**
Burkitt Lymphoma is caused by translocation activation of what genes?
c-MYC 8q24
IGH 14q32
Mantle cell lymphoma is caused by translocation activation of what genes?
CCND1 11q13
IGH 14q32
Follicular lymphoma is caused by translocation activation of what genes?
IGH 14q32
BCL2 18q21
Ewing sarcoma is caused by translocation activation of what genes?
FLI1 11q24
EWSR1 22q12
Prostatic adenocarcinoma is caused by translocation activation of what genes?
TMPRSS2 (21q22.3)
ETV1 (7p21.2)
ETV4 (17q21)
What is the function of cyclines?
CDK4; D cyclins
Form a complex that phosphorylates RB, allowing the cell to progress through the G1 restriction point
What is the function of the ARF family of genes?
INK4/ARF family (CDKN2A-C)
p16/INK4a binds to cyclin D-CDK4 and promotes the inhibitory effects of RB
p14/ARF increases p53 levels by inhibiting MDM2 activity
What is the function of RB?
Cell Cycle checkpoint component
Tumor suppressive “pocket” protein that binds E2F transcription factors in its hypophosphorylated state, preventing G1/S transition; also interacts with several transcription factors that regulate differentiation
What is the function of p53?
Cell Cycle Checkpoint component
Tumor suppressor altered in the majority of cancers; causes cell cycle arrest and apoptosis. Acts mainly through p21 to cause cell cycle arrest. Causes apoptosis by inducing the transcription of pro-apoptotic genes such as BAX. Levels of p53 are negatively regulated by MDM2 through a feedback loop. p53 is required for the G1/S checkpoint and is a main component of the G2/M checkpoint.
What is the NF1 gene?
Tumor suppressor gene
Protein: Neurofibromin-1
Function: Inhibitor of RAS/MAPK signaling
Familial Syndrome: Neurofibromatosis type 1 (neurofibromas and malignant peripheral nerve sheath tumors) - i.e. skin lesions
Specific Cancers: Neuroblastoma, juvenile myeloid leukemia
What is the NF2 gene?
Tumor Suppressor Gene
Protein: Neurofibromin-2/merlin
Function: Cytoskeletal stability, Hippo pathway signaling
Familial Syndromes: Neurofibromatosis type 2 (acoustic schwannoma and meningioma)
Sporadic Cancers: Schwannoma, meningioma (leads to hearing loss and brain tumors, not skin lesions)
What is the PTEN gene significant for?
Tumor Suppressor Gene
Protein: Phosphatase and tensin homologue
Function: Inhibitor of PI3K/AKT signaling
Familial Syndromes: Cowden syndrome (variety of benign skin, GI, and CNS growths; breast, endometrial, and thyroid carcinoma)
Sporadic Cancers: Diverse cancers, particularly carcinomas and lymphoid tumors
What is the RB gene significant for?
Tumor Suppressor Gene
Protein: Retinoblastoma (RB) protein
Function: Inhibitor of G1/S transition during cell cycle progression
Familial Syndromes: Familial retinoblastoma syndrome (retinoblastoma, osteosarcoma, other sarcomas)
Sporadic Cancers: Retinoblastoma; osteosarcoma carcinomas of breast, colon, lung
What is the gene VHL significant for?
Tumor Suppressor Gene
Protein: Von Hippel Lindau (VHL) protein
Function: Inhibitor of hypoxia-induced transcription factors (e.g., HIF1α)
Familial Syndromes: Von Hippel Lindau syndrome (cerebellar hemangioblastoma, retinal angioma, renal cell carcinoma)
Sporadic Cancers: Renal cell carcinoma
What is the gene TP53 significant for?
Tumor Suppressor Gene
Protein: p53 protein
Function: Cell cycle arrest and apoptosis in response to DNA damage
Familial Syndromes: Li-Fraumeni syndrome (diverse cancers)
Sporadic Cancers: Most human cancers
What are the genes BRCA1, BRCA2 significant for?
Tumor Suppressor Genes
protein: Breast cancer-1 and breast cancer-2 (BRCA1 and BRCA2
function: Repair of double-stranded breaks in DNA
familial syndromes: Familial breast and ovarian carcinoma; carcinomas of male breast; chronic lymphocytic leukemia (BRCA2)
sporadic cancers: rare
What is the gene WT1 significant for?
Tumor Suppressor Gene
Protein: Wilms tumor-1 (WT1)
Function: Transcription factor
Familial Syndromes: Familial Wilms tumor
Sporadic Cancers: Wilms tumor, certain leukemias
What is the gene MEN1 significant for?
Tumor Suppressor Gene
Protein: Menin
Function: Transcription factor
Familial Syndromes: Multiple endocrine neoplasia-1 (MEN1; pituitary, parathyroid, and pancreatic endocrine tumors)
Sporadic Cancers: Pituitary, parathyroid, and pancreatic endocrine tumors
What is the major form of underlying cancer and causal mechanism for Cushing Syndrome as a paraneoplastic syndrome?
Small-cell carcinoma of lung
Pancreatic carcinoma
Neural tumors
Mechanism: ACTH or ACTH-like substance
What is the major form of underlying cancer and causal mechanism for SIADH as a paraneoplastic syndrome?
Small-cell carcinoma of lung; Intracranial neoplasms
Mechanism: Antidiuretic hormone or atrial natriuretic hormones
What is the major form of underlying cancer and causal mechanism for hypercalcemia as a paraneoplastic syndrome?
Squamous cell carcinoma of lung
Breast carcinoma
Renal carcinoma
Adult T-cell leukemia/lymphoma
Mechanism: Parathyroid hormone-related protein (PTHRP), TGF-α, TNF, IL-1
What is the major form of underlying cancer and causal mechanism for hypoglycemia as a paraneoplastic syndrome?
Ovarian carcinoma
Fibrosarcoma
Other mesenchymal sarcomas
Mechanism: Insulin or insulin-like substance
What is the major form of underlying cancer and causal mechanism for polycythemia as a paraneoplastic syndrome?
Gastric carcinoma
Renal carcinoma
Cerebellar hemangioma
Hepatocellular carcinoma
Mechanism: Erythropoietin
What is the major form of underlying cancer and causal mechanism for carcinoid syndrome as a paraneoplastic syndrome?
Hepatocellular carcinoma
Bronchial adenoma (carcinoid)
Pancreatic carcinoma
Mechanism: Serotonin, bradykinin
What is the major form of underlying cancer and causal mechanism for myasthenia gravis as a paraneoplastic syndrome?
Bronchogenic carcinoma
Thymic neoplasms
Mechanism: Immunological
What is the major form of underlying cancer and causal mechanism for acanthosis nigricans as a paraneoplastic syndrome?
Gastric carcinoma
Lung carcinoma
Uterine carcinoma
Mechanism: Immunological; secretion of epidermal growth factor
What is the major form of underlying cancer and causal mechanism for dermatomyositis as a paraneoplastic syndrome?
Bronchogenic
Breast carcinoma
Mechansim: Immunological
- look for heliotropic rash, mm weakness
What is the major form of underlying cancer and causal mechanism for Trousseau syndrome as a paraneoplastic syndrome?
Venous thrombosis (Trousseau phenomenon)
Pancreatic carcinoma
Bronchogenic carcinoma
Other cancers
Mechanism: Tumor products (mucins that activate clotting)
What is the major form of underlying cancer and causal mechanism for DIC as a paraneoplastic syndrome?
Acute promyelocytic leukemia
Prostatic carcinoma
Mechanism: Tumor products that activate clotting
What is the major form of underlying cancer and causal mechanism for nonbacterial thrombotic endocarditis as a paraneoplastic syndrome?
Advanced cancers
Mechanism: Hypercoagulability
What are some direct-acting carcinogens?
Alkylating Agents
β-Propiolactone
Dimethyl sulfate
Diepoxybutane
Anticancer drugs (cyclophosphamide, chlorambucil, nitrosoureas, and others) (Many cancers especially leukemias)
Acylating Agents
1-Acetyl-imidazole
Dimethylcarbamyl chloride
What are some polycyclic and heterocyclic aromatic hydrocarbon procarcinogens that require metabolic activation?
Polycyclic and Heterocyclic Aromatic Hydrocarbons
Benz[a]anthracene
Benzo[a]pyrene
Dibenz[a,h]anthracene
3-Methylcholanthrene
7,12-Dimethylbenz[a]anthracene
What are some aromatic amines, amides, and azo -dyes that are procarcinogenic?
Aromatic Amines, Amides, Azo Dyes
2-Naphthylamine (β-naphthylamine)
Benzidine
2-Acetylaminofluorene
Dimethylaminoazobenzene (butter yellow)
What are some procarcinogenic plant and microbial products?
Natural Plant and Microbial Products
Aflatoxin B1 (Liver cancer via p53 inactivation)
Griseofulvin
Cycasin
Safrole
Betel nuts (Oral cancer)
Others
Nitrosamine and amides
Vinyl chloride, nickel, chromium
Insecticides, fungicides
Polychlorinated biphenyls
Arsenic typically causes what kinds of occupation cancers? How is exposure mediated?
Lung carcinoma, skin carcinoma
By-product of metal smelting; component of alloys, electrical and semiconductor devices, medications and herbicides, fungicides, and animal dips
Asbestos typically causes what kinds of occupation cancers? How is exposure mediated?
Lung, esophageal, gastric, and colon carcinoma; mesothelioma
Formerly used for many applications because of fire, heat, and friction resistance; still found in existing construction as well as fire-resistant textiles, friction materials (i.e., brake linings), underlayment and roofing papers, and floor tiles
Benzene typically causes what kinds of occupation cancers? How is exposure mediated?
Acute myeloid leukemia
Principal component of light oil; despite known risk, many applications exist in printing and lithography, paint, rubber, dry cleaning, adhesives and coatings, and detergents; formerly widely used as solvent and fumigant
Beryllium and beryllium compounds typically cause what kinds of occupation cancers? How is exposure mediated?
Lung carcinoma
Missile fuel and space vehicles; hardener for lightweight metal alloys, particularly in aerospace applications and nuclear reactors
Cadmium and cadmium compounds typically cause what kinds of occupational cancers? How is exposure mediated?
Prostate carcinoma
Uses include yellow pigments and phosphors; found in solders; used in batteries and as alloy and in metal platings and coatings
Chromium compounds typically causes what kinds of occupational cancers? How is exposure mediated?
Lung carcinoma
Component of metal alloys, paints, pigments, and preservatives
Nickel compounds typically cause what kinds of occupational cancers? How is exposure mediated?
Lung and oropharyngeal carcinoma
Nickel plating; component of ferrous alloys, ceramics, and batteries; by-product of stainless-steel arc welding
Radon and its decay products typically cause what kinds of occupational cancers? How is exposure mediated?
Lung carcinoma
From decay of minerals containing uranium; potentially serious hazard in quarries and underground mines
Vinyl chloride typically cause what kinds of occupational cancers? How is exposure mediated?
Hepatic angiosarcoma
Refrigerant; monomer for vinyl polymers (PVC industry); adhesive for plastics; formerly inert aerosol propellant in pressurized containers
Ultraviolet radiation causes what kinds of skin cancers?
- Nonmelanoma skin cancers - total cumulative exposure to UVB/UBC radiation
- squamous cell carcinoma, basal cell carcinoma
•Melanomas - intense intermittent exposure (sunbathing)
Ionizing radiation - electromagnetic or particulate - can cause what kinds of tumors via what mechanisms?
•Medical or occupational exposure, nuclear plant accidents (decreasing order)
•Acute and chronic myeloid leukemia
•Cancer of the thyroid in the young
•Cancers of the breast, lungs, and salivary glands
•Radioactive mine workers have 10X increase in lung cancer
•Cancers of skin, bone, and GI tract (x-ray researchers - skin cancers)
•Atomic bomb detonations
•Leukemias-principally acute and chronic myelogenous after 7 years
•Solid tumors afterwards (e.g., breast, colon, thyroid, and lung)
Intrinsic Field Subtractor
- inability to wear clothing, blue skin coloration, exiling yourself to Mars, not killing Veidt and foiling his dastardly plan
What RNA viruses are oncogenic? What cancers can they cause?
- HTLV-1 – adult T-cell leukemia/lymphoma
- HCV – hepatocellular carcinoma
What DNA viruses are oncogenic? What cancers can they cause?
- HBV – hepatocellular carcinoma
- HPV- papillomas (types 1, 2, 4, 6, 7, & 11), carcinomas of cervix, anus, penis & oropharynx (types 16 &18)
- HHV-8 – Kaposi sarcoma & primary effusion lymphoma
- EBV – Burkitt lymphoma, Hodgkin lymphoma & nasopharyngeal carcinoma
- CMV (HHV-5) – mucoepidermoid carcinoma
- Merkel cell polyomavirus – Merkel cell carcinoma
What fungi and parasite infections can cause cancer?
- Fungi
- Aspergillus – aflotoxin B1-associated hepatocellular carcinoma (p53 mutation)
- Parasites
- Schistosoma haematobium – bladder cancer
- Schistosoma japonicum – colon cancer
- Opisthorchis viverrini – cholangiocarcinoma
What bacterial infections can cause cancer?
•Helicobacter pylori – extranodal marginal zone (MALT) lymphoma and gastric adenocarcinoma
What are 5 inherited autosomal recessive syndromes of defective DNA repair?
Xeroderma pigmentosum (nucleotide excision repair of cross-linked pyrimidine dimers)
Hereditary nonpolyposis colon cancer syndrome (DNA mismatch repair)
Ataxia-telangiectasia (DNA repair by homologous recombination)
Bloom syndrome (DNA repair by homologous recombination)
Fanconi anemia (DNA repair by homologous recombination)
What are some examples where there are familial clustering of cancer cases, but the role of the inherited predisposition is unclear on an individual level?
Breast cancer (BRCA1 & BRCA2)
Ovarian cancer (BRCA1 & BRCA2)
Pancreatic cancer (BRCA2)
What are some inherited autosomal recessive conditions with defects in DNA repair?
Xeroderma pigmentosa
Ataxia telangiectasia
Bloom Syndrome
Fanconi anemia
What is abnormal in xeroderma pigmentosa, and what does it result in?
Autosomal recessive
•Xeroderma pigmentosa - Nucleotide excision repair abnormality associated with extreme sensitivity to ultraviolet (UV) rays affects the eyes and skin (cancers), may also have CNS problems (increased pyrimidine dimers)
What is abnormal in ataxia telangiectasia, and what does it result in?
Autosomal recessive
•Ataxia telangiectasia – ATM gene defect (involved in DNA repair) associated with progressive difficulty with coordinating movements, weakened immune system, leukemias and lymphomas
What is abnormal in Bloom syndrome, and what does it result in?
Autosomal recessive
•Bloom syndrome – Helicase abnormality associated with short stature, sun-sensitive skin changes, an increased risk of cancer, and other health problems
What is abnormal in Fanconi anemia? What does it result in?
Autosomal recessive
•Fanconi anemia – FA process defects associated with aplastic anemia, hypopigmentation, café-au-lait spots, skeletal problems, defects of the genitourinary tract; gastrointestinal tract; heart; eye and ears with hearing loss and acute myeloid leukemia
What is abnormal in hereditary nonpolyposis colorectal cancer/Lynch syndrome? What does it result in?
Autosomal Dominant!
•Hereditary nonpolyposis colorectal cancer (HNPCC) = Lynch syndrome DNA mismatch repair abnormality leading to microsatellite instability associated with colorectal, endometrial, gastric, ovarian, ureteral, CNS, small bowel, hepatobiliary tract and skin cancers
Match the following genes to the inherited predisposition:
- RB*
- p53*
- p16/INK4A*
- RB* Retinoblastoma
- p53* Li-Fraumeni syndrome (various tumors)
- p16/INK4A* Melanoma
Match the following genes to the inherited predisposition:
- APC*
- NF1, NF2*
- BRCA1, BRCA2*
APC
Familial adenomatous polyposis/colon cancer
NF1, NF2
Neurofibromatosis 1 and 2
BRCA1, BRCA2
Breast and ovarian tumors
Match the following genes to the inherited predisposition:
- MEN1, RET*
- MSH2, MLH1, MSH6*
- PTCH*
MEN1, RET
Multiple endocrine neoplasia 1 and 2
MSH2, MLH1, MSH6
Hereditary nonpolyposis colon cancer
PTCH
Nevoid basal cell carcinoma syndrome
Match the following genes to the inherited predisposition:
- PTEN*
- LKB1=STK11*
- VHL*
PTEN
Cowden syndrome (epithelial cancers)
LKB1=STK11
Peutz-Jegher syndrome (epithelial cancers)
VHL
Renal cell carcinomas
