Chapter 7 Part 4 Flashcards
Steps in chemical carcinogenesis
- Initiation resulting from exposure of a cell to a significant amount of carcinogen
- DNA damage that is unrepairable
- Promotion of tumor development
Direct acting carcinogen
require no metabolic conversion to become a carcinogen, CA treatments can be direct acting carcinogens and cause development of secondary cancers
Indirect-Acting carcinogen
carcinogens that require metabolic conversion to become active
Initiator
agent that causes DNA damage and eventually leads to rapid and irreversible damage
Promoter
agent that contributes to tumor growth only after the application of an initiator
Most common metabolizer of carcinogens
cytochrome P-450-dependent mono-oxygenases
Why does carcinogen metabolism vary among individuals?
polymorphisms of CYP450 cause differences in gene product and enzyme productivity
What breaks down polycyclic aromatic hydrocarbons?
CYP1A1
Main target of carcinogens
DNA
Are carcinogen caused DNA mutations entirely random?
No, carcinogens may be more attracted to DNA sequences or bases and produce “hotspots”
aflatoxin B1 preferentially binds what sequence/mutation?
T:A transversion in codon 249 that produces an Arg to Ser substitution
Types of carcinogenic radiant energy
UV rays, ionizing electromagnetic and particulate radiation
CA types associated with increased UV radiation
squamous cell carcinoma, basal cell carcinoma, melanoma of the skin
Wavelength range of UVA
320-400 nm
Wavelength range of UVB and CA associated
280-320 nm, cutaneous CAs
Wavelength range of UVC
200-280 nm
What causes the carcinogenicity of UVB light
formation of pyrimidine dimers in DNA
How does dimerization effect DNA?
crosslinking of DNA distorts the helix and prevents proper pairing, can be fixed by repair mechanisms
xeroderma pigmentosum
nucleotide excision repair process is damaged/defective
Ionizing radiation examples
x-rays, gamma-rays, a and b particles, protons and neutrons
CA risk associated with CT scans
3 fold higher risk of leukemia development in children who receive 2 or 3 CTs, 3 fold increase in brain tumors in children that have 5-10 CTs
Hierarchy of tissues vulnerable to radiation induced CA
myeloid leukemias (granulocytes), thyroid, breast, lungs, salivary glands
What tissues are typically not affected by radiation?
skin, bone, GI tract
CA associated with HTLV-1
adult T-cell leukemia/lymphoma
In what areas of the world is adult T-cell leukemia/lymphoma most commonly seen?
Japan, Caribbean basin, South America, and Africa
Major target of HTLV-1
CD4 T cells
Infection of HTLV-1 occurs via
blood exposure, sexual intercourse, breastfeeding
Genes in HTLV-1
gag, pol, env, tax
What is Tax responsible for
essential for viral replication, alters host genome to increased pro-growth signal via PI3/AKT, and increases genomic instability
CA associated with HPV
squamous cell carcinomas of cervix, anogenital region, head and neck
HPV genital warts are associated with which strains?
HPV-6 and -11
Where is HPV DNA inserted?
E1/E2 reading frame
What two viral genes are most responsible for HPV’s oncogenic potential?
E6 and E7
Actions of E6
stimulates TERT (catalytic portion of telomerase), degrades p53,
Actions of E7
speed cells through G1/S checkpoint, inactivates p21 and p27, activate cyclins A and E
tumors associated with EBV
Burkitt lymphoma, B-cell lymphomas in immunosuppressed individuals, subset of Hodgkin lymphoma, nasopharyngeal and gastric carcinomas, rare T and NK cell lymphomas
Most common EBV associated tumors
B-cells and nasopharyngeal carcinoma
EBV complement receptor
CD21
LMP-1 gene EBV
oncogene, acts like CD40 receptor, activates NF-kB and JAK/STATE to promote B-cell survival and proliferation, also prevents apoptosis by activating BCL-2
EBNA-2 gene EBV
transactivates cyclin D and SRC genes in host, encodes viralIL-10 which prevents macrophages and monocytes from attacking T cells
Burkitt Lymphoma
neoplasm of B lymphocytes, commonly in central Africa and New Guinea
How does EBV contribute to Burkitt lymphoma?
weakens the immune system to set the state for an 8;`14 translocation and other mutations
Populations in which nasopharyngeal carcinomas are endemic
southern China, parts of Africa, Inuit people of arctic, all due to EBV
Estimated percent of hepatocellular carcinomas caused by hepatitis?
70-80%
Dominant effect of HBV and HCV
chronic inflammation, hepatocyte death, genomic damage, hepatocyte proliferation
Dominant mechanism of HPV associated cancer
activation of NF-kB pathway to prevent apoptosis
CA associated with H. pylori
gastric adenocarcinoma, MALT lymphoma
Pathogenesis of H. pylori induced gastric CA
multifactorial; involved chronic inflammation and reparative gastric cell proliferation
H. pylori pathogenecity gene
CagA
H.pylori in MALT lymphomas
B cell proliferation and inflammation promotors
Cancer cachexia
equal loss of fat and lean muscle, elevated BMR, evidence of systemic inflammation
Leading cytokine contributing to cachexia
TNFa
Can a benign tumor be deadly?
Yes, it may cause compression of other surrounding structures that will eventually lead to the death of the patient
Possible complications of GI tumors
obstruction, intussusception,
Benign tumors in endocrine glands…
can become functional and cause a greater release of hormone
Erosiveness of tumors may cause…
ulceration, infections, bleeding, hemoptysis, melena
Paraneoplastic syndrome
signs and symptoms that can not readily be explained by the presence of a tumor, may be the earliest manifestation of cancer
Hypercalcemia as a paraneoplastic syndrome
most common, occurs due to calcemic humoral substance production
CA associated with hypercalcemia
squamous cell carcinoma of lung, breast and renal carcinoma, adult t-cell leukemia/lymphoma
Molecules associated with hypercalcemia
PTHRP, TGF-a TNF, IL-1
Most common endocrinopathy
Cushing syndrome
CA associated with Cushing syndrome
small-cell carcinoma of the lung, pancreatic carcinoma, neural tumors
Neuromyopahtic neoplastic syndromes
take diverse forms possibly caused by self reactive antibodies; mechanisms are not entirely known
Acanthosis nigricans
disorder characterized by gray-black patches of thickened and hyperkeratotic skin with a velvety appearance
CA associated with acanthosis nigricans
gastric, lung, uterine carcinomas
Hypertrophic osteoarhthropathy
periosteal new bone formation at distal ends of long bones, arthritis of adjacent joints, clubbing of digits
CA associated with hypertrophic osteoarthropathy
lung carcinoma
Why grade tumors?
allows the ability to quantify the probable clinical aggressiveness of a given neoplasm and its extent and spread
Grading cancers is based on…
degree of differentiation and number of mitoses/architectural features
Staging of cancers is based on…
size of primary lesion, extent of spread to lymph nodes, presence or absence of blood borne metastases
TNM staging
primary Tumor, Node involvement, Metastases
Methods of tissue sampling
needle aspiration, excision or biopsy, cytologic smears
Fine needle aspiration
aspirating cells from tumor, often rapid and reliable
Cytologic smears
often used for bladder, lung, endometrium, cervix to identify tumor cells
Cytologic features evaluated in a smear
anaplasia, dysplasia, cellular changes
Immunohistochemistry
identifying cell products or markers using antibodies
How can immunohistochem be used to categorize tumors?
Abs specific to cytoskeletal proteins in different cells, ags can be used to determine the location of origin, used to determine prognosis
Flow cytometry
quantitatively measures cell characteristics, especially cellular antigens expressed by liquid tumors
Circulating tumor cell assessment
permits detection, quantification and characterization of solid tumors circulating in the blood
Diagnosis of malignant neoplasms
PCR-based evaluation, DNA microarrays
Prognosis of malignant neoplasms
evaluation of genetic alterations; NMYC gene amplification and 1p deletions
Detection of minimal residual disease
assessed by PCR amplification of sequences unique to the clone
Diagnosis of hereditary predisposition to CA
detection of germline mutations to consider prophylactic surgery and counseling
Guiding therapy with oncoprotein-directed drugs
identification of genetic lesions, treatments that can be directed against the effects of oncoproteins
Difficulties of NextGen sequencing
expensive and lengthy process
Major impacts of cancer genome sequencing
ID of new mutations that underlie cancers, description of genetic lesions, greater appreciation of genetic heterogeneity
Diagnostic path that will most likely evolve…
morphologic and molecular techniques
Genetic complexity of tumors
chromothripsis is a likely culprit of cancer cell development - single catastrophic event that lead to formation of multiple breaks, results in many gene rearrangements
Tumor markers for diagnosis
can be used for detection of cancers and effectiveness of therapy
Sensitivity/specificity of tumor markers
low; may come from nonneoplastic conditions
Tumor associated with HCG
trophoblastic tumors, testicular tumors
Tumor associated with calcitonin
medullary carcinoma of thyroid
Tumor associated with catecholamines and metabolites
pheochromocytoma
Tumor associated with alpha-fetoprotein
liver cell cancer
Tumor associated with carcinoembryonic antigen
carcinoma of colon, pancreas, lung, stomach heart
tumor associated with prostatic acid phosphatase
prostate CA
Tumors associated with neuron-specific enolase
small-cell CA of lung, neuroblastoma
Tumor associated with immunoglobulins
multiple myeloma
Tumor associated with prostate-specific antigen
prostate CA
Tumor associated with CA-125
Ovarian CA
Tumor associated with CA-19-9
Colon cancer, pancreatic cancer
Tumor associated with CA 15-3
Breast CA
Tumor associated with TP53, APC, RAS mutants
colon CA
Tumor associated with TP53 and RAS mutants in stool and serum
pancreatic CA
Tumor associated with TP53, RAS mutants in sputum and serum
lung CA
Tumor associated with TP53 mutants in urine
Bladder CA
