Molecular and Genetic Basis of Neoplasia

Question 1

what is neoplasia?

Answer 1

disorder of cell growth triggered by a series of acquired mutations affecting a single cell and its clonal progeny; genetic disease

autonomous growth
escape form normal restraints on cell proliferation

Question 2

what are the three most common new cancer cases for men and for women?

Answer 2

men: prostate, lung and bronchus, colon and rectum
women: breast, lung and bronchus, colon and rectum

Question 3

what are the four most common cancers that result in death for men and for women?

Answer 3

men: lung and bronchus, prostate, colon and rectum, pancreas
women: lung and bronchus, breast, colon and rectum, pancreas

Question 4

define the differences between benign and malignant neoplasms.

Answer 4

benign: localized, incapable of invasion into surrounding tissue, incapable of metastasis, good clinical behavior/prognosis
malignant: capable of invasion into surrounding tissue, capable of metastasis, bad clinical behavior/prognosis (death most often due to metastatic spread)

Question 5

what are systemic effects of cancer?

Answer 5

local invasion or impingement, functional activity, bleeding and secondary infections, rupture or infarction, cachexia (cytokine mediated effect of cancer in the later stages of cancer when it has become large/metastized - causes a hypermetabolic state in the body…associated with severe weight loss and anorexia)

Question 6

what are paraneoplastic syndromes? give 2 examples.

Answer 6

patterns of symptoms or symptom complexes associated with cancer that cannot be directly explained by local or distant spread of the cancer or by the elaboration of hormones indigenous to the tissue from which the tumor arose

cushing syndrome: small cell carcinoma of lung
hypercalcemia: squamous cell carcinoma of lung

Question 7

what are tumor markers? when do you use them?

Answer 7

biochemical products produced by tumor cells

can be used for screening, but mostly for follow-up, detection of recurrence; also for aiding in diagnosis (limited scope) and staging

Question 8

what is the difference between cancer staging and grading?

Answer 8

grading: histologic dtermination of degree of differentiation (how closely does the cancer cell resemble normal cells)
staging: multi-modality determination of extent of spread of malignant neoplasm (clinical, radiological, pathological, biochemical components) - looking at invasion, absolute size, and metastasis

Question 9

what is the single most important thing done when diagnosing cancer? How is this done?

Answer 9

staging; TNM
T: characteristics of primary tumor (size, extent of invasion)
N: involvement of regional lymph nodes
M: distant metastasis

strong correlation with clinical behavior/prognosis

Question 10

describe the two basic characteristics of neoplastic cells

Answer 10

increased proliferation and decreased cell death (aberration in apoptotic pathways)

Question 11

what is transformation?

Answer 11

the accumulation of nonlethal mutations in critical genes that confer survival advantage

Question 12

what types of cells normally cause cancer?

Answer 12

somatic; only a small proportion of all genes have the potential to cause cancer when mutated

only a small fraction of mutations are constitutional (present in all cells) but these are important because the can predispose to cancer and can be passed on to future generations

Question 13

how cancer associated genes be dysregulated?

Answer 13

chromosomal changes (translocations, deletions, gene amplification, chromothrypsis), point mutations, epigenetic changes, noncoding RNAs

Question 14

what are the hallmarks of cancer? (10)

Answer 14

1. evading growth suppressors
2. enabling replicative immortality
3. tumor-promoting inflammation
4. activating invasion and metastasis
5. genomic instability (mutator phenotype)
6. inducing angiogenesis
7. resisting cell death
8. deregulating cellular energetics
9. sustaining proliferative signaling
10. avoiding immune destruction

Question 15

how are oncogenes formed/ activated

Answer 15

GOF - only one allele needs to be mutated to form an oncogene…too much/little protein or abnormal protein

Question 16

how are tumor suppressor genes formed/activated

Answer 16

LOF - inactivation of both alleles or inactivation of protein function

Question 17

what are the classes of oncogenes?

Answer 17

growth factors, growth factor receptors, proteins involved in signal transuction, nuclear regulatory proteins (TF), cell cycle regulators (cyclins and CDK)

Question 18

how do these cells evade apoptosis?

Answer 18

over expression of BCL-2…protects cell form mitochondrial apoptotic pathway
ex: follicular lymphoma

Question 19

how do cells regain replicative immortality

Answer 19

evade senescence and escape mitotic crisis by activating telomerase

Question 20

what is necessary for tumor growth beyond 1-2 mm?

Answer 20

sustained angiogenesis…VEGF

Question 21

what is the difference between invasion and metastasis?

Answer 21

invasion is more local and metastasis is distant locations; both are multistep processes

note: there are different molecular mechanisms operational in different neoplasms

Question 22

how does metabolism change in cancerous cells/tumors?

Answer 22

shifts balance towards aerobic glycolysis from oxidative phosphorylation: Warburg effect

• decreased ATP output
• increased glucose uptake (basis for PET scan)
• provides metabolic intermediates for synthesis of cellular components
• metabolic reprogramming induced by deregulated pathways due to mutated oncogenes and tumor suppressor genes (ex: PI3K/AKT and MYC)

Question 23

how does cancer evade the host defense?

Answer 23

1. tumor antigens…overexpressed/aberrantly expressed cellular proteins; produced by oncogenic viruses; results in altered cell surface glycolipids and glycoproteins
2. antitumor effector mechanisms…cytotoxic T lymphocytes, natural killer cells and macrophages
3. immune surveillance and escape…selective outgrowth of antigen-negative variants; loss or reduced expression of MHC molecules; activation of immunoregulatory pathways; secretion of immunosuppressive factors by cancer cells; induction of regulatory T cells

basically:

• failure to produce tumor antigen
• mutations in MHC genes or genes needed for antigen processing
• production of immunosuppressive proteins or expression of inhibitory cell surface proteins

Question 24

what contributes to the genomic instability in cancer?

Answer 24

1. defective mismatch repair genes (MSH & MLH)…ex: HNPCC/Lynch
2. Defective nucleotide excision repair….xeroderma pigmentosum; skin cancer due to UV exposure
3. defective DNA repair by homologous recombination…ataxia-telangiectasia, fanconi anemia, bloom syndrome, BRCA1/BRCA2 mutations

Question 25

how does inflammation cause/help/harm cancer?

Answer 25

• release of growth factors that promote proliferation
• removal of growth suppressors
• enhanced resistance to cell death
• inducing angiogenesis
• activating and assisting invasion and metastasis
• evading immune destruction

can prevent cancer from growing but can also allow cancer to continue to divide and potentially cause more cancer