Molecular Basis of Neoplasia - Nelson

Question 1

Define neoplasia.

Answer 1

“New growth”

_{An abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after cessation of the stimuli which invoked the change.}

Question 2

What is the underlying pathogenic mechanism of neoplasia?

Answer 2

• Stimulus causes genetic alterations in a single cells
• Alteratings in DNA are passed on to the progeny of the tumor cell and all subsequent tumor cells
• Allows excessive and unregulated proliferation that becomes autonomous

Question 3

What is the key difference between benign and malignant neoplasms?

Answer 3

• Benign
  
  • cannot spread to other tissues
  • does not metastasize
• Malignant
  
  • have the capability to metastasize

Question 4

What are the four types of genes typically mutated in cancer?

Answer 4

1. Growth-promoting proto-oncogenes
2. Growth-inhibiting tumor suppressor genes
3. Genes that regulate programmed cell death (apoptosis)
4. Genes involved in DNA repair

Question 5

What are the 8 essential alterations involved in the malignant transformation of cells?

Answer 5

1. Self-sufficiency in growth signals
2. Insensitivity to growth-inhibitory signals (inactivation of tumor suppressor genes)
3. Altered cellular metabolism (aerobic glycolysis, a.k.a. the Warburg effect)
4. Evasion of apoptosis
5. Limitless replicative potential
6. Sustained angiogenesis
7. Ability to invade and metastasize
8. Ability to evade the host immune response

Question 6

Define proto-oncogene.

Answer 6

A normal gene that can become an oncogene due to mutations or increased expression.

Question 7

Define oncogene.

Answer 7

• A gene that has the potential to cause cancer.
  
  • In tumor cells, they are often mutated or expressed at high levels.

Question 8

Define oncoprotein.

Answer 8

• A protein that is coded for by an oncogene.
• Have the ability to promote cell growth in the absence of normal growth-promoting signals

Question 9

For a given proto-oncogene, how many alleles are typically mutated in order to generate an activating mutation?

Answer 9

Generally, only one allele needs to become mutant to create an effect.

Question 10

What are some of the functional types of proto-oncogene mutations?

Answer 10

• ABL = nonreceptor tyrosine kinase activity
• HER (ERBB₂) = receptor synthesis
• MYC = nuclear transcription
• RAS = guanosine triphosphate signal transduction
• RET = receptor synthesis
• SIS = growth factor synthesis
• ABL-BCR = fusion gene
• BRAF = associated with melanomas
• KIT = results in activation of tyrosine kinase receptor c-KIT

Question 11

What is the rationale of performing Her2/neu testing in breast cancer and KRAS mutation analysis in colon cancer?

Answer 11

• Her2/neu
  
  • can treat with monoclonal antibody to Her2/neu receptor if present
  • trastuzumab (Herceptin)
• KRAS mutation analysis
  
  • can treat with EGFR monoclonal antibody that blocks ginding of the growth factor
    
    • prevents downstream signaling

Question 12

Define tumor suppressor gene.

Answer 12

Genes that regulate the formation of products that inhibit cell proliferation and prevent uncontrolled growth.

Question 13

What are three functions of tumor suppressor genes?

Answer 13

1. Regulation of the cell cycle
2. Regulation of nuclear transcription
3. Regulation of cell differentation

Question 14

What is the “two hit” hypothesis for suppressor gene defects?

Answer 14

Both alleles of tumor suppressor genes need to be damaged for loss of growth inhibition.

• homozygous for the mutant allele
• if one mutant allele is inherited, need one sporadic mutation
• two sporadic mutations

Question 15

How can an inherited mutation of a suppressor gene can give rise to an increased risk of familial cancer?

Answer 15

• All somatic cells inherit one mutant allele from a carrier parent
• only need one sporadic (acquired) mutation to cause cancer

Question 16

What are the malignancies associated with inheritance of BRCA1/2 and APC mutations?

Answer 16

• BRCA1/2
  
  • greatly increased risk of developing breast cancer in ther lifetimes
  • also at increased risk for other malignancies such as ovarian cancer
• APC
  
  • type of colon cancer: familial adenomatosis polyposis (FAP)
  • there is 100% risk of colorectal adenocarcinoma

Question 17

How can overexpression of BCL-2 lead to follicular lymphoma?

Answer 17

BCL2 gene products regulate and prevent apoptosis.

• overexpression of BCL2 protein products protects the lymphocytes from apoptosis, allowing them to survive for long periods (reduced cell death)

Question 18

How can overexpression of telomerase lead to limitless replication?

Answer 18

• telomerase reactivation
• Allows cells to excape the bridge-fusion-breakage cycle, thus promoting their survival and tumorigenesis.
• cells do not become senescent (continue to divide and grow)

Question 19

How do cancer cells initiate neoangiogenesis?

Answer 19

• tumor cells produce angiogenesis promoters
  
  • VEGF

Question 20

What are the four major steps involved in invasion and metastases?

Answer 20

• Invasion of the extracellular matrix
• Vascular dissemination
• Homing of tumor cells
• Colonization

Question 21

What are some of the ways that cancer cells can evade immunologic detection?

Answer 21

• Selective outgrowth of antigen-negative variants
• Loss or reduced expression of MHC molecules
• Tumor cells may downregulate the expression of costimulatory factors on antigen-presenting cells
• Secretion of immunosuppressive factors
• Induction of regulatory T cells

Question 22

What is the number of alleles that need to be mutated for dysfunction of DNA repair?

Answer 22

One?

• Individuals born with inherited defects in DNA repair mechanisms are at greatly increased risk of developing cancer.
• DNA repair genes themselves are not oncogenic, but their abnormalities greatly enhance the occurrence of mutations in other genes during the process of cell division.

Question 23

What is the defect in Hereditary Nonpolyposis Colon Cancer Syndrome (HNPCC)?

Answer 23

• inactivation of genes involved in DNA mismatch repair
  
  • defect allows mutations to accumulate in the genome

Question 24

What are some of the structural chromosome changes that can be seen in malignancies?

Answer 24

• Chromosomal translocations
• Deletions
• Gene amplification
• Chromothrypsis (chromosome “shattering”)

Question 25

How are gene expression profiles used in the assessment of breast cancer?

Answer 25

• determines the expression of a panel of 21 genes in tumor tissue
• calculates Breast Cancer Recurrence Score for individuals with a particular cancer and treatment
  
  • i.e. predicts recurrence rate after 10 years

Question 26

What is the Warburg effect? How this effect is used in the imaging of cancer?

Answer 26

• Altered cell metabolism in cancer cells
  
  • cancer cells quite consistently shift their glucose metabolism to aerobic glycolysis
• The metabolic change can be used to visualize tumors via positron emission tomagraphy (PET) scanning
  
  • inject pt with a non-metabolizable derivative of glucose that is preferentially taken up into tumor cells (as well as normal, actively dividing tissues)

Question 27

How is the new classification system of cancer different from the old classification system?

Answer 27

• Classification according to therapeutic targets
  
  • “Molecular classification of cancer”
• Old: cell of origin and morphology