GP 24 - Pathology of Neoplasia 4

Question 1

What are the major types of genes and genetic changes that lead to a transformed cell?

Answer 1

Mutations and Epigenetic changes of oncogenes, tumor supressor genes, and apoptosis regulating genes.

Question 2

What are the four classes of carcinogenic agents?

Answer 2

• Chemical
• Physical
• Oncogenic Virus
• Bacterial Infection

Question 3

List the major chemical carcinogens we need to know and the types of cancer they cause.

Answer 3

• Direct Acting
  
  • Alkylating/Acylating Agents - lymphoma and leukemia
    
    • Cyclophosphamide (alkylating)
    • 1-Acetyl-imidazole (acylating)
• Indirect Acting (require metabolism)
  
  • Polycyclic Aromatic Hydrocarbons - lung cancer
    
    • Tobacco
  • Aromatic Amines and Azodye - liver and bladder CA
  • Nitrosamines and Amides - gastric cancer
  • Asbestos - mesothelioma and lung cancer

Question 4

Describe the general mechanism for chemical carcinogenesis

Answer 4

• Initiation Phase - carcinogen causes the mutation in the cell
• Promotion Phase - further changes allow for clonal expansion of mutated cell

Question 5

What are the two primary types of radiation carcinogenesis?

Answer 5

UV Rays

Ionizing Radiation

Question 6

What type of cellular damage does UV radiation cause and what are the most common types of cancer caused by it?

Answer 6

• UV radiation causes direct DNA damage, most notably the formation of pyrimidine dimers. This can overwhelm the nucleotide excision repair (NER) mechanism
• Common cancers
  
  • Melanoma
  • Squamous cell cancer
  • Basal cell cancer

Question 7

What types of radiation are ionizing and how does ionizing radiation damage a cell? What are the common types of cancers caused by ionizing radiation?

Answer 7

Ionizing radiaiton does damage by directly damaging DNA, altering proteins, inactivating enzymes, injuring membranes, and generating free radicals.

• Types of Ionizing Radiation
  
  • X-rays
  • Atomic Bomb - leukemia
  • Therapeutic Irradiation - thyroid cancer

Question 8

List the DNA and RNA oncogenic viruses we need to know and the types of cancers they cause.

Answer 8

• DNA Oncogenic Viruses
  
  • HPV - papilloma (skin, larynx), cervical cancer
  • EBV - nasopharyngeal carcinoma, Burkitt’s lymphoma
  • HBV/HCV - hepatocellular carcinoma
  • HHV-8 (herpes) - Kaposi’s Sarcoma (blood/lymph vessels)
• Oncotenic Retroviruses (RNA viruses)
  
  • Human T-cell leukemia virus (HTLV-1) - leukemia, lymphoma
  • Acute transforming - several different viruses and cancers
  • Slow transforming - several different viruses and cancers
    *

Question 9

How do oncogenic DNA viruses typically cause cancers?

Answer 9

They code for proteins which bind to specific host proteins (usually tumor suppressors) involved in the regulation of cell proliferation.

Question 10

Describe the basic carcinogenic mechanism of HTLV-1

Answer 10

• Infects T cells
• Codes for a viral Tax protein that stimulates proliferation, enhances cell survival, and interferes with cell cycle controls
  
  • Proliferation is initially polyclonal but secondary mutations may cause monoclonal outgrowth, which is leukemia

Question 11

Give the example of bacterial infection associated cancer we need to know.

Answer 11

H. pylori infection can cause B cell lymphoma in mucosa associated lymphatic tissue (MALT). Often called a MALToma

Question 12

What are driver and passenger mutations? Where in the genome do these mutations usually reside?

Answer 12

Driver Mutations - direct contributors to the development or progression of cancer. Usually tightly clustered within cancer genes

Passenger Mutations - acquired mutations to do not affect cellular behavior. These occur at random throughout the genome

Question 13

What are proto-oncogenes, oncogenes, and oncoproteins?

Answer 13

Proto-oncogenes - normal genes that play key roles in controlling cell proliferation and differentiation

Oncogenes - deregulated/altered proto-oncogenes that lead to development of cancer

Oncoproteins - the protein products of oncogenes

Question 14

What are the two most common point mutations seen in human cancers and why?

Answer 14

1. RAS (oncogene) mutations because the RAS genes control the activity of several GTP binding porteins that switch proteins on/off that control cell growth, differentiation, and survival
2. TP53 (tumor suppressor) mutations because the p53 protein senses DNA damage and helps repair by slowing the cell cycle. It also upregulates the BAX protein, leading to apoptosis.

Question 15

What is gene translocation? What are the examples of translocation causing cancer that we need to know?

Answer 15

Gene Translocation is the rearrangement of parts of non-homologous chromosomes.

• The translocation of the ABL oncogene from chromosome 9 to the BCR locus on chromosome 22 (t(9:22)) causes increased tyrosine kinase activity, resulting in chronic myelogenous leukemia (CML) and sometimes ALL
• The translocation of the CMYC oncogene from chromosome 8 to just after the IgH gene on chromosome 14 (t(8:14)with IgH) causes increased MYC protein production, resulting in Burkitt’s lymphoma
• CCND1 t(11:14) with IgH leads to overexpression of cyclin D1, resulting in mantle cell lymphoma

Question 16

What is gene amplification? What examples of it causing cancer do we need to know?

Answer 16

Gene amplification is the multiple replication of a gene within a genome, often resulting in increased presence of that gene’s product.

• N-MYC amplification leads to neuroblastoma
• ERBB2 (aka - HER2/neu) amplification leads to increased epidermal growth factor expression, resulting in breast and/or stomach cancer

Question 17

Why type of cancer does PDGF cause if it becomes an oncoprotein?

Answer 17

Astrocytoma (brain cancer - transformed astrocytes)

Question 18

Describe what the RB gene is and how it causes disease.

Answer 18

The retinoblastoma gene codes for the RB protein which binds and inhibits txn factor E2F causing cell cycle arrest at the G1-S checkpoint.

A loss of function mutation in RB frees up E2F and unchecked cell proliferation occurs, resulting in retinoblastoma.

Question 19

List the tumor suppressor genes we need to know and the cancers they cause when a loss of function mutation occurs.

Answer 19

• RB - retinoblastoma
• p53 - lung, colon, breast, and ovary cancers
• NF1 - hereditary neurofibromatosis
• BRCA1 and BRCA2 - breast carcinomas
• APC - adenomatous polyposis cell
• DCC - colon cancer
• WT-1 - Wilm’s tumor

Question 20

What are mutator genes? What are they also known as? Which ones do we need to know about?

Answer 20

Mutator (caretaker) genes are genes that code for proteins involved in DNA repair and stability. Mutations of these genes does not directly cause cancer, but it does allow for more mutations to occur unrepaired, possibly leading to cancer.

MSH2 and MLH1 are caretaker genes that, when mutated, can lead to the formation of hereditary non-polyposis colon cancer

Question 21

What is meant by the phrase “carcinogenesis is a multi step process?”

Answer 21

It means that mutation of a single oncogene/tumor suppressor is not usually enough to cause a malignant neoplasm. Several different genes must be mutated along the way to malignancy