Tumor Biology

Question 1

c-KIT is a proto-oncogene that is overactive in gastrointestinal stromal tumors (GIST)… What do you use to treat?

Answer 1

Imatinib or Gleevac… A tyrosine Kinase inhibitor.

Question 2

Her-2-Neu (gene is ERB-B2) is a biomarker for poor prognosis breast and ovarian cancers. How do you treat it?

Answer 2

Treat with Trastuzumab/Herceptin. Predicts unresponsiveness to estrogen therapy.

ERB-B2 is a proto-oncogene for breast and ovary cancer.

Question 3

What oncogene is driving astrocytomas and osteosarcomas?

Answer 3

Overexpression of SIS (oncogene), which leads to production of excessive beta-PDGF (platelet-derived growth factor). The cancer cells develop responsiveness to this factor, and drive a positive feedback autocrine loop.

Question 4

Which type of Ras is in pancreas, colon?

Answer 4

K-RAS. Proto-oncogene. Activated by breaking its intrinsic GTPase to self-regulate its activity.

Question 5

Which type of Ras is in bladder, kidney?

Answer 5

H-RAS. Proto-oncogene. Activated by breaking its intrinsic GTPase to self-regulate its activity.

Question 6

Explain the translocation involved in Chronic Myelogenous Leukemia (CML) and (sometimes) Acute Lymphoblastic Leukemia (ALL)

Answer 6

Due to translocation t(9,22) of Abl on chromosome 9, where it is tightly regulated, to constitutive active chromosome 22. Chromosome 22 is called the Philadelphia chromosome.

BCR-ABL fusion is constitutive, and can be blocked using imatinib or gleevac (same thing), a tyrosine kinase inhibitor.

Question 7

Explain Burkitt Lymphoma Pathogenesis and Risk Factor

Answer 7

One mechanism of its formation is a translocation (t8;14) which pushes the TF c-myc in front of the highly active immunoglobulin heavy chain on chromosome 14. This leads to constitutive production of c-Myc in B cells.

Note: This cancer is often driven in Epstein-Barr Virus in immunocompromised patients, where their B cells are being targeted to be overactive. An adequate T cell response to EBV is needed to prevent this lymphoma. EBV can cause a wide range of other B-cell lymphomas.

Question 8

What transcription factor is upregulated in 25-30% neuroblastoma cases?

Answer 8

n-MYC (n is for neuro!)

It can either be amplified on its chromosome many times in a row (known as a HSR or homogenously staining region), or it can be replicated many times into many independent bodies known as double minutes (can make thousands of gene amplifications using either mechanism).

Detected via FISH for the gene not the protein!

Question 9

Explain Mantle Cell Lymphoma Pathogenesis

Answer 9

Caused by a translocation of Cyclin D1 from chromosome 11 to 14 t(11;14)

Leads to overactivity of CDK4, hyperphosphorylation of Rb, release of E2F, promotion of entry into S phase.

Question 10

Explain Li-Fraumeni Syndrome

Answer 10

When a patient inherits a single mutation of p53, meaning they only need one more “hit” to set off error-prone cell division. Predisposed to very early age cancers.

Question 11

Explain Familial Adenomatous Polyposis Pathogenesis and Presentation

Answer 11

Presents with:

1. > 100 mucosal polyps (500-2500)
2. Polyp carpet.

Treated with Prophylactic colectomy.

Pathogenesis:
Caused by a mutation in APC, which is a tumor suppressor gene… two “hits” are required! Patients inherit one null mutation, the second one is somatic usually.

APC mechanism:

1. Degrades beta-catenin.
2. Without APC, beta-catenin accumulates and complexes with TCF, which is a transcription factor that stimulates growth factor production.

Question 12

Two Apoptotic Factors You Must Know:

Answer 12

Pro-apoptosis (genome stabilizing): BAX

Anti-apoptotic (cell survival): BCL-2

Question 13

Explain Follicular Lymphoma Pathogenesis

Answer 13

Mediated by an IgH-BCL-2 Fusion t(14;18), resulting in overexpression of BCL-2, the anti-apoptotic (technically not considered a “proto-oncogene).

Note: This tumor is a bit more slow growing, because tumor progression (at least initially) is being driven by an inability to apoptose, rather than by uncontrolled proliferation. That said, a tumor like this may not respond as well to treatments that target rapid division (at least initially)

Question 14

Direct carcinogens have which fundamental biochemical features?

Answer 14

They are electron-deficient, or electrophilic compounds that strip things from electron-rich nucleic acids.

Alkylating agents are the classic.

Question 15

How are indirect-acting carcinogens activated?

Answer 15

Mediated by body processing.

Question 16

Name two genetic variations that increase potency of oncogenic initiators?

Answer 16

CYPIAI… 10% of caucasian people have a highly inducible form. More readily activates polycyclic aromatic hydrocarbons, making them more potent carcinogens in these people.

Glutathione-S-transferase… 50% have deletions in this. It is involved in detoxifying polycyclic aromatic hydrocarbons. People that cannot detox will experience a more potent effect via polycyclic aromatic hydrocarbons.

Question 17

Explain Initiators vs Promoters

Answer 17

Initiators either directly or indirectly cause permanent DNA mutation.

Promoters are not tumorigenic, but enhances proliferation and pushes cell through cell cycle even if they are mutated. Alcohol, bile salts, phenols, hormones, phorbol esters can all be complicit in oncogenesis through these mechanisms.

Question 18

What are Polycyclic Aromatic Hydrocarbons?

Answer 18

Among the most potent chemical carcinogens; they are INITIATORS.

3 fused benzene rings

Coal, oil, iron, steel, tobacco smoke. Many cancers

Question 19

Ionizing Radiation (x-rays and gamma rays) predispose you to what types of cancers?

Answer 19

Internal cancers. Leukemias, breast, colon, thyroid, lung to name a few. Generated from nuclear fission reactions (bombs or reactor leaks), radiologic testing (x-rays, CT scan), occupational exposures.

Question 20

How does UV light cause damage?

Answer 20

Creates pyrimidine dimers, which have to be fixed by the nucleotide excision pathway. People with defects in this pathway develop xeroderma pigmentosum.

Can also directly mutate proto-oncogenes, and causes the full gamut of skin cancer (Basal cell carcinoma, squamous cell carcinoma, melanoma)

Question 21

HPV causes papillomas and carcinomas where?

What are the high risk strains?

Answer 21

Squamous papilloma of oral cavity, larynx

Squamous dysplasia, carcinoma in situ, and squamous cell carcinoma of genitourinary tract and anus or larynx.

Mediated by integration into host cell chromosome.

High risk strains: 16, 18, 31, 33
Low Risk: 6, 11

They different in the affinity of E6 and E7 for host cell machinery, which promotes host division (mechanisms will not be tested).

Question 22

Hepatitis B and C mechanism for hepatocellular carcinoma (HCC)

Answer 22

Promote a chronic host inflammatory response, with constant regeneration. Constant cell proliferation and immune response resulting in tissue injury promote an oncogenic environment in the liver, resulting in cirrhosis and possibly cancer.

Chronic Inflammation = Pathologic Hyperplasia in tissues with regenerative potential

Question 23

H pylori pathogenesis and two cancers it can cause

Answer 23

Causes a chronic host inflammatory response. Endless cycle of regeneration leads to metaplasia (to a mature cell type that can better tolerate damage) to dysplasia (developmentally delayed epithelium) to carcinoma (no longer responsive)

Leads to MALToma and gastric adenocarcinoma

MALToma = mucosa-associated lymphoid tissue in GI tract.

MALTomas are encouraged by polyclonal expansions that select for lymphocyte clonal populations with additional mutations.