10 Tumor Biology

Question 1

What is the multi-hit theory of carcinogenesis?

Answer 1

This theory postulates that cells must acquire multiple mutations or aberrations in order to develop into cancer. Different types of tumors may result from different cellular changes.

Question 2

What biological processes are thought to contribute to cancer development, growth, and persistence?

Answer 2

1. Aberrant cell signaling controlling mitosis and cell differentiation
2. Decreased apoptosis, or programmed cell death
3. Angiogenesis, or the growth of new blood vessels

Question 3

What are some molecular techniques used to analyze causes of head and neck cancer development?

Answer 3

1. Immunohistochemistry (IHC): Stains for proteins in tumor specimens.
2. Fluorescent in situ hybridization (FISH): Uses fluorescent probes to analyze for DNA translocations.
3. Next generation sequencing: Several methods that allow a wide number of genes to be analyzed for mutations simultaneously.

Question 4

What are oncogenes, proto-oncogenes, and tumor suppressor genes?

Answer 4

An oncogene is a gene that confers the potential to cause cancer, and a proto-oncogene is a normal gene that can contribute to cancer formation when mutated. A tumor suppressor gene is one that protects a cell from transitioning to cancer. Mutations in tumor suppressor genes that cause loss of function may allow the cell to progress to cancer, especially when combined with overexpression of oncogenes and mutations in proto-oncogenes.

Question 5

What are the most common risk factors for head and neck squamous cell cancer (HNSCC) worldwide?

Answer 5

1. Tobacco use
2. Alcohol consumption
3. Human papillomavirus (HPV) infection, especially in oropharyngeal cancer
4. Betel nut chewing

Question 6

What is the concept of field cancerization?

Answer 6

Field cancerization refers to epithelium changes adjacent to an invasive cancer showing precancerous alterations such as dysplasia or carcinoma in situ. This is more common in smoking-related cancers, implying that such risk factors may be more broadly impacting the tissues.

Question 7

Which “high-risk” HPV virus type is most commonly implicated in HNSCC?

Answer 7

HPV type 16

Question 8

How does HPV cause HNSCC?

Answer 8

HPV is a DNA virus that will insert genes into host DNA which then act as oncogenes.

1. E6 protein: An oncoprotein that inactivates p53, a host tumor suppressor protein that blocks apoptosis
2. E7 protein: An oncoprotein that inactivates the retinoblastoma (Rb) tumor suppressor protein and promotes host DNA synthesis and cell cycle progression through the release of E2F.

Question 9

How is HPV tested for in patients with HNSCC?

Answer 9

1. HPV DNA in-situ hybridization: This looks for HPV DNA in cancer cells.
2. P16 protein over expression by immunohistochemistry: P16 is downstream of Rb and, when Rb is destroyed by HPV oncoproteins, P16 protein levels increase.
   
   • not as specific

HPV-negative SCC: p53 mutations | ↓ p16 | ↑ pRb

HPV-positive SCC: wild type p53 | ↑ p16 | ↓ pRb

Question 10

What key molecular pathways appear to be important in HNSCC for pathogenesis and potential treatment targets?

Answer 10

1. p53, a tumor suppressor altered in most HPV-negative HNSCC
2. Epidermal growth factor receptor (EGFR)
3. Phosphoinositide 3-kinase (PI3K)
4. NOTCH-1
5. Cyclin D1

Question 11

How do p53 mutations cause oncogenesis in HNSCC?

Answer 11

1. Wild-type p53 is a tumor suppressor protein that plays a role in apoptosis and cell cycle regulation. Mutations of the TP53 gene allow increased cell survival and growth in an unregulated fashion.
2. Mutations are present is most HPV-negative HNSCC but only a minority of HPV-postive tumors (E6 affects normal p53, not the gene)

Question 12

What is the role of EGFR in HNSCC?

Answer 12

1. EGFR is a member of a family of tyrosine kinases that is overactivated in HNSCC. This results in increased activation of downstream pathways including Ras/Raf/MAPK, PI3K-Akt, and transcription pathways promoting angiogenesis, proliferation, metastasis, and invasion.
2. EGFR is upregulated in up to 90% of HNSCC.
3. It may have different levels of importance in HPV-positive and HPV-negative tumors.

Question 13

Which molecular pathway has the only FDA-approved targeted drug for treatment of HNSCC?

Answer 13

EGFR is the only molecular pathway that has a FDA-approved targeted drug to treat HNSCC. The targeted therapy is cetuximab, an IgG1-human monoclonal antibody against the extracellular domain of EGFR.

Question 14

What is the role of the PI3K pathway in HNSCC?

Answer 14

1. The PI3Ks are a family of enzymes that play a role in cellular regulatory mechanisms (downstream from EGFR as well). In HNSCC their signaling is increased, activating mTOR proteins resulting in increased cell growth, survival, proliferation, and migration.
2. Mutations of the PI3KCA gene have been found in 6% to 20% of HNSCC.
3. PIK3CA mutations appear to be more common in HPV-positive cancers.

Question 15

How does the NOTCH pathway play a role in HNSCC?

Answer 15

1. The NOTCH family of receptors are thought to play a tumor suppressor role in squamous cell cancers. Patients with a NOTCH-1 inactivation mutation have a dysregulated pathway thought to promote cancer cell survival.
2. NOTCH is mutated in 12% to 15% of HNSCC.

Question 16

What receptors are overexpressed in salivary gland tumors and may be exploited as potential biological targets for treatment?

Answer 16

1. c-kit is a proto-oncogene that can stimulate growth and differentiation. It is mainly increased in adenoid cystic carcinoma (78% to 92%) and some mucoepidermoids (0% to 40%). Clinical trial with c-kit inhibitors have been disappointing to date.
2. EGFR is increased in adenoid cystic carcinoma (36% to 85%), mucoepidermoid (53% to 100%), adenocarcinoma (60%), salivary duct cancers (9% to 40%), and others.
3. HER-2/neu receptor is involved in cell growth and differentiation. It is increased mostly in salivary duct cancers (44% to 83%), but can also be found in adenocarcinomas (14% to 21%), mucoepidermoids (0% to 38%), and adenoid cystic carcinoma (2% to 36%).
4. Androgen receptor is increased in salivary duct cancers (43% to 100%) and adenocarcinomas (21%).

Question 17

What recurring translocations occur commonly in salivary gland cancers?

Answer 17

1. t(11;19) producing a fusion protein CRTC1-MAML2 is seen in mucoepidermoid carcinomas (found in about 30%).
2. t(6;9) MYB-NFIB translocations are seen in adenoid cystic carcinomas. It is estimated that 80% to 90% of adenoid cystic carcinomas have MYB activation by gene fusion.
3. t(12;15) ETV-NTRK3 translocations are seen in mammary analogue secretory carcinomas (found in >90%).

Question 18

What are the different histologic types of thyroid cancer and what cells do they arise from?

Answer 18

1. Papillary: well differentiated tumor of the thyroid epithelium
2. Follicular: well differentiated tumor of the thyroid epithelium
3. Medullary: neuroendocrine tumor of the parafollicular or C cells of the thyroid gland
4. Anaplastic: undifferentiated tumors of the thyroid follicular epithelium
5. Hürthle cell: follicular epithelium

Question 19

What genetic mutations are commonly found in papillary thyroid cancer (PTC)?

Answer 19

1. RET/PTC: RET codes for a glial cell line–derived neurotrophic factor receptor that has tyrosine kinase activity.
   
   1. Patients can have somatic or germline mutations (MEN-2 syndromes).
   2. Mutations occur in about 40% of PTC.
2. NTRK1: A nerve growth factor with tyrosine kinase activity
3. BRAF: Activates the RAF/MEK/MAPK signaling pathway promoting tumorigenesis, invasion, metastasis, and recurrence. Mutations occur in 40% to 60% of PTC.

Question 20

What genetic mutations are commonly found in follicular thyroid cancers (FTC)?

Answer 20

1. Translocation t(2;3)[q13:p25]: Resulting in a fusion protein of PAX8 (a thyroid transcription factor) and PPAR-gamma-1 (a transcription factor that stimulates cell differentiation and inhibits cell growth). Estimated to be in about 40% of FTC.
2. HRAS/KRAS/NRAS: Proto-oncogenes that affect the MAPK and PI3K-AKT pathways promoting tumorigenesis, invasion, and metastasis (30% to 45% of FTC).
3. PTEN: The mutation or deletion inactivates the gene which activates the PI3K pathway promoting tumorigenesis and invasiveness (10% to 15% of FTC)

Question 21

What genetic mutations are commonly found in anaplastic thyroid cancer (ATC)?

Answer 21

1. BRAF: V600E activating mutation (25% of ATC)
2. TP53: An inactivating mutation that promotes tumor progression. Seen in 70% to 80% of ATCs
3. PIK3CA: An activating mutation affecting the PI3K-AKT pathway promoting tumorigenesis and invasiveness (15% to 25% of ATC)
4. RAS: Activating mutation affecting the MAPK and PI3K-AKT pathways (20% to 30% of ATC)

Question 22

What is the major gene mutated in medullary thyroid cancer (MTC)?

Answer 22

1. RET: A proto-oncogene that has gain-of-function mutations in medullary thyroid cancer resulting in tumor pathogenesis
   
   1. Sporadic MTC: Somatic mutations seen in 20% to 80%, often associated with worse prognosis
   2. Familial MTC: >95% have RET mutations. Seen in patients with MEN2A, MEN2B, and familial MTC.