Nelson- Neoplasm

Question 1

Define Neoplasm

Answer 1

New growth

Abnormal mass of tissue
Growth exceeds and is uncoordinated w/ normal tissue
Persists once the stimuli stops that invoked the change

Question 2

What is the pathogenic mechanism of neoplasia?

Answer 2

Genetic alterations in a single cell>
passed to progeny thrpugh clonal proliferation>
tissue mass

Question 3

What is the key difference between benign and malignant neoplasms?

Answer 3

Benign
CAN’T spread to other tissues (don’t metastasize)
NOT locally invasive

Malignant
CAN spread to other tissues
Locally invasive and destroys adjacent structures

Question 4

What are the 4 types of genes that are typically mutated in cancer?

Answer 4

1. Proto-oncogenes (growth promoting)
2. Tumor suppressor genes (growth inhibiting)
3. Genes that regulate 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 (proliferate w/out external stimuli)
2. Insensitivity to growth-inhibitory signals (TSGs)
3. Evasion of apoptosis
4. Limitless replicative potential (telomeres)
5. Sustained angiogenesis
6. Ability to invade and metastasize
7. Defects in DNA repair
8. Escape from immune attack

Question 6

What is a proto-oncogene?

Answer 6

Make the proteins involved in growth signaling pathways

Question 7

What are oncogenes?

Answer 7

Created by mutated proto-oncogenes–> oncoproteins

Gene that has the potential to cause cancer.

Question 8

What’s an oncoprotein?

Answer 8

Oncoproteins resemble the normal products of proto-oncogenes except they’re devoid of regulatory elements–> autonomous growth.

Question 9

How many alleles are typically mutated in order to generate an activating mutation?

Answer 9

Only ONE allele needs to be mutated.

Question 10

Which fusion gene results in increased tyrosine kinase activity?

Answer 10

ABL-BCR

Question 11

Which gene results in the over expression of cell membrane epidermal growth factor receptor?

Answer 11

Her2/NEU
In breast cancer

*Treat w/ monoclonal Ab to Her2/NEU receptor (trastuzumab)

Question 12

What does the RAS mutation cause and how does it relate to colon cancer?

Answer 12

Persistent activation of the RAS signal

KRAS for colon cancer

Question 13

What gene mutation is associated w/ melanomas?

Answer 13

BRAF

Question 14

What gene is mutated in gastro-intestinal tumors?

Answer 14

KIT–> activation of tyrosine kinase receptor (c-KIT)

Question 15

CML is associated w/ what mutation?

Answer 15

ABL
Translocation y(9:22)

Question 16

Breast carcinoma is associated w/ what mutation?

Answer 16

HER

Amplification

Question 17

Burkitt’s lymphoma is associated w/ what mutation?

Answer 17

MYC
Translocation t (8:14)

Question 18

Neuroblastoma is associated w/ what mutation?

Answer 18

N-MYC

Amplification

Question 19

Leukemia is associated w/ what mutation?

Answer 19

RAS

Point mutation

Question 20

Osteogenic sarcoma is associated w/ what mutation?

Answer 20

SIS

Question 21

Why do you perform a her2/neu test in breast cancer?

Answer 21

Because 25% of breast cancers over express an epidermal GF called HER-2/NEU.
Pts with this GF can be treated w/ a monoclonal Ab (Trastuzumab)

Question 22

Why do you perform a KRAS mutation analysis in colon cancer?

Answer 22

Because KRAS mutations are found in 40% of CRC.

Question 23

What is a tumor suppressor gene?

Answer 23

Genes that inhibit cell proliferation and prevent uncontrolled growth

Question 24

What are the functions of TSGs?

Answer 24

Regulate the cell cycle at checkpoints
Regulate nuclear trxn
Regulate cell differentiation

Question 25

What is the two hit hypothesis for suppressor gene defects?

Answer 25

Explains sporadic and inherited occurence of tumors. 1. homozygous for a mt allele 2. One mutant allele is inherited and the second loses it's heterozygosity for the normal gene

Question 26

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

Answer 26

You only need to get the gene from one parent to inherit the disease. *Autosomal dominant

Question 27

What are malignancy is associated w/ inheritance of BRCA1/2?

Answer 27

Women w/ this mut have a greatly increased risk of developing breast cancer in their life time (60%).

Question 28

What are malignancy is associated w/ inheritance of APC mutations?

Answer 28

APC mut--> loss of tumor supressor function--> large numbers of adenomatous polyps in the colon and rectum 100% risk of colorectal adenocarcinoma

Question 29

How does the over-expression of BCL-2 lead to follicular lymphoma?

Answer 29

BCL-2 usually regulated and prevents apoptosis by limiting the release of cyt c. Overexpressed BCL2--> Protects lymphocytes from apoptosis> Reduced B cell death (rather than explosive proliferation). slow growing lymphoma

Question 30

How does the over expression of telomerase lead to limitless replication?

Answer 30

All malignant neoplasms maintain telomeres through the up-regulation of telomerase. Telomeres prevent gene loss after multiple cell divisions and generally shorten over time. When they're too short they're considered damaged and sensce.

Question 31

How do cancer cells initiate neoangiogenesis?

Answer 31

Angiogenesis is controlled by an increased production of VEGF/ loss of angiogenesis inhibitors.

Question 32

What cytokine is involved w/ neoangiogenesis?

Answer 32

VEGF

Question 33

What are the steps involved in invasion and metastases?

Answer 33

1. Invasion of ECM: dissociaton of tumor> degradation of basement membrane/connective tissue> attachment of tumor cells to ECM proteins, migration of tumor cells w/in ECM, enter into vasculature 2. Vascular dissemination and colonization: Tumor cells attach to endothelial cells of capillary bed. Colonization occurs d/t tumor cells secreting cytokines, GFs and ECM molecules that make metastatic site habitable for tumor cells.

Question 34

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

Answer 34

``` o Outgrowth of antigen negative variants o Loss/reduction of expression of MHC molecules o Immunosuppression o Antigen masking (glycocalyx molecules) o Apoptosis of cytotoxic T cells ```

Question 35

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

Answer 35

Translocations Deletions Amplifications **Accumulation of multiple mutations

Question 36

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

Answer 36

Breast cancer assays are used to determine the expression of 21 genes in tumor tissue. A recurrence score is calculated from the gene expression results. Based on a genetic profile you can calculate the % of recurrent cancer after 10 years of first incident.