CNBY Exam 2

Mutation

change in a DNA sequence that affects genetic information

cell may not transcribe RNA

what happens when there is a mutation in a promoter?

truncated protein loses "off switch"

what happens when there is a mutation in the structure?

increases the copy number of the gene so there are more of the protein and when stimulated create overwhelming response to grow

what does amplification do?

new "fusion protein"

what does chromosomal translocation create?

transition

DNA mutations where a purine (A or G) is exchanged for another purine (G or A) or a pyrimidine (C or T) is exchanged for another pyrimidine (T or C). Can be silent, or can change amino acid during translation.

translocation

DNA mutations whereby the part of one chromosome is transferred to, or exchanged for, another part of a different chromosome

transversion

mutations whereby a purine is exchanged for a pyrimidine, or vice versa

Insertion

additional base pair is added

deletions

Mutation involving the removal of one or more nucleotide pairs from a gene (can be at base pair level or at whole gene level)

Sustaining proliferative signaling

when cells do not require external signals to continue growing and dividing (normal cells require mitogenic growth signals)

growth stimulating pathways

what do oncogenes mimic to sustain proliferative signaling

Oncogenes

genes whose products are capable of transforming a normal cell into a cancer cell

result from the mutation of normal genes (proto-oncogenes)

how are oncogenes created?

1. Src

name the 5 common oncogenes-1

2. Ras

name the 5 common oncogenes- 2

3. Myc

name the 5 common oncogenes- 3

4. Bcr-Abl

name the 5 common oncogenes- 4

5. Her2/neu

name the 5 common oncogenes

if cancer-causing genes (Ras) could be transferred directly from cancer cells to normal cells. cancer cell DNA should make normal cells proliferate

what did Robert Weinberg study?

1. mixed a solution of DNA and CaCl2 with HEPES buffered saline solution

describe Robert Weinberg's experiment to test his theory-1

2. DNA binds to calcium phosphate to form tiny white particles

describe Robert Weinberg's experiment to test his theory-2

3. particles are ingested by cells and would ingest DNA bound to it

describe Robert Weinberg's experiment to test his theory

• transferred mouse cancer cell DNA to normal cells = grew in clumps = cancer

what did Chiaho Shih do/discover?-1

• confirmed in human cells

what did Chiaho Shih do/discover?

1. Weinberg (MIT)

Group 1

2. Mariano Barbacid (NCI)

Group 2

3. Michael Wigler (NY)

what 3 groups isolated the same gene (Ras)?

Ras

what was the first "native" human oncogene discovered?

• pancreatic (90%)

what cancers can Ras mutations cause?-3

• papillary thyroid (60%)

what cancers can Ras mutations cause?-2

• colon (50%)

what cancers can Ras mutations cause?-1

• non-small cell lung (30%)

what cancers can Ras mutations cause?-4

Myc

a transcription factor, binds to regions of the DNA to promote transcription (make RNA, which then will be translated to protein)

mycelocytomatosis (leukemia + sarcoma)

what does Myc stand for?

chromosomal translocation

how is Myc altered in humans?

• Burkitt lymphoma (B-cell lymphoma)

in what human cancers is Myc consistently altered by chromosomal translocation?-2

• multiple myeloma (plasma cell)

in what human cancers is Myc consistently altered by chromosomal translocation?

Myc

what is one of the most highly amplified oncogenes in several human cancers (colon, lung, stomach, cervic)?

Philadelphia chromosome

An abnormal chromosome produced by translocation of parts of the long arms of chromosomes 9 and 22.

• David Hungerford and Peter Nowell

who discovered the Philadelphia Chromosome (shortened chromosome 22)?

Janet Rowley

Who found the missing head of chromosome 22 attached to chromosome 9?

• APL and AML

what else did Janet Rowley discover?

Bcr-Abl

what is the name of the unique fusion of 2 genes on different chromosomes in the Philadelphia chromosome?

• BCR: breakpoint cluster region protein

what does BCR do

• ABL: ABL Kinase

What does Abl do

• Bcr-Abl = constitutively active kinase

what does Bcr-Abl do?

Gleevac (imatinib)

what is the drug that targets Bcr-Abl?

Bcr-Abl trug that causes deep remission for CML patients

what is the first targeted molecular therapy for cancer?

Her2 has extracellular domain (large fragments hang outside unlike Ras, Myc, Src, and Brc-Abl)

what makes Her2 unique?

EGFR

what family is Her2 a part of?

Dennis Slamon

who found that Her2 was increased in ~20% of breast cancer samples?

Her2 positive

which is the more aggressive type of Her2 cancer?

Trastuzumab - Herceptin

antibody drug to target outside domain of Her2

Evading growth suppressors

-mutation (inactivation) of tumor-suppressor genes

loss or mutation (usually both copies) of tumor suppressor gene and oncogene and Allows unregulated cellular growth

what leads to tumor formation?

• regulate and monitor cell cycle progression

Tumor suppressors do-2

• regulate processes to repair DNA damage

what do tumor suppressor genes do?

1. Rb

1

2. TP53

2

3. BRCA 1/2

what are 3 common tumor suppressor genes?

two hit hypothesis

Tumor suppressor genes typically require both copies to be inactivated before an effect is seen. discovered by Alfred Knudson

• inherited only 1 genetic change needed because they inherited one mutation already

Difference between sporadic and inherited-2

• sporadic requires 2 genetic changes

difference between sporadic and inherited

• oncogenes: make them more active

mutations in oncogenes-2

• suppressors: lose their power to stop division

mutations in oncogenes vs mutations in suppressors

Rb

what protein is a gatekeeper for cell division?

sequesters a protein called E2F unless activated by a signal to release

what does Rb do in a resting state?

Rb is phosphorylated and releases E2F. the E2F will bind to DNA and control expression of genes that progress cell from G1 to S phase for proliferation

what does Rb do in normal proliferation?

Rb is not present so E2F is free to start proliferative signal whenever

what happens to Rb if there is cancer?

1. Lynch Syndrme

ex. 1

2. Li-Fraumeni Syndrome

ex. 2

3. BRCA 1/2 mutations

what are 3 examples of hereditary cancers/syndromes?

Lynch syndrome

known as hereditary non-polyposis colorectal cancer (HNPCC) that can cause colon cancer at a younger age

• MLH1

syndrome 1

• MSH2

syndrome 2

• MSH6

syndrome 3

• PMS2

syndrome 4

• EPCAM

what genes are mutated in Lynch syndrome?-5

no, but it greatly increases risk

will everyone who has Lynch syndrome get cancer?

• colorectal

what cancers are common among those with Lynch syndrome?-8

• stomach

what cancers are common among those with Lynch syndrome?-7

• pancreas

what cancers are common among those with Lynch syndrome?-6

• urinary tract

what cancers are common among those with Lynch syndrome?-5

• prostate

what cancers are common among those with Lynch syndrome?-4

• ovary and uterus

what cancers are common among those with Lynch syndrome?-3

• sweat gland (sebaceous carcinoma)

what cancers are common among those with Lynch syndrome?-2

• kidney

what cancers are common among those with Lynch syndrome?

Li-Fraumeni syndrome

a condition caused by a germline mutation in tumor suppressor gene TP53; more rare but increases risk by 50% of developing cancer by 40 and 90% chance of cancer by 60

• brain

what cancers are common among patients with Li-Fraumeni Syndrome?-5

• sarcoma

what cancers are common among patients with Li-Fraumeni Syndrome?-4

• breast

what cancers are common among patients with Li-Fraumeni Syndrome?-3

• lymph/leukemia

what cancers are common among patients with Li-Fraumeni Syndrome?-2

• adrenals

what cancers are common among patients with Li-Fraumeni Syndrome?

Guardian of the Genome

what is TP53's nickname?

• cell cycle arrest

what are the functions of P53 (protein)?-4

• DNA repair

what are the functions of P53 (protein)?-3