molecular basis for carcinogenesis I-III

Question 1

Properties of malignant cancer cells

Answer 1

unresponsive to normal proliferation control signals, De-differentiated, Invasive, Metastatic, Clonal origin, Increased transport of glucose, lack of contact inhibition, immortality, grow w/o solid surface

Question 2

multi-step process for cancer

Answer 2

1) Normal cell, 2) increased proliferation, 3+4) early/progressive neoplasia, 5) carcinoma, 6) metastasis

Question 3

gene mutations leading to cancer

Answer 3

Activated oncogenes (stimulate proliferation) or silenced tumor suppressor genes (normally inhibit cellular proliferation)

Question 4

cytogenetic abnormalities associated with malignancy

Answer 4

Translocations and deletions can effect promotors of oncogenes and tumor suppressor genes, aneuploidy leads to poor outcome in cancer, Loss of Heterozigosity

Question 5

Knudson theory

Answer 5

two-hit theory. Example: Retinoblastoma first hit is inherited mutation in pRB, second the LOH that leads to tumor growth

Question 6

Events that lead to LOH

Answer 6

mutation, mitotic recombination, chromosome loss, or environmental factors

Question 7

dominant cancer syndromes

Answer 7

Familial Adenomatous Polyposis (FAP-APC gene), Familial Retinoblastoma (RB gene; gene is recessive, but due to LOH is inherited dominantly), familial Creast and Ovarian Cancer (BRCA1 and BRCA2 genes) and Wilms tumor

Question 8

recessive cancer syndroms

Answer 8

Xeroderma pigmentosa (XP gene), Ataxia-telangiectasia (AT gene), Bloom’s syndrom, and Fanconi’s congenital aplastic anemia (FA genes)

Question 9

RB (Retinoblastoma) gene identification

Answer 9

Cytogentic analysis of cells w/ retinoblastomas had abnormal structure in 13q14, some retinoblastoma patients cells lack RB completely (PCR or Southern hybridization), others have a partial deletion or other recombination of RB

Question 10

RB gene protein properties

Answer 10

prevents cell entry into S phase when hypophosphorylated, phosphorylation by CDKs inactivate RB protein allowing cells to go from G1 to S phase, it is a tumor suppressor, universal protein, often a target of animal tumor viruses such as SV40 or HPV

Question 11

APC gene

Answer 11

tumor suppressor: regulates localization of Beta-catenin protein (kept in plasma membrane bound to E-cadherin) by degradation of any unbound/free Beta-catenin. W/o APC (lost in FAP patients) Beta-catenin goes to nucleus and rpoduces transcription of oncogens like c-myc.

Question 12

BRCA1 and BRCA2 genes

Answer 12

tumor suppressor: funtion in DNA repair and their loss may give tise to many mutations needed for malignancy

Question 13

p53 is not an oncogene

Answer 13

p53 mutant genes were dominant to the wild-type gene. Later found that mutant p53 protein can bind wild-type p53 and inactivate it.

Question 14

p53 “gaurdian of the genome”

Answer 14

cells missing p53 accumulate mutations at a high rate. P53 prevents potentially deleterious mutations through the replication of damaged DNA, inducing apoptosis in cells with too much

Question 15

p53 function

Answer 15

transcription factor important for gene expression, preventing cells from replicating damaged or foreign DNA. Also required for apoptosis. W/o p53 damaged DNA is replicated => mutations => cancer

Question 16

oncogenic viruses target Rb and p53

Answer 16

p53 interferes with life cycle of viruses. HPV E6 protein and Adenovirus E1B protein inactivated p53. RB protein is inactivated by HPV E6 protein and SV40 T antigen. Both inactivations are major routes to cancer

Question 17

oncogene discovery

Answer 17

discovered in certain oncogenic retroviruses with on particular viral gene segment v-onc, tumors rapidly grew from infected cells. Method. Take cells, put in agar, watch for proliferation.

Question 18

oncyogenic viral gene segments

Answer 18

v-src - Rous Sarcoma virus caused fibrosarcoma in birds, v-erb avian erythroblastosis virus, v-abl - Abelson leukemia virus from mice, v-myc - usually fused with portion of gag gene and is capable of neoplastic transformation

Question 19

v-src gene

Answer 19

codes pp60v-src protein - membran bound protein kinase that phosphorylates tyrosine residues in different proteins. These proteins further affect gene expression

Question 20

v-erb-B gene

Answer 20

protein is similar to cell surface receptor epidermal growth factor (EGFR), raises possibility this protein has growth stimulating properties. It exhibits tyrosine specific protein kinase activity

Question 21

v-abl gene

Answer 21

protein that phosphorylates tyrosine residues. Similar to c-ABL found in BCR-ABL translocation

Question 22

c-onc

Answer 22

endogenous oncogenes

Question 23

oncogenes as molecular markers

Answer 23

either quantitative (too much protein) or qualitative (overactive or unregulated protein) responsible for cancerous effects. Elucidation of function can help with theropies

Question 24

quantitative changes

Answer 24

N-myc amplified in neuroblastoma, HER2/neu (aka erbB2) amplified in 20% of breast cancers. Higher amplification correlates to poor pronosis

Question 25

qualitative changes

Answer 25

c-ras in human bladder caner cells have mutation in codon 12 or 61. Detection => poor prognosis

Question 26

heat maps

Answer 26

created by hybridization of tumor DNA with “gene chip” containing all human genomic DNA sequences as molecular probes. Used to correlate molecular data (gene copy number and gene expression) with relevant clinical info (tumor grade, survival, age, tumor stage)

Question 27

Breast cancer Xpress Chip

Answer 27

measures expression of 123 genes known to be altered in breast cancer. Tests for BRCA1 and p53 tumor suppressors and oncogenes like estrogen receptor (ER) and erbB2. used for diagnosis. Prognosis, and therapy.

Question 28

treatment for high erbB2 and high ER

Answer 28

Herceptin and tamoxifen respectively