Molecular Basis of Cancer

Question 1

four classes of normal genes that are the principal targets of genetic damage

Answer 1

growth-promoting oncogenes

growth-inhibiting tumor suppressor genes

genes that regulate apoptosis

genes involved in DNA repair

Question 2

mutator phenotype

Answer 2

a propensity to mutations, possibly due to damage in DNA repair genes

Question 3

eight essential alterations for malignant transformation

Answer 3

self-sufficiency in growth signals

insensitivity to growth-inhibitory signals

evasion of apoptosis

defects in DNA repair

limitless replicative potential

sustained angiogenesis

ability to invade and metastasize

ability to evade the immune system

Question 4

insertional mutagenesis

Answer 4

viral DNA is inserted near a protooncogene inducing a change in this cellular gene converting it into a cellular oncogene

Question 5

herceptin

Answer 5

a monoclonal antibody drug that targets breast tumors which overexpress HER-2/neu

Question 6

imatinib mesylate (Gleevec)

Answer 6

treatment for chronic myeloid leukemia, targets fusion protein BCR-ABL tyrosine kinase

Question 7

ras oncogenes

Answer 7

most common abnormality of dominant oncogenes in human tumors

normally involve codons 12, 59, or 61

carcinomas have KRAS

bladder tumors have HRAS

hematopoietic tumors have NRAS

Question 8

MYC oncogene

Answer 8

commonly found in tumors

dysregulation in Burkitt lymphoma

amplification in breast, colon, lung carcinomas

N-MYC amplification in neuroblastomas

Question 9

tumor suppressor genes

Answer 9

proteins that regulate growth inhibition

both copies need to be lost for cancer to develop, so these are recessive cancer genes

INK4a/ARF in familial melanomas

TGF-beta in HNPCC

NF1 and 2 in neurofibromatosis types 1 and 2

VHL on chromosome 3 in renal cell cancers

PTEN on chromosome 10q23 in endometrial carcinomas and glioblastomas

WT-1 gene on chromosome 11p13 in Wilms tumor

DCC gene on chromosome 18q21 in colon and renal carcinomas

Cadherin family in breast, esophagus, colon, ovarian cancer

Question 10

“two-hit” hypothesis

Answer 10

two mutations are necessary for cancer to develop, the first hit can be in genetically inherited mutations

the second hit happens in one of these mutant cells to generate cancer

Question 11

common tumor suppressor genes

Answer 11

RB gene on chromosome 13q14, loss or mutation predispose it to the development of retinoblastoma and osteosarcomas

WT-1 gene in Wilms tumor on chromosome 11, vonHippel Lindau (VHL) gene in celar cell renal carcinoma

Question 12

About how many genes have to be mutant before the malignant process begins?

Answer 12

loss of normal cell cycle control along with at least four regulators of the cell cycle

Question 13

p53 gene

Answer 13

“guardian of the genome”, located on chromosome 17p13.1 and mutated in more than 50% of human tumors

acts as a “molecular policeman” and leads to cell-cycle arrest and initiation of apoptosis in response to DNA damage

tumors with intact p53 respond very well to radiation and chemotherapy

Question 14

APC/beta-catenin pathway

Answer 14

individuals with mutated APC on chromosome 5q21 develop thousands of adenomatous polps in their colon at a very early age

Question 15

bcl-2

Answer 15

anti-apoptotic gene, overexpressed in B-cell follicular lymphomas

in some cancers such as lymphomas, bcl-2 on 18q21 is translocated to the immuoglobin heavy-chain locus in 14q32, causing it to become overexpressed

Question 16

angiogenesis

Answer 16

formation fo blood vessels around a tumor

stimulates tumor growth by secreting factors such as PDGF

tumor blood vessels differ from normal vessels in that they are tortuous and leaky

Question 17

angiogenic switch

Answer 17

essential for tumor growth, involves increased production of angiogenic factors or loss of angiogenic inhibitors

area of targeteed treatment using inhibitors of angiogenesis such as endostatin

Question 18

metastasis signature

Answer 18

tumor cells need the right combination of gene products to complete all the seps involved in metastasis

Question 19

two phases of the metastatic cascade

Answer 19

invasion of the ECM and vascular dissemination

homing of tumor cells

Question 20

invasion of the ECM

Answer 20

detachment of tumor cells from each other

attachment to matrix components

degradation of ECM

migration of tumor cells

attachment of tumor cells to laminin and fibronectin

protease degradation

escape from immune system by forming platelet aggregates in blood

Question 21

“homing” of tumor cells

Answer 21

adherence of the migrating tumor cell to the endothelium and going through the basement membrane

CD44 adhesion molecule important

proteases also important for integration of the cell

chemokines and cytokines are important for location

Question 22

important types of defeccts of DNA repair

Answer 22

mismatch repair, nucleotide excision repair, recombination repair

Question 23

BRCA-1 and BRCA-2 genes

Answer 23

two genes associated with the development of breast and ovarian cancer

60-85% lifetime risk of development of breast cancer,a nd 15-40% lifetime risk for the development of ovarian cancer

gene is important for homologous recombination leading to DNA repair

Question 24

adenoma-carcinoma sequence of colorectal cancers

Answer 24

the best example of a molecular model for multistep carcinogenesis

the buildup of mutations and lack of suppression leads to carcinoma

Question 25

gatekeeper genes

Answer 25

oncogenes and tumorsuppresssor genes

Question 26

caretaker genes

Answer 26

genes that do not directly control tumor growth bt affect genome stability such as repari genes

Question 27

RET protooncogene

Answer 27

associated with MEN type IIA and IIB, familial medullary thyroid carcinoma and Hirschsprung disease

Question 28

hereditary nonpolyposis cancer syndrome (HNPCC)

Answer 28

a condition of familial cancers of the colon that results from defects in DNA mismatch repair genes

Question 29

hallmark of defective mismatch repair

Answer 29

microsatellite instability

Question 30

diseases arising from defects in DNA repair by homologous recombination

Answer 30

ataxia-telangiectasia syndrome, Bloom syndrome, and Fanconi anemia