3 Neoplasia Iii

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oncogenes [protooncogenes] are derived from normal cell genes involved in {3}

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normal growth, repair, entering cell cycle

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oncoproteins usually affect

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signaling transduction pathways (ie. GF, GF-R, signal transduction proteins, nuclear regulatory, cell cycle regulators) --> second messenger --> nuclear transcription

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impt proto-oncogene involved in astrocytomas and osteosarcomas (name type of protein)

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c-sis
PDGF / PDGF-R

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oncogenes that are homologs of FGF

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hst-1
int-2

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overexpressed in stomach cancer

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hst-1 (FGF homolog)

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amplified in bladder, breast ca, hepatocellular carcinoma

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int-2 (FGF homolog)

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ras (oncogene) causes overexpression of __(1)__ which is related to __(2)__ which is expressed in __(3)__ and __(4)__

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1. TGF-a
2. EGF
3. astrocytoma
4. hepatocellular ca

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involved in follicular thyroid cancer {2}

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HGF = hepatocellular growth factor
c-met = HGF receptor

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several oncogenes encode GF-R that are

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always on - even w/o binding of ligand

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RET protooncogene = receptor for ___ expressed in ___

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glial cell line-derived neurotrophic factor with tyrosine kinase activity;
neuroendocrine cells of the thyroid, adrenal medulla and parathyroid

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point mutation of RET assoc w/

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MEN 2A and 2B and familial medullary thyroid carcinoma [c-cells secrete calcinotin]

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Somatic rearrangement of RET assoc w/

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sporadic papillary carcinoma

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point mutation in fms which encodes ___ leads to ___

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CSF-1, myeloid leukemia

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overexpressed in 80% of SCC of lung and less commonly in carcinomas of bladder, GI tract and astrocytomas

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erb-b1 (EGFR)

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amplified in adenocarcinoma of the breast, ovary, lung, stomach and salivary gland

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erb B2 (Her2-neu)

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receptor for stem cell steel factor

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kit, involved in GI and other soft tissue tumors

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single most common abnormality of dominant oncogenes in human tumors

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ras (GTP protein)

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Non receptor associated tyrosine kinase

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c-abl

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nuclear regulator protein oncogenes

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myc, myb, jun, fos

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most common nuclear regulator protein involved in human cancers (breast, lung, colon, etc)

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myc

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N-myc amplification is seen with

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neuroblastoma, and small cell carcinoma of lung

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C-myc is involved in what translocation and disease?

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Burkitts lymphoma t(8,14)

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L-myc amplication seen in

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small cell carcinoma of lung

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cyclin and cyclin dependent kinases (CDK)'s do what?

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force quiescent cells to enter cell cycle

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mut in genes that encode ____ are implicated in several human cancer

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cell cycle regulators (cdk-i, etc)

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cyclin gene overexpressed in many cancers (breast, esophagus, liver, translocated in subset of lymphomas -- mantle cell lymphomas)

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Cyclin D

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amplification of ___ noted in glioblastoma, melanoma and sarcomas

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cdk4

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tumor suppressors - name the molecules that regulate nuclear transcription and cell cycle

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Rb, p53, WT-1, p16 (INK4a), KLF6, BRCA-1, BRCA-2

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location of Rb

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13q14

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job of Rb

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regulate cell cycle

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Knudson's 2 hit theory:
somatic mut of Rb

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inherited mut in Rb in all somatic cells (2nd hit in retinal cell)

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Knudson's 2 hit theory:
sporadic case of Rb

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both mut occur sporadically in single retinal cell

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Rb is found in all cells.
Active form?
Inactive form?

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active: underphosphorylated
inactive: hyperphosphorylated

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fxn of active Rb

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prevent G1 --> S transition
binds/sequesters E2F (TF)

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p53 - chromosome location. __% of tumors have a mut in p53

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17q13.1
over 50% human tumors have mut

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p53 fxn

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cell cycle arrest in response to DNA damage -- prevents propagation of genetically damaged cells

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tumors assoc w somatic mut in p53

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breast, lung, colon

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tumors assoc w/ inherited mut in p53

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Li Fraumeni Syndrome
multiple carcinomas (breast, brain)
sarcomas

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p53 binds ___ and ____

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binds DNA and stimulates transcription

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2 major effects of p53

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1. arrest of cell cycle (cdki p21)
2. apoptosis (Bax)

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what can stimulate the activation of normal p53

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hypoxia

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p53 can be inactivated by

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transforming proteins of DNA virus, E6 of HPV (bind and degrade p53)

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therapeutic implications of p53

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chemo and radiation therapy cause DNA damage tumor cells with normal P53 gene are more likely to respond to this therapy, than tumors that carry the mutant gene.

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WT
location:
fxn:
dz assoc:

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chromosome 11p13
nuclear transcription
Wilms tumor (nephroblastoma)

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p16 (INK4a)
fxn:
dz assoc

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cell cycle regulation via cdki
somatic: pancreatic, breast, esophageal
inherited: malignant melanoma

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KLF6
fxn:
dz assoc:

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encodes TF
mut in more than 70% of primary prostate cancer

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APC
fxn:
dz assoc (somatic/familial)

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inhibition of signal transduction, downregulates b-catenin
somatic: carcinoma of stomach, colon, pancreas, melanomas
familial: FAMILIAL ADENOMATOUS POLYPOSIS COLI / COLON CANCER

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PTEN
location:
fxn:
dz assoc

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Phosphatase and tensin homolog, located on chromosome 10q23
cell cycle arrest and apoptosis - p27 Cip/Kip
endometrial and prostate cancer

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SMAD 2 and SMAD 4 (DPC4)
fxn:
dz:

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TGF-β growth inhibitory signal transduction
SMAD 4 is inactivated in 50% of pancreatic cancers
SMAD2 is present in some colorectal cancers

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NF-1 protein product

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neurofibromin

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NF1 fxn:
dz assoc:

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inhibit RAS signal transduction
inhibits p21 (cell cycle inhibitor)

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NF2 protein product

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merlin

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NF2 fxn:
dz:

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cytoskeleton stability
somatic: schwannomas, meningiomas
familial: Neurofibromatosis type II, acoustic schwannomas and meningiomas

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TGF-β receptor
fxn
dz assoc

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growth inhibition
somatic: carcinoma of colon

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E-cadherin
fxn
dz assoc

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adhesion
somatic: stomach carcinoma
inherited: familial gastric cancer

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Bcl-2
location
fxn

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18q21
overexpression = evade apoptosis, survive long period of time, accumulate B-lymphocytes resulting in lymphadenopathy and marrow infiltration

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85% of ______ carry a characteristic t(14;18)(q32;q21) translocation which prevents apoptosis

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follicular B cell lymphomas
fused w/ Ig-H (heavy chain) 14q32

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Bcl-2 family
apoptotic members:
antiapoptotic members:

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apop: bak, BAX, bim

anti-apop: bcl-2, bcl-x

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mismatch repair
mut in:
dz:

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Germ line mutation of MSH2 (2p16) and MLH1 (3p21) account for 30% of cases.
Hereditary Nonpolyposis Cancer Syndrome

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microsatellite instability is hallmark of mismatch repair in

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Hereditary Nonpolyposis Cancer Syndrome
Cancers of the cecum and proximal colon (patients are < 50 years), also associated with endometrial and ovarian cancers.

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dz assoc w/ mut in NER

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xeroderma pigmentosum
(pyr dimers, UV damage)

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dz assoc w/ defect in homologus recombination

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AR disorders : Ataxia-telangiectasia, Bloom syndrome and Fanconi anemia- increased chance of leukemia lymphoma.

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gene mutation involved in Ataxia-telangiectasia

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ATM

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characteristics of ataxia telangiectasia

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Cerebellar ataxia, defective lymphocyte maturation and proliferation
Immunodeficiency, acute sensitivity to ionizing radiation and susceptibility to lymphoid malignancies.

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BCRA-1 located

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chromosome 17

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BCRA-2 location

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chromosome 13

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Individuals who inherit mutations of BRCA 1 and 2 susceptible to

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breast cancer
(10-20% of breast cancers are familial and mutation of BRCA-1 and BRCA-2 account for 80% of familial breast cancer.)

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Germ line mutation of BRCA-1
dz involved?

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breast and ovarian cancer

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Germ line mutation of BRCA-2
dz:

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ovary (<BRCA-1) and male breast cancer.

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telomeres - how they function

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Telomerase shortening is a tumor suppressor mechanism
absent in most somatic cells
adding telomerase would increase life span