Molecular Basis of Cancer Flashcards
2.4
Proto-oncogenes
Oncogenes are mutated genes that promote autonomous cell proliferation in cancer.
Pro-onocogenes are normal genes, which are activated by “gain of function” mutation leading to cancer
Tumor supressor
Are normal genes that slow down cell division or tell cell to die at the right time. (apoptosis)
Tumor suppressor are inactivated by ‘loss of function’ mutations which lead to cancer
Categories of onocogenes
- Growth factor - PDGFB
- Growth Factor receptor- ERBB1 and 2
- Signal transducer - RAS gene family
- Nuclear regulator - MYC
- Cell cycle regulator- Cyclins and CDK
The most frequently mutated oncogenic pathway in humans
Receptor Tyrosine kinase pathway
- Growth factor
-RAS
-GAP
Oncoproteins that are activated by mutations in cancer
- Growth Factor
- RAS - 90% of the cancer the RAS is mutated. When mutated they do not have GTPhase activity inside the RAS and GAP cannot do his function.
- PI3K
- MYC
- D-cyclins
When MYC and D-Cyclins are mutated the cell will continue to divide and multiple the cell cancers.
Tumor suppressors proteins
- GAPs are the one that will inactive the GTP bind to RAS by hydrolysis.
- PTEN is going to inactive PI3K and prevent from activating AKT signaling
GAPs break RAS signaling and PTEN breaks AKT/PKB signaling
Oncogene activation mechanism
Proto-oncogenes are activated by 3 mechanism
- Point mutation
- Gene amplification
- Chromosomal translocation
a. Overexpression- a piece of another one binds to promotor and promotes his overexpression. IG gene enchances MYC activity.b. Chimeric protein - Translocation happen but they are fuse together to create a Hybrid. ABL-BCR hybrid will increase Tyrosine kinase activity.
Chronic Myeloid Leukemia
Example of Chimeric protein.
t (9;22)
Fusion of ABL oncogene and BCR locus (ABL-BCR hybrid gene) will increase the activity of Tyrosine kinase to activate the growth factors for signaling pathways
Burkitt Lymphoma
Example of Overexpression
Is when IG gene will enhance the activity of MYC oncogene. They do not fusion to create an hybrid gene.
Chromosome 14 (IGH) and 8 (c-MYC)
Diffuse Large B- cell lymphoma translocation
Chromosome 14 ( IGH) and Chromosome 3 (BCL-6)
Burkitt lymphoma translocation
Chromosome 14 (IGH) and Chromosome 8 (c-MYC)
Mantle cell lymphoma translocation
Chromosome 14 (IGH) and Chromosome 11 (CCND1/Cyclin D1)
Follicular Lymphoma translocation
Chromosome 14 (IGH) and Chromosome 18 (BCL-2)
c-SIS/ PDFB
Platelet derived growth factor
overexpression causes Astrocytoma
ALK; ERBB1 (EGFR)
Receptor tyrosine kinase
A point mutation causes Lung adenocarcinoma (NSCLC)
ERBB2 (HER2/neu)
Receptor tyrosine kinase
Amplification causes Breast Carcinoma
RET
Receptor tyrosine kinase
point mutation causes
- Pheochromocytoma- tumor that grows from cells called chromaffin cells
- Medullary thyroid carcinoma
-MEN2A and 2B
c-KIT
Cytokine receptor (CD117)
Point mutation causes Gastrointestinal Stromal Tumors
KRAS
GTP binding Protein
Point mutation causes
-Colon tumor
-Lung tumor
-Pancreatic tumor
NRAS
GTP binding protein
Point mutation causes Hemotologic malignancies
HRAS
GTP binging protein
point mutation causes Bladder and Kidney cancer
ABL
Non receptor tyrosine kinase
t (9;22)- ABL-BCR
Chronic myeloid leukemia
BRAF
Serine/ threonine kinase
point mutation Melanoma, hairy cell leukemia
JAK2
non receptor tyrosine kinase
point mutation Myeloproliferative disorder
C-MYC
Transcription factor
t( 8;14) involving IGH
Burkitt lymphoma
N-MYC
Transcription factor
Amplification- Neuroblastoma
L-MYC
transcription factor
amplificacion- lung carcinoma (smalll cell)
CCND1
Cyclin D1
t(11;14) involving IgH
Mantle cell lymphoma
CDK4
Cyclin- dependent kinase
amplification- Melanoma
Two mutation affecting the cell cycle regulator
- Gain of function mutation in Cyclin D and CDK4.
They phosphorylates the RB so that he can free E2F and promote the cycle to enter to S-phase. - Loss of function mutation in the gene that inhibit G1/S.
-CDK inhibitor
- RB
-TP53
CDK inhibitors (p16 and p21) are supposed to stop the CDK from working.
RB dephosphorylated is blocking E2F and transcription is blocked.
TP53 makes a protein that is found inside the nucleus of cells and plays a key role in controlling cell division and cell death. Is important regulator of GS1/M
The most common neoplasm related to RB mutation
Retinoblastoma and Osteosarcoma
Retinoblastoma is involve in a two mutation hit. Involving both alleles of Rb
What are the two activators for p53 following DNA damage?
ATM and ATR
What happens in DNA damage?
DNA damage promotes MDM2 degradation and p53 stabilization
TP53
Regulates the cell cycle
Most frequently mutated gene in human cancer.
Most of mutations a acquired in somatic cells nor inherited.
Exception- Li Fraumeni syndrome
They have a broad of variety/spetrum of multiple cancer on early onset.
Li-Fraumeni syndrome
Individuals inherited one mutated p53 allele.
They have a broad spectrum of cancer. Sarcomas, brain tumor, leukemias, carcinomas.
APC: gatekeeper of colonic neoplasia
The APC is gonna downregulate the growth promoting signaling pathway by destroying beta catenin. this inhibits proliferation.
If APC is not working it cannot destroyed the beta-catenin and the cancer cell will proliferate.
Loss of function mutation in APC is responsible for Familial adenomatous polyposis (FAP). Condition where adenomatous polyps arise in the colorectal epithelium
Ways to lead to proliferation of cancer cell by APC gatekeeper pathway
- No E-cadherin
- over-expression of Beta catenin
- APC nor functioning
Familial adenomatous polyposis (FAP)
Loss of function mutation in APC is responsible for Familial adenomatous polyposis (FAP). Condition where adenomatous polyps arise in the colorectal epithelium
Germline Loss of function of E-cadherin gene ( CDH1)
Familial gastric carcinoma and infiltrating lobular carcinoma (ILC) of the breast cancer.
The beta catenin is bind do E-cadherin. NO binding will cause Beta catenin to be free and common cause for breast cancer.
TGF- beta
TGF- beta is a potent inhibitor of cell proliferation by turning ON anti-proliferative gene (CDK inhibitors) and turning OFF the genes that drive the cell growth (MYC, Cyclins, CDKs).
The lost of TGF-Beta is critical role for most pancreatic cancers.
Von Hippel- Lindau Tumor Suppressor (VLH)
VLH is involved in the ubiquitination and degradation of HIF (Hypoxia inducible factor)
Normoxia- Hydroxylation in the presence of O2 HIF is detached from VHL and HIF is degraded.
Pseudohypoxia - “Von hippel lindau syndrome” the cell is not hypoxic but the VLH is not functioning so they think the cell is hypoxic and there is no degradation of HIF.
‘Loss of function’ of VLH
the Von Hippel Lindau syndrome predisposes to
- Hemangioblastomas
- renal cell carcinomas
- pheochromocytoma
Loss RB1; Ch13
Inhibitor of G1/S transition (E2F binding)
Familial retinoblastoma
osteosarcoma
Loss TP53; Ch 17q
Regulates cell cycle and apoptosis
Li-Fraumeni syndrom- family history of differents cancer at young on set.
Loss CDK2A- p16/INK4a
Inhibitor of cyclin D/CDK4,6 (block the cell progression from G1 to S)
Familial melanoma
familial pancreatic carcinoma
Loss APC, Ch5q
Regulates levels of Beta-catenin protein
Familial adenomatous polys and carcinoma
LOSS BRCA1, 17q and 2, 13q
Repair DNA double- standed breaks
Familial breast and ovarian cancer
THE FAMILY HAVE TO HAVE A HISTORY OF BREAST CANCER AND OVARIAN
LOSS NF1 (GAP), 17p- Neurofibromin
Inhibitor of RAS/MAPK signaling
Neurofibromatosis type 1
LOSS NF2, Ch22- Merlin
Contact dependent growth inhibition
Neurofibromatosis Type 2
VHL; Ch 3
Inhibitor of hypoxic induced transcription factor (HIF)
Von Hippel Lindau syndrome
Cerebellar hemangioblastoma
Renal cell carcinoma
PTEN
Inhibitor of PI3K/AKT signaling
Prostate cancer
Breast cancer
Endometrial cancer
WT1, Ch11
Familial Wilms tumor (neuroblastoma)
MSH2 and 6; MLH1
DNA mismatch repair
Hereditary non-polyposis colorectal cancer
TSC1 (9)- HAMARTIN
TSC2 (16)- TUBERIN
inhibitor of mTOR signaling
Tuberous sclerosis
MEN 1 - Menin
Inhibit Jun D- mediated transcription factor
Multiple endocrine neoplasia type 1
(Pituitary, parathyroid, pancreatic tumor)
SMAD 2 and 4
Antiproliferative responses to TGF-B
Juvenile polyposis, Pancreatic cancer
