• tumor suppressor genes
• proto-oncogenes (include cell cycle and apoptosis)
• DNA repair genes

1. DNA damage
2. failure of DNA repair
   1. mut. in genes affecting DNA repair or growth or apoptosis
3. mutation in genome of somatic cells
   1. activation of growth promoting oncogenes
   2. inactivation of tumor suppressor genes
   3. alterations in genes that regulate apoptosis
4. this all leads to upregulated cell proliferation and decreased apoptosis
5. causes clonal expansion
6. via angiogenesis, escape from immunity, additional mutations, you get tumor progression
7. eventually forms malignant neoplasm
8. invasion and metastasis

• mutation (usually somatic), but if in germ line, you get hereditary forms of cancer
• chromosomal translocation- transfer of a portion of one chromosome to another chromosome, ex:
  • Burkitt's Lymphoma
  • CML
  • follicular lymphoma trans. 14,18
  • mantle cell lymphoma trans. 11,14
• gene amplification (increase in number of copiies of genes)- seen in neuroblastoma

based on biochemical roles of normal counterparts

• GF's
• cell surface R's
• intracellular signal trnasduction pathways
• TF's  (DNA binding nuclear proteins)
• cell cycle proteins (cyclins and CDPK's)
• inhibitors of apoptosis

Mechanism of oncogene action: GF's and examples of cancers caused by these oncogenes

1. bind to R's
2. autocrine and paracrine stimulation

Also influenced by methylation of acetylation of the genes that code for them.

If cancer, overexpression of GF's

• example (from PDGF like polypeptides)
  • human sarcomas
  • glioblastoma

• for oncogenes, you only need one altered form
• for tumor suppressor genes, you need both alleles altered for abnormal function

Most GF type cancers are not the cause of genetic alteration of the GF, but rather the overexpression of the GF genes.

• normally, binding of GF's to their receptors will stimulate intrinsic tyrosine kinase activity
  • this will generate a potent mitogenic stimulation
• can be activated to oncogenes via:
  • enhanced activation of promoters
  • chromosomal translocation
  • gene amplification
  • mutation or deletions can activate R's independent of ligand binding

• point mutations of c-met protooncogene, which encodes hepatocyte growth factor
• RET protooncogene translocation seen in papillary carcinoma of thyroid
• amplification of Her-2/neu gene results in autocrine activation mediated by over expression of GF (in EGF family) in some BREAST, ovarian, and gastric cancers

• non receptor PK's
• RAS proteins

• p21- active when bound to GTP and inactive when bound to GDP
  • convert GTP to GDP with intrinsic GTPase activity of p21
• mutant forms have uncontrolled activity- which enhances mitotic activity
• most frequent dominant mutation in human cancers

• mechanism- increase in expression can lead to enhanced mitotic activity
• ex: tranlocation of c-myc from chromosome 8 to 14 (Burkett's lymphoma)

• overexpression or increased copy number of cyclins seen in cancers
• examples: overexpression of cyclin D1 (max expression in G1 and activates its respective CDK [CDK4] only in G1) in mantle cell lymphoma (translocation 11,14)

• G1: mostly cyclin D and activates CDK4
• S: CDK4 allows passage into S phase, and cyclin E is the highest expression
  • when cyclin E high enough, activiate CDK2, allowing passage into G2
• G2: mainly cyclin A expressed and when high enough, activates CDK2

1. BCL-2 on chromosome 18 brought to chromosome 14 (translocation)
2. this brings it under control of Ig heavy chain gene promotor on chrom. 14
3. causes overexpression of anti-apoptotic protein BCL-2
4. this will result in follicular B cell lymphoma

• cell surface- TGF beta R (E cadherin)
• inner aspect of pllasma membrane- NF-1
• cytosol- APC
• nucleus
  • RB
  • p53
  • BRCA1 and 2

• codes for protein that when phosphorylated, binds to E2F TF, allowing G1-S phase transition
  • w/o phosphorylation, binds E2F, prevents cell reeplication
• when mutated and or lost, does not bind E2F, permitting dysregulated cell proliferation
• leads to retinoblastoma- can be
  • heriditary (infant born with missing or mutated allele, so increase chance of tumor development)
  • sporadic (in adults, requires two genetic hits since they havent inherited altered RB allele)

• chromosome 17
• normal function
  1. in response to DNA damage, p53 level rises and prevents cell from entering S phase
  2. if repair not possible, initiate apoptosis
• mutation most common genetic change in cancer
• in absence of normal p53, DNA damage may accumulate favoring cell transformation

• Rb gene
• p53
• WT-1
• NF-1
• VHL
• BRCA1 and BRCA2
• PTEN
• APC

• Wilms tumor
• breast cancer

• renal cell carcinoma
• hemangioblastoma
• PHEO

• prostate cancer
• gliomas
• thyroid cancer

• colorectal cancer
• ovarian cancer
• malignant melonoma

• HTLV1 virus- T cell leukemia
• HPV- uterine cervical cancer
• Hep B- hepatocellular carcinoma
• Epstein Barr virus
  • Burkitt lymphoma
  • nasopharyngeal carcinoma
• Human herpes virus 8
  • Kaposi sarcoma
  • body cavity based lymphoma

• GF- PDGF beta chain
• protooncogene- SIS
• mode of activation- overexpression
• associated human tumor
  • astrocytoma
  • osteosarcoma

GF oncogenes: FGF's (protonocogene, mode of activation, associated human tumors)

• proto-oncogenes- HST-1, INT-2
• mode of activation
  • overexpression
  • amplification
• associated human tumor
  • stomach cancer
  • bladder cancer
  • breast cancer
  • melanoma

• protooncogene
  • ERB-B1 (ECFR)
  • ERB-B2
• mode of activation
  • overexpression
  • amplification
• associated human tumor
  • squamous cell carcinomas of lung
  • gliomas
  • breast cancer
  • ovarian cancer

• protooncogene- RET
• modes of activation- pt of mutation
• associated human tumors
  • multiple endocrine neoplasia 2A and B
  • familial medullary thyroid carcinoma

• protooncogene- PDGF R
• mode of activation- overexpression
• associated human tumor- gliomas

• protooncogene- KIT
• mode of activation- pt mutation
• associated human tumors
  • GI stromal tumors
  • other soft tissue tumors

• protooncogene: RAS
• mode of activation- pt mutation
• associated human tumors
  • colon, lung, pancreatic tumors
  • bladder and kidney tumors
  • melanomas
  • hematologic malignancies

• protooncogene- ABL
• mode of activation- translocation
• associated human tumors
  • chronic myeloid leukemia (9 [ABL loc] to 22 translocation where ABL is next to BCR)
  • acute lympoblastic leukemia

• c myc
  • mode of activation- translocation
  • associated human tumor- Burkitt lymphoma
• n myc
  • mode of activation- amplification
  • associated human tumor
    • neuroblastoma
    • small cell carcinoma of lung
• l myc
  • mode of activation- amplification
  • associated human tumor
    • small cell carcinoma of lung

• cyclin D
  • mode of activation- translocation
  • associated human tumor- mantle cell lymphoma (11,14 translocation)
• cyclin E
  • amplification produces breast and esophageal cancers
  • overexpression produces breast cancer

• 8,14- Burket's lymphoma
• 10, 14

• location- cell surface
• function- growth inhibition
• tumor associated with somatic mutation- carcinomas of stomach
• tumor associated with inherited mutation- NONE

• location- cell surface
• function- cell adhesion
• tumors associated with somatic mutation- carcinoma of stomach
• tumors associated with inherited mutations- familial gastric cancer

• location- inner aspect of plasma membrane
• function
  • inh. of RAS signal transduction
  • inh. of p21 cell cycle inhibitor
• tumors associated with somatic mutations- neuroblastomas
• tumors associated with inherited mutations
  • neurofibromatosis type 1
  • sarcomas

• location- cytosol
• function- inh. of signal transduction
• tumors associated with somatic mutations
  • carcinomas of stomach
  • colon cancer
  • pancreatic cancer
  • melanoma
• tumors associated with inherited mutations
  • familial adenomatous polyposis coli/ colon cancer

• location- nucleus
• function- regulation of cell cycle
• tumors associated with somatic mutations
  • retinoblastoma
  • osteosarcoma
  • breast carcinoma
  • colon carcinoma
  • lung carcinoma
• tumors associated with inherited mutations
  • retinoblastoma
  • osteosarcoma

• location- nucleus
• function (all in response to DNA damage)
  • cell cycle arrest
  • apoptosis
• tumors associated with somatic mutations- most human cancers
• tumors associated with inherited mutations
  • Li Fraumeni syndrome
  • multiple carcinomas and sarcomas

• location- nucleus
• function- DNA repair
• tumors associated with somatic mutations- unknown
• tumors associated with inherited mutations
  • carcinomas of female breast and ovary
  • carcinomas of male breast

1. normal colon cell has deletion of good copy of APC gene on chromosome 5
2. forms a small polyp
   1. has mutation of RAS on chromosome 12
   2. deletion of tumor suppressor genes on chromosome 18
3. forms larg polyp with nest of malignant cells (increasingly disorganized- dysplasia)
4. deletion and or mutation of p53 on chromosome 17 finally leads to colon cancer
5. eventually metastasis

• RB
• p53
• BRCA1 and 2

• DNA is susceptible to progressive accumulations of mutations
• these mutations could affect protooncogenes and tumor suppressor genes thus contributing to risk of cell transformation

• hypermethylation silences genes
  • if we methylated the promoter of tumor suppresor genes or DNA repair genes, we could develop cancer
• histone acetylation cause increase transcriptional active

• they normally shorten with age
• when cells lose the telomeres, cells lose their ability to replicate
• telomerase keeps the telomeres from getting shortened
  • normally, not active in somatic cells
  • in 90% of human tumors, telomerase activity can be detected