Neoplasia Oncogene vs Tumor Suppressor

Describe Oncogenes

• Definition?

• Which type of genes affected?

• Common Genes affected?

Oncogenes:

• Definition:

  • Mutated genes -> excessive growth/over expression 

    • Gain of Function Mutation in only one allele

• Occurs in genes:

  • Signal transduction proteins

  • Growth factor receptors

  • Growth factors

  • Nuclear regulatory proteins

  • Cell cycle regulators – cyclins

• Common genes affected 

  • KRAS, 

  • BRAF,

  • EGFR,

  • MYC

1. Draw out the Growth factor Receptor Pathway

   1. What is the type of mutation in signal transduction proteins that causes uncontrolled growth?

Point Mutations

Describe the RAS gene (KRAS)

• What are they?

  • Types?

• STATS

• How does KRAS mutation → oncogene

• What are they?

  • Signal Transducers genes

    • KRAS, NRAS, HRAS

      • KRAS = most common

• STATs

  • 15-20% of all human tumors have RAS mutations

  • Found in:

    • 90% of pancreatic adenocarcinoma

    • 50% of colon, endometrial and thyroid cancers

    • 30% of lung adenocarcinomas

• How does KRAS mutation -> Oncogene:

  • KRAS (inactive) -> KRAS (active) via GDP -> GTP

    • Active -> inactive via GTPase activity (backwards)

  • Mutation -> reduce GTPase activity

  • Continuous active RAS = continuous growth signal

NOTE: When RAS gene mutations are present in a tumor, growth receptor mutations are usually absent

Describe the BRAF gene

• What is it?

• Clinical Importance

BRAF gene

• What is it?

  • member of serine/threonine protein kinase family

• Clinical Importance:

  • Mutation (V600E) -> 100% of hairy cell leukemia and 60% of melanoma

Describe Growth Factor Receptors

• Encoded by?

• Mech

• Mutations?

• Notable Receptor Names?

• List some growth receptor mutations and associated cancers

Growth factor receptors

• Encoded by?

  • Oncogenes

• Mech:

  • Tyrosine kinase receptors tranduces growth signal across cell membrane

• Mutations

  • point mutations, amplifications and translocations

• Notable Receptor Names

  • EGFR, HER2 and ALK 

• Growth Receptor mutation and associated cancers

  • EGFR point mutation -> lung adenocarcinomas

  • HER2 amplification -> Breast Carcinoma

  • ALK translocation to EML4 -> fusion protein EML4-ALK -> lung adenocarcinoma

What do Glioblastomas  express that correlates to its own growth?

Expresses PDGF (platelet derived growth factor) + own receptor -> own growth

Describe MYC

• Function/Mech

• Related Cancers/Mutations

MYC 

• Function/Mech:

  • Promotes Cell Division

    • Induces trxn of:

      • Cyclin D2, Cyclin E, + various CDKs

    • Removes Cell Cycle Brakes

• Related Cancers/Mutations

  • Burkitt lymphoma (Translocation)

  • Neuroblastoma (amplification)

Describe Cyclins and CDK (Cyclin dependent kinases) 

• Function? Chekcpoints?

• Related Cancers/Mutations

Cyclins and CDK (Cyclin dependent kinases) 

Function:

• Regulates progression through cell cycle

• Two main checkpoints: G1/S and G2/M

Related Cancers/Mutations

• D- Cyclin: Gain of function mutation -> unregulated growth/function as oncogenes

• Lymphoma: translocations of Cyclin D1

Draw out how cyclin/CDKs progress the cell cycle

Describe Tumor Suppressor Gene

• Function

• Notable Genes

• Mutation

• What do these genes control?

• Common genes affected → cancer?

Tumor Suppressor Gene

• Function:

  • recognize DNA abnormality -> cell growth inhibition

    •  Cell cycle arrest or apoptosis

• Notable Genes:

  • Retinoblastoma (RB)

  • Tumor Protein 53 (p53)

• Mutation:

  • Loss of Function

• Occur In genes that control:

  • Cell cycle progression

  • Mitosis signaling pathway

  • DNA repair

    • EX: BRCA: breast cancer

    • EX: DNA mismatch repair: Colon Cancer

• Common genes affected:

  • APC, VHL

Describe Retinoblastoma

• What is it

• Genetics?

• Knudson two-hit hypothesis?

• Function? Mech?

• How can Retinoblastoma lose function?

Retinoblastoma

• What is it?

  • Primary intraocular malignancy in children

• Genetics:

  • 40% inherited (germline), 60% sporadic

  • Autosomal dominant

  • Mutation in retinoblastoma gene

    • Increases risk of dev. Retinoblastoma 10,000x

• Knudson two-hit hypothesis

  • Two mutations are req. for dev. of retinoblastoma (one on each allele)

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Retinoblastoma function

• Inhibits G1/S transition 

• Stops cell cycle in non-phosphorylated state 

Mech:

• In non-phosphorylated state -> stops cell cycle

  • By blocking trxn of S phase genes

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How can Retinoblastoma lose function

• Mutations in both RB genes

• CDK4 + cyclin D genes amplification

• cyclin dependent kinases inhibitors ((p16/INK4a)) Loss of Function

• Virus that inhibits RB (HPV)

Describe p53

• Nickname?

• Clinical Importance

• Function

• Mech.

• P53 loss of function consequences:

• What is Li-Fraumeni syndrome

Tumor protein 53 (p53)

• Nickname?

  • Nicknamed “Guardian of Genome” b/c trxn. regulator

• Clinical Importance:

  • Loss of function mutation -> detected in 50% of cancers

• Function:

  • Controls cell cycle arrest and DNA repair

• Mechanism:

  • DNA damage, hypoxia, cell stress -> detected by ATM/ATR proteins -> release p53 from MDM2 -> accumulation

    • If DNA can’t repair -> p53 induces apoptosis/cease mitosis

• P53 loss of function consequences:

  • accumulation of mutations

  • continued cell proliferation 

  • increased risk of malignant transformation

  • Cancers w/ p53 mutations -> resistant to chemo + radiation therapy

    • Lung/colon

• Li-Fraumeni syndrome

  • P53 inherited mutations -> 25x risk of developing Cancers (wide range)

Draw out the p53 pathway

Differentiate between Syndromic and Sporadic mutations

Syndromic: Germline mutations inherited

Sporadic: Somatic Mutations Acquired

Describe the PTEN gene (Phosphatase and tensin homolog)

• Function

• Describe Cowden Syndrome

  • Gene?

  • Consequence?

• Function:

  • Negative regulator of PI3K/AKT signaling

• Cowden Syndrome

  • Gene: Autosomal dominant

  • Consequence:

    • Benign growths of skin

      • (lipoma, fibromas)

    • Increased risk of breast/endometrial carcinoma

Describe the APC gene (Adenomatous polyposis coli)

• Function?

• Describe Adenomatous polyposis coli

  • Gene?

  • Consequence?

  • Stats?

APC gene (Adenomatous polyposis coli)

• Function:

  • Tumor Suppressor gene -> inhibits mitosis signaling pathway

• Adenomatous polyposis coli

  • GENE: Autosomal dominant

  • Consequence:

    • 1 mutant allele -> 1000s of adenomas

    • 2 mutant allele -> colon cancer

  • Stats

    • 70-80% of sporadic colon cancer have mutations in APC (somatic mutations)

Describe the VHL gene

• Function

• Describe Von Hippel-Lindau syndrome

  • Gene

  • Consequences

• Function:

  • Regulates cellular response to O2 levels

• Von Hippel-Lindau syndrome

  • GENE: Autosomal dominant

  • Consequence:

    • renal cell carcinoma Risk

    • Clear cell type Risk

    • Pheochromocytoma Risk

    • Sporadic Renal Cell cancer

      • Has VHL mutations