USMLE: Oncogenes and Tumor Suppressor Genes

Oncogenes

Gain of function ➡️ Increase cancer risk.

Only need damage to 1 allele.

ALK

Receptor Tyrosine Kinase

Lung Adenocarcinoma

HER2/neu (ERB-B2)

Growth Factor receptors

Tyrosine kinase

Overexpression of growth factor receptors that are amplified in breast cancer.

Breast, ovarian and gastric carcinoma

JAK2

Tyrosine Kinase

Chronic Myeloproliferative disorders

RET

Growth Factor Receptor

Tyrosine kinase

MEN 2A and B

Medullary Carcinoma of the thyroid

c-kit

Growth Factor Receptor

Cytokine receptor

Gastrointestinal stromal tumor (GIST)

RAS (70% of human tumors)

KRAS

Signal Transducer

GTPase ➡️ When growth factor binds to the receptor, GDP ➡️ GTP and a message is sent to the nucleus.

RAS & GTPase have the ability to dephosphorylate GTP ➡️ GDP which turns off the signal.

Point Mutation

Colon cancer, lung cancer, pancreatic cancer

BCR-ABL

Tyrosine kinase

CML, ALL

c-myc

Nuclear Regulator

Transcription factor

Burkitt lymphoma (8,14): Lymphoma of B-Cells with myc being translated to the heavy chain region in B-Cells (Chromosome 14).

Starry sky appearance. Blue represents the cancer cells, the white represents macrophages.

N-myc

Nuclear Regulator

Transcription factor

Neuroblastoma

Small cell carcinoma of the lung

L-myc

Nuclear Regulator

Transcription factor

Lung tumor

Cyclin and CDK's

Cell cycle regulators

Cyclin and CDK forms a complex that phosphorylates the retinoblastoma protein, which promotes progression through the G1 ➡️ S phase.

Cyclin D1 (CCND1)

Cell cycle regulator

Cyclin

Mantle Cell Lymphoma t(11,14): B-Cell lymphoma. Cyclin D is translated to Chromosome 14, allows the cell to go from G1 ➡️ S phase.

Expansion of the mantle, which is right outside of the follicle.

BRAF

Serine/threonine kinase

Melanoma

non-Hodgkin lymphoma

papillary thyroid carcinoma

CDK4

Cyclin-dependent kinase

Melanoma

S100+, Neural Crest derived

bcl-2

Inhibits apoptosis (antiapoptotic molecule)

Follicular and DLBC lymphomas

Tumor Suppressor Genes

Loss of function ➡️ Increases cancer risk; both alleles must be lost for expression of disease.

Two-hit hypothesis

p53

Regulates the progression of the cell cycle from G1 ➡️ S phase.

In response to DNA damage, p53 slows the cell cycle and upregulates DNA repair enzymes. If DNA repair is not possible, p53 induces apoptosis by upregulating BAX (proapoptotic) and downregulating BCL-2 (antiapoptotic), cytochrome C leaks out of the mitochondria. Both copies of p53 must be knocked out for tumor formation (Knudson's two-hit hypothesis)

Germline mutation results in Li-Fraumeni Syndrome (2nd hit is somatic) ➡️ Develop multiple types of carcinomas and sarcomas.

SBLA syndrome: Sarcoma, Breast, Leukemia, Adrenal

Rb

Inhibits E2F; blocks G₁➡️ S phase

When Rb is phosphorylated by the cyclin/CDK complex, E2F is released and the cell is able to progress through G1 ➡️ S phase.

If Rb is mutated, E2F is constitutively free = uncontrollable growth. Both copies must be mutated. Sporadic mutation (both hits are somatic) = Unilateral Retinoblastoma.

Germline Mutation = familial retinoblastoma (2nd hit is somatic) = bilateral retinoblastoma and osteosarcoma.

Retinoblastoma, Osteosarcoma, & HPV (16, 18)

APC

Negative regulator of beta-catenin/WNT pathway

Colorectal cancer associated with FAP

BRCA1 and 2

DNA repair protein

Breast cancer

Ovarian cancer

Pancreatic cancer

MEN1

MEN1, produces Menin

MEN type 1

Pituitary

Parathyroid

Pancreas

NF1

Ras GTPase activating protein (Neurofibromin) .

Neurofibromatosis type 1 (Neurofibromas are derived from Schwann Cells = Neural Crest)

NF2

Merlin (schwannomin) protein

Neurofibromatosis type 2

DPC4/SMAD

DPC (Deleted in Pancreatic Cancer)

Pancreatic cancer

DCC

DCC (Deleted in Colon Cancer)

Colon cancer

p16

Cyclin dependent kinase inhibitor 2A

Melanoma

PTEN

Tyrosine Phosphatase of PIP3 (PKB-AKT activation)

Breast cancer

Prostate cancer

Endometrial cancer

TSC1

Hamartin protein

Tuberous Sclerosis

TSC2

Tuberin protein (Twoberin)

Tuberous Sclerosis

ERB-B1

Proto-oncogene

Squamous Cell Carcinoma of the lung

VHL

Inhibits hypoxia inducible factor 1a

von-Hippel-Lindau & RCC

WT1/WT2

Transcription Factor that regulates urogenital development

Wilms Tumor (nephroblastoma)

Does NOT cross the midline (vs. Neuroblastoma)

"Wilms is a whimp... Never crosses the line."

What is the adenoma-to-carcinoma sequence?

Normal Epithelium ➡️1⃣ Early Adenoma ➡️2⃣ Late Adenoma ➡️3⃣ Adenocarcinoma

1⃣APC = Progression from normal mucosa to small polyp.

2⃣K-RAS = Increase in the size of the polyp. K-RAS is a protooncogene.

3⃣P53 = Malignant transformation requires mutations in both P53 & DCC