Oncogenes, Tumor Suppressors, Carcinogens & Tumor Markers

Oncogene

Gain-of-function mutation converting proto-oncogene → oncogene

Tumor suppressor gene

Loss-of-function mutation increasing cancer risk; both alleles must be lost (“2 hit hypothesis”)

ALK

Receptor tyrosine kinase; associated with lung adenocarcinoma

EGFR (ERBB1)

Receptor tyrosine kinase; lung adenocarcinoma

HER2 (ERBB2)

Receptor tyrosine kinase; breast and gastric carcinomas

RET

REceptor Tyrosine kinase; MEN2A

BCR-ABL

Non-receptor tyrosine kinase from t(9;22) Philadelphia chromosome; CML and ALL

JAK2

Non-receptor tyrosine kinase; myeloproliferative neoplasms

BRAF

Serine/threonine kinase; melanoma

c-KIT (CD117)

Cytokine receptor tyrosine kinase; GIST and mastocytosis

MYC (c-myc)

Transcription factor; Burkitt lymphoma t(8;14)

MYCN (N-myc)

Transcription factor; neuroblastoma

KRAS

RAS GTPase oncogene; pancreatic

BCL-2

Antiapoptotic oncogene inhibiting apoptosis; follicular lymphoma t(14;18)

APC

Tumor suppressor regulating β-catenin/WNT pathway; colorectal cancer and FAP

BRCA1/BRCA2

DNA repair tumor suppressor genes; breast

CDKN2A

Encodes p16; inhibits G1→S transition; melanoma

DCC

“Deleted in Colorectal Cancer”; tumor suppressor associated with colorectal carcinoma

SMAD4 (DPC4)

“Deleted in Pancreatic Cancer”; tumor suppressor in pancreatic and colorectal cancer

MEN1

Encodes menin tumor suppressor; MEN1 syndrome

NF1

Neurofibromin tumor suppressor; Ras GTPase activating protein; neurofibromatosis type 1

NF2

Merlin/schwannomin tumor suppressor; neurofibromatosis type 2

PTEN

Tumor suppressor inhibiting PI3K/AKT pathway; prostate

RB1

Tumor suppressor inhibiting E2F; blocks G1→S; retinoblastoma and osteosarcoma

TP53

“Guardian of genome”; activates p21 to arrest G1→S; mutated in most cancers; Li-Fraumeni syndrome

Li-Fraumeni syndrome

Germline TP53 mutation causing sarcoma

TSC1

Encodes hamartin; tuberous sclerosis

TSC2

Encodes tuberin (“2berin”); tuberous sclerosis

VHL

Tumor suppressor inhibiting HIF-1α; von Hippel-Lindau disease

WT1

Urogenital development transcription factor; Wilms tumor

Proto-oncogene vs tumor suppressor

Proto-oncogenes require 1 activating mutation; tumor suppressors require loss of both alleles

Aflatoxin (Aspergillus)

Stored grains/nuts; hepatocellular carcinoma

Alkylating agents

Chemotherapy carcinogens causing leukemia/lymphoma

Aromatic amines (β-naphthylamine)

Textile dyes and tobacco smoke exposure; transitional cell carcinoma of bladder

Arsenic exposure

Herbicides/smelting/wood preservation; hepatic angiosarcoma

Asbestos

Shipyards and roofing exposure; bronchogenic carcinoma > mesothelioma

Tobacco smoke and bladder

Transitional cell carcinoma

Tobacco smoke and cervix

Squamous cell carcinoma

Tobacco smoke and esophagus

Squamous cell carcinoma and adenocarcinoma

Tobacco smoke and kidney

Renal cell carcinoma

Tobacco smoke and larynx

Squamous cell carcinoma

Tobacco smoke and lung

Squamous cell carcinoma and small cell carcinoma

Tobacco smoke and oropharynx

Squamous cell carcinoma

Tobacco smoke and pancreas

Pancreatic adenocarcinoma

Ethanol and esophagus

Squamous cell carcinoma

Ethanol and liver

Hepatocellular carcinoma

Ethanol and breast

Breast cancer

Ionizing radiation

Leukemia and papillary thyroid carcinoma

Nickel/chromium/beryllium/silica

Occupational exposure causing lung cancer

Nitrosamines

Smoked foods; gastric cancer (intestinal type)

Radon

Uranium decay byproduct in basements; lung cancer; 2nd leading cause after smoking

Vinyl chloride

PVC pipe production exposure; hepatic angiosarcoma

EBV

Burkitt lymphoma

HBV/HCV

Hepatocellular carcinoma

HHV-8

Kaposi sarcoma

HPV 16/18

Cervical

H pylori

Gastric adenocarcinoma and MALT lymphoma

HTLV-1

Adult T-cell leukemia/lymphoma

Clonorchis sinensis

Cholangiocarcinoma

Schistosoma haematobium

Squamous cell carcinoma of bladder

Tumor markers

Used mainly to monitor recurrence and therapy response; not primary screening tools

Alkaline phosphatase (ALP)

Elevated in bone/liver metastases

AFP (α-fetoprotein)

Hepatocellular carcinoma

AFP pregnancy association

Increased in neural tube and abdominal wall defects; decreased in Down syndrome

hCG

Hydatidiform mole

hCG source

Produced by syncytiotrophoblasts

CA 15-3 / CA 27-29

Breast cancer markers

CA 19-9

Pancreatic adenocarcinoma marker

CA-125

Epithelial ovarian cancer marker

Calcitonin

Medullary thyroid carcinoma marker; elevated in MEN2A/MEN2B

CEA

Carcinoembryonic antigen; colorectal and pancreatic cancer marker; nonspecific

CEA minor associations

Gastric

Chromogranin A

Neuroendocrine tumor marker

LDH

Marker for testicular germ cell tumors

Neuron-specific enolase

Neuroendocrine tumors including small cell lung carcinoma

PSA

Prostate-specific antigen; prostate cancer marker; also elevated in BPH/prostatitis

PSA utility

Best for monitoring recurrence after treatment; controversial screening benefit

Liquid biopsy

Detection of circulating tumor DNA/RNA/cells in blood or urine for cancer profiling and monitoring

Chromogranin and synaptophysin stain

Identify neuroendocrine tumors

Cytokeratin stain

Marks epithelial tumors (carcinomas)

Desmin stain

Marks muscle tumors (rhabdomyosarcoma)

GFAP stain

Marks glial tumors (astrocytoma

Neurofilament stain

Marks neuronal tumors (neuroblastoma)

PSA immunostain

Identifies prostate cancer origin

PECAM-1/CD31 stain

Endothelial marker for vascular tumors (angiosarcoma)

S-100 stain

Neural crest tumors including melanoma

TRAP stain

Hairy cell leukemia marker

Vimentin stain

Mesenchymal marker for sarcomas; also positive in RCC

P-glycoprotein (MDR1)

ATP-dependent drug efflux pump causing chemotherapy resistance

Philadelphia chromosome

t(9;22) creating BCR-ABL fusion oncogene

Burkitt lymphoma genetics

c-MYC translocation t(8;14)

Follicular lymphoma genetics

BCL-2 translocation t(14;18)

Retinoblastoma gene function

RB inhibits E2F to stop G1→S progression

p53 function

Activates p21 causing cell cycle arrest at G1→S after DNA damage

p16 function

CDK inhibitor blocking G1→S transition

Neurofibromin function

Ras GTPase activating protein turning off Ras signaling

PTEN function

Inhibits PI3K/AKT survival pathway

VHL function

Degrades HIF-1α under normoxic conditions

c-KIT marker

CD117 positivity classic for GIST

Hairy cell leukemia markers

BRAF mutation and TRAP positivity