1. Basic Science of Surgical Oncology
Sharmila Roy-Chowdhury, M.D.
Assistant Professor
Division of Surgical Oncology

2. Objectives
Learn basic information about the science of surgical oncology:
Genetic basis of cancer
Oncogenes
Tumor suppressor genes
Tumor markers
Chemotherapy agents

3. Hereditary mutations Gene changes that come from a parent
Exist in all cells of the body, including reproductive cells
The mutation can be passed from generation to generation.
Also called germline mutations.
Accounts for 5% to 10% of cancers

4. Acquired mutations Most cancers are caused by acquired mutations.
Occurs when DNA in a cell changes during the person’s life.
Can be caused by environmental influences such as exposure to radiation or toxins.
Not hereditary
Sporadic or somatic mutations

5. Oncogenes
Normal cellular genes (protooncogenes) "picked up" by retroviruses, mutations introduced that cause constitutive activity, and inserted into cells.
Gain of function after mutational damage.
Divided into four classes

6. Oncogenes

7. Oncogenes
Class I : growth factors
PDGF
EGF
TGFa

8. Oncogenes Class II-receptors Cell surface receptors (tyr kinases)
fms (CSF-1 R)
erbB, neu (EGF R)
ros (insulin R)
kit (SCF R)
met (HGF R)
Intracellular receptors
erbA (thyroid hormone R)

9. Oncogenes Class III-intracellular transducers Protein Tyr kinases
src, yes, fes, abl, ret
Protein Ser/Thr kinases
mos, raf
G proteins
ras (2nd most commonly altered "oncogene" in human cancer)
Phospholipase C
crk

10. Oncogenes Class IV : nuclear transcription factors
jun, fos, myc, myb, ski, rel, p53

11. Tumor Suppressor Genes
Defined as any gene whose loss of function leads to tumor progression
Block cellular proliferation

12. Tumor Suppressor Genes
Rb-1
inhibits the transcription factor E2F
p53
induces apoptosis of cells with damaged DNA
"watchdog" of the genome
most commonly altered "oncogene" in human cancer
Li-Fraumeni syndrome

13. Oncogenes/TSs by Cancer
Breast
BRCA1/2
HER-2/neu (Epidermal growth factor oncogene)
Trastuzumab, Herceptin

14. Oncogenes/TSs by Cancer
Colon
DCC
APC
responsible for FAP
p53
ras
MSH/MLH
mismatch repair
microsatellite instability
HNPCC
Lynch syndromes

15. Oncogenes/TSs by Cancer
Pancreas
ras
p53
MEN
men1 (MEN 1)
ret (MEN 2A, 2B, heriditary Hirschsprung’s dz)

16. Oncogenes/TSs by Cancer
GIST
c-kit
Imatinib, Sunitinib
Gleevec, Sutent
tyr kinase inhibitors
originally designed for use in CML

17. Tumor Markers Tumor Markers Type of Cancer Prostate CA Colorectal CA
breast CA
pancreatic CA
biliary CA
PSA
CEA
CA 15-3
CA 19-9

18. Tumor Markers AFP b-hCG 5-HIAA hepatocellular CA testicular CA
Choriocarcinoma
carcinoid
AFP
b-hCG
5-HIAA

19. Tumor Markers Calcitonin Thyroglobulin CA 125 Gastrin
medullary thyroid CA
differentiated thyroid CA
ovarian CA
gastrinoma

20. Tumor Markers Insulin (with low glucose) PTH (with high Ca) LDH
insulinoma
parathyroid adenoma/CA
testicular CA
Melanoma
lymphoma

21. Chemotherapeutics
5-FU
inhibits thymadylate synthase

22. Chemotherapeutics
Methotrexate
inhibits dihydrofolate reductase

23. Chemotherapeutics Gemcitabine
competes with dCTP for DNA incorporation
Cyclophosphamide, ifosfamide, melphalan, mitomycin C, dacarbazine
alkylating agents
Platinum agents
damage DNA by forming adducts

24. Chemotherapeutics Adriamycin, topotecan, irinotecan Taxol
topoisomerase inhibitors
Taxol
microtubule inhibitor

25. Biological Therapeutics
Trastuzumab
Monoclonal Ab against Her-2/neu
Breast CA
Rituximab
Monoclonal Ab against CD-20
B cell lymphoma

26. Biological Therapeutics
Cetuximab
mAb against EGFR
Colon CA
Bevacizumab
mAb against VEGF