Transcript Multidisciplinary Approach to GI Cancers

Basic Science of
Surgical Oncology
Sharmila Roy-Chowdhury, M.D.
Assistant Professor
Division of Surgical Oncology
Surgical Oncology
Objectives

Learn basic information about the science of
surgical oncology:





Genetic basis of cancer
Oncogenes
Tumor suppressor genes
Tumor markers
Chemotherapy agents
Surgical Oncology
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
Surgical Oncology
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
Surgical Oncology
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
Surgical Oncology
Oncogenes
Surgical Oncology
Oncogenes

Class I :
growth
factors



PDGF
EGF
TGFa
Surgical Oncology
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)
Surgical Oncology
Oncogenes

Class III-intracellular
transducers

Protein Tyr kinases


Protein Ser/Thr kinases


mos, raf
G proteins


src, yes, fes, abl, ret
ras (2nd most
commonly altered
"oncogene" in human
cancer)
Phospholipase C

crk
Surgical Oncology
Oncogenes

Class IV : nuclear
transcription factors

jun, fos, myc, myb,
ski, rel, p53
Surgical Oncology
Tumor Suppressor Genes


Defined as any gene whose loss of
function leads to tumor progression
Block cellular proliferation
Surgical Oncology
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
Surgical Oncology
Oncogenes/TSs by Cancer

Breast


BRCA1/2
HER-2/neu (Epidermal growth factor
oncogene)

Trastuzumab, Herceptin
Surgical Oncology
Oncogenes/TSs by Cancer

Colon


DCC
APC




responsible for FAP
p53
ras
MSH/MLH




mismatch repair
microsatellite instability
HNPCC
Lynch syndromes
Surgical Oncology
Oncogenes/TSs by Cancer

Pancreas



ras
p53
MEN


men1 (MEN 1)
ret (MEN 2A, 2B, heriditary
Hirschsprung’s dz)
Surgical Oncology
Oncogenes/TSs by Cancer

GIST

c-kit




Imatinib, Sunitinib
Gleevec, Sutent
tyr kinase inhibitors
originally designed for use in CML
Surgical Oncology
Tumor Markers
Tumor Markers
Type of Cancer

PSA

Prostate CA

CEA

Colorectal CA

CA 15-3

breast CA

CA 19-9


pancreatic CA
biliary CA
Surgical Oncology
Tumor Markers
AFP
hepatocellular CA
testicular CA

b-hCG
Choriocarcinoma
testicular CA

5-HIAA

carcinoid
Surgical Oncology
Tumor Markers

Calcitonin


Thyroglobulin


CA 125

medullary thyroid
CA
differentiated
thyroid CA
ovarian CA

Gastrin

gastrinoma
Surgical Oncology
Tumor Markers

Insulin (with low
glucose)


PTH (with high Ca)


LDH



insulinoma
parathyroid
adenoma/CA
testicular CA
Melanoma
lymphoma
Surgical Oncology
Chemotherapeutics

5-FU

inhibits thymadylate synthase
Surgical Oncology
Chemotherapeutics

Methotrexate

inhibits dihydrofolate reductase
Surgical Oncology
Chemotherapeutics

Gemcitabine


Cyclophosphamide, ifosfamide,
melphalan, mitomycin C, dacarbazine


competes with dCTP for DNA
incorporation
alkylating agents
Platinum agents

damage DNA by forming adducts
Surgical Oncology
Chemotherapeutics

Adriamycin, topotecan, irinotecan


topoisomerase inhibitors
Taxol

microtubule inhibitor
Surgical Oncology
Biological Therapeutics

Trastuzumab



Monoclonal Ab against Her-2/neu
Breast CA
Rituximab


Monoclonal Ab against CD-20
B cell lymphoma
Surgical Oncology
Biological Therapeutics

Cetuximab



mAb against EGFR
Colon CA
Bevacizumab


mAb against VEGF
Colon CA