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