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

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

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

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

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

Oncogenes

Oncogenes Class I : growth factors PDGF EGF TGFa

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)

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

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

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

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

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

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

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

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

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

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

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

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

Chemotherapeutics 5-FU inhibits thymadylate synthase

Chemotherapeutics Methotrexate inhibits dihydrofolate reductase

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

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

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

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