CANCER

Introduction What is cancer? Genetic disease of somatic cells Rarely inherited Unrestrained growth of cells Abnormal proliferation Loss of normal restraints preventing cells from spreading to other parts of the body (metastasis)

Cancer Clonal origin Multiple mutations are required All cancerous cells within an individual are daughter cells from a single cancerous cell Primary vs secondary tumors Multiple mutations are required Several layers of protection against development of cancer

Genomic Instability Once a cancerous mutation occurs, other mutations occur more easily: mutator phenotype Chromosomal mutations (translocations, e.g.) Defective DNA repair Epigenetic modifications

Abnormal Cell Proliferation: Cell Cycle Dysregulation Cell cycle checkpoints keep mutated cells from dividing

Proto-oncogenes and Tumor-suppressor genes

Proto-oncogenes ras family genes Normal function Mutant Cell cycle progress Mutant Oncogenes promote abnormal cell proliferation

Tumor Suppressor Genes p53 family genes Normal function Cell cycle checkpoint regulation G1/S and G2/M Mutant Allow cells with mutations to proliferate Can lead to a mutator phenotype

Multi-Step Progression to Cancer Familial adenomatous polyposis Inherit a mutant copy of APC gene Second mutation in the other allele  “Loss of heterozygosity” APC is a tumor-suppressor gene Mutation of APC  polyp formation Further mutations result in malignant metastatic colorectal cancer

Multi-Step Progression to Cancer

Virally-Caused Cancer 2nd leading cause of human cancer is viral infection 1st cause is smoking Typically caused by DNA viruses Viruses rely on host cell machinery to replicate Viruses contain genes to “turn on” host cells Examples HPV Human papillomavirus HTLV Human T-cell leukemia virus Hep B -- Human herpesvirus B Epstein- Barr virus