CHAPTER 19: THE GENETICS OF CANCER Cancer = genetic disease at somatic cell level, abnormal gene products from mutated/abnormally expressed genes -> uncontrolled growth 19.1 Single nucleotide substitutions, chromosome rearrangements, amplifications, deletions -> cellular function changes (DNA repair, cell division, apoptosis, cellular differentiation, migratory behavior, & cell-cell contact) What is Cancer? All have abnormal proliferation -> benign (cell growth/division) + metastasis to 2ndary tumors -> metastases/malignant Clonal Origin of Cancer Cells Clonal = common ancestral cell that accumulated specific cancer-causing mutations -- reciprocal chromosomal translocation (leukemia/lymphomas) -> evident in all cancer cells b/c specific breakpoints ---- tumors are not identical because they have subclones with their distinctive mutations Driver/Passenger Mutations Driver mutation = tumorigenic mutations, passenger mutations = no contribution to tumor phenotype -- passenger mutation may contribute to tumor resistance b/c possible drug resistance phenotypes Cancer Stem Cell Hypothesis Cancer stem cell: only cells in tumor/tumor subclone that proliferate, undifferentiated cells with self-renewal capacity -- cancer could be from stem cells or somatic cells reverting to stem cell like Cancer as a Multistep Process (mutations/clonal expansions) Evidence it’s multistep: exponential rise with age, increased exposure to carcinogens Tumorigenesis: 2+ genetic alterations releasing cancer cells from proliferation/malignancy controls -> clonal expansions -- colorectal cancer: epithelial cell -> adenoma/polyp (cluster) [inactivation in APC tumor suppressor gene needed for differentiation] -> KRAS mutation [regulate cell growth] -> carcinoma [TP53, PI3K, TGF-b controls cell growth, division, apoptosis, signaling, cell-cycle regulation] 19.2 Loss of genomic integrity -> increase in mutations (mutator phenotype) Genome Instability and Defective DNA Repair: point mutations, chromosomal effects (translocations, aneuploidy, chromosome loss, DNA amplification + deletions) -- Chronic myelogenous leukemia (CML): translocation where C-ABL gene on chr 9 translocated to BCR gene on chr 22 ---- creates Philadelphia chromosome (BCR-ABL) fusion -> chimeric BCR-ABL protein -> proliferation ---- normal ABL = protein kinase transferring growth factor from external -> nucleus -- Xeroderma pigmentosum (XP): sensitivity to UV light/carcinogens -> skin cancer because lack nucleotide excision repair -- hereditary nonpolyposis colorectal cancer (HNPCC): mutations in DNA repair genes (MSH2, MSH6, MLH1, MLH3) Chromatin Modifications and Cancer Epigenetics Epigenetics: chromosome associated changes affecting gene expression, not DNA nucleotide sequence -- DNA methylation or histone modification (acetylation/phosphorylation) -> decreased DNA repair/cell cycle control or increased cell proliferation gene products 19.3 Differentiated cells: specialized, nondividing, quiescent cells -> stimulated to grow by signals/growth factors Cell Cycle/Signal Transduction Early-mid G1: enter cell cycle (G1/S/G2/M) or quiescence (G0) [cell is active but does not growth] -- G0 cells can be stimulated to enter cell cycle by growth factors/hormones (signal transduction: external signal -> nucleus] Cell-Cycle Control and Checkpoints: G1/S, G2/M and M checkpoints -- G1/S: size monitor/DNA dmg repair [CDK4/cyclin D -> DNA polymerase/ligase] -- G2/M: physiological condition monitoring, DNA must be done replicating/repaired -- M: spindle-fiber system must be formed, spindle fibers-kinetochore must be attached Cyclins/cyclin-dependent kinases: cyclin binds to CDK -> cyclin-CDK complex activation -> phosphorylation proteins to advance cell through cycle Apoptosis Control: cell cycle halt if DNA replication/repair/chromosome assembly defective Apoptosis: nuclear DNA fragments, cell structures disrupt, cell dissolves in apoptotic bodies [taken up phagocytic cells] -- caspases: initiate apoptosis 19.4 Proto-oncogenes: encode transcription factors -> increase gene expression of products that cause cell to divide -- when mutated/abnormally expressed = oncogene, gain of function [only 1 allele needs to be mutated, dominant cancer phenotype] -- c-myc, c-kit, RARa, cyclins, VEGF Tumor-suppressor gene: gene w/ products that regulate cell-cycle checkpoints + initiate apoptosis -- mutated = can’t stop cell from progressing or can’t repair genetic damage [2 alleles must be lost of function] -- RB1 (HPV suppresses RB), TP53, BRCA1/BRCA2 (homologous DNA repair) The ras Proto-oncogene: signal transduction molecules associated with cell membrane + regulate cell growth/division -- inactive via GDP -> active via GTP binding -- mutations prevent GDP -> GTP hydrolyzing = permanent on TP53 tumor suppressor gene: encodes p53 (transcription factor) that represses/stimulates more genes -- p53 normally bound to MDM2; MDM2 tags p53 for degradation, prevents activation of p53 -- MDM2 usually dissociates in response to DNA damage -> transcription activation domain on p53 -- increase in p53 = increase in MDM2 -> negative feedback loop -- p53 causes cell-cycle arrest at G1/S or G2/M or retard S phase, DNA repair, apoptosis -- @ G1/S p53 stimulates p21 gene transcription which inhibits CDK4/cyclin D1 complex -- most cancer mutations = inactive p53, some cause gain in function -> gene products affecting chromatin modifications 19.5 -- primary tumor -> secondary tumor by secreting protease to digest ECM + basal lamina (WBC can do it) -- metastasis controlled by cell-adhesion molecules, cytoskeleton regulates, & proteolytic enzymes ---- E-cadherin glycoprotein lower in epithelial tumors (cell-cell contact) ---- breast cancer abnormally express MMP1 (metastasize to bone) or MMP1/2 (lungs) [TIMPs = inhibitors of MMPs] 19.6 Most cancer causing alleles (cancer predisposition genes) are in tumor suppressor gene but need somatic mutations -- RB1 causes retinoblastoma; PTs with heterozygous RB1 have mutations in both alleles for tumors ---- lost of 2nd wild-type (loss of heterozygosity) b/c chromosome deletions/rearrangements -- FAP disease: 1 APC mutant copy on chr 5 long arm [deletion, frameshift, point mutations] -> no cycle control ---- APC usually tumor suppressor controlling growth/differentiation 19.7 Natural environmental: 10% cancer, could be natural or growth factors/hormones|UV/ionizing radiation|diet Human Made: chemicals, air, pollutants, tobacco smoke (DNA methylation pattern changes) [greatest] Viruses: [second greatest] -> induce mutations + other mutations = cancer