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