cancer genetics

cancer

heterogenous group of disorders chracterized by the prescence of cells that do not responsd to the normal controls on division

two main properties of cancer

uncontrolled cell dvision and ability of these cells to spread to other sites of the body

most common cancers in the unoted states

breast, prostate, lung, colon and rectum and skin

malignant

tumor consisting of cells that invade other tissues

metastasis

the movement of cells that separate from malignant tumors to other sites making secondary tumors

cause of cancer

alterations in DNA

signals that regulate cell division

moelcules that stimulate cell division and molecules that inhibit it

when can cell division be stimulated

stimulatory gene can be made hyperactive or active at inappropriate times

why are mutations in stimulatory genes usually a dominant act

the amount of gene product produced by a single allele is usally sufficent

oncogenes

dominant acting genes that stimulate cell division leading to the formation of tumors and contributing to cancer

how do oncogenes arise

mutated copy of a normal cellcular gene

cell divsion being stimulated when inhibitory genes are made inactivce

mutated inhibitory gene act in a recessive manner, needing both copies to be remoced to remove all inhibition

tumor supressor genes

gene that normally inhibits cell division. recessive mutations in such genes contribute to cancer

protooncogenes

normal cellualr gene responsible for basic cellular function but when mutated can become an oncogene and contribute to cancer

proto-oncogenes to oncogenes

virus infects a cell, protooncogene may be incorportated into the viral genome by recombination. vural genome may mutate into oncogene that when inserted back to host cell can cause rapid cell division and cancer

how do tumor supressor genes work

both alleles must be mutated before the inhibition of cell division is removed, failure of their function promotes cell proliferation

how can someone be predisposed to cancer

individuals can inherit one defective copy of a tumor supressor gene but the other allele is normal

how are heterozygotes for tumor supressor genes predisposed to cancer

the inactivation or loss of the one remaining normal allele is all trhat is required to completely eliminate the tumor suppressor gene product

loss of heterozygosity

inactivation of the remaining wild type for a tumor supressor gene

mechanism for loss of heterozygosity

deletion on the chromosome that carried the normal copy of the tumor suppressor gene

dominant acting mutations of tumor supressor gene

mutation alters the sequence or the expression of the tumor supressor protein in a way that it gains a new function contributing to cancer

haploinsufficicency

appearance of a mutant phenotype in an individual that is heterozygous for a normally recessive trait

what is though to be the cuase of haploinsufficiency

dosage effects,

errors in the cell cycle making cancer

errors arising in one or more of the components that regulate the cell cycle

effects of errors in the cell cycle

cells dividing at inappropriate times or rates making cancer

stages of the cell cylcle

g1, s, g2

g0 stage

nondoviding cells passing from g1, to be functional but are not actively growing or dividing

how are key events of the cell cycle controlled

cyclin dependent kinases

kinases

enymes that phosphorylate other proteins

when are kinases functional

when associated with cyclin

cyclins in the cell cycle

levels of cyclins varying thruout the cell cycle but when bound to a CDK, cyclin specifies which proteins the CDK will phosphorylate

when do cyclins appear

each cyclin appears at a specific point in the cell cycle because its synthesis and destruction is regulated by another cyclin

g1 to s transition

guided by g1/s checkpoint wihich is at the end of g1 right before s phase

how is the cell prevented from passing thru g1/s checkpoint

retinoblastoma protein which binds to a transcription factor called E2F and keeps it inactove

g1, cyclin d and cyclin e

continuously increase in concentration and combine with associated CDK

cyclin-C-CDK AND cyclin E-CDK

phosphorylate molecules of RB, but late G1 RB phosphorylation is donw and inaciivates RB

without the inhibitory effects of RB what happens

E2F is release and transcription factor E2F stimulates transcription of genes that produce enzymes needed for DNA replication, cell moves to s phase

what is associated with retinoblastoma

mutations occuring in the gene that encodes the RB protein

what happens when RB gene is mutated

cells pass thru the g1/s checkpoint without the controls preventing cell proliferation.

apoptosis

process of programmed cell death in which the cells DNA is degraded, its nucleus and cytoplasm shrink and the cell undergoes phagocytosis by other cells without loss of its content

apoptosis and cancer

cellular abnormalities that would stimulate apoptosis tehrefore inhibtiing it and cannot undergo programmed cell death

ability of cell to initiate apoptosis is dependent on

p53 which is inactive in many human cancers

autophagy

process for destroying cell components

process of autophagy

vesicles within the cell engulf cytoplasm, damaged organellsand other components and transport them to lysosomes where components are degraded and consituents are recycled

genes that regulaye telomerase and cancer

sequences that regulate the expression of the telomerase gene are mutated allowing the enzyme to be expressed and the cell is able to divide indefinetly

cancer and angiogenesis

tumor cells genes enocding angiogeneis are often overexpressed compared to normal cells and inhibitor of angiogenesis promoting factors may be inactivated or underexpressed

epigentics and cancer

change in chromatin structure affect gene expression. genes endoding proteins that are regulators of epigentic changes are mutaed

colorectal cancer initiation

adenomatous polyps that over time enlarge and have abnormal characteristics of cancer cells

colorectal cancer development

after growth to polyps these tumors may invade muscle layer surrounding the gut and metastasize

common pathway of colorectal cancer

loss of tumor supressor gene APC, polyp is made on colon wall, bengign precancerous tumor grows, activation of oncogene ras, an adenoma grows, loss of tumor supressor gene p53, carcinoma develops, loss of antimetasisis gen, the cnacer metastasizes

chromosome rearrnagments associated with cancer

deletions, inversions and translocations

deletions and cancer

can result in the loss of one or more tumor supressor genes

first way that inversions and translocation contributes to cancer

chromosome breaks that accompnay these mutations can lie within tumor supressor genes and disrupt their function causing cell proliferation

second way translocations and inversioncontribute to cancer

they can bring together two different genes generating a fusion protein that stimulates some aspect of the cancer process

third mechanism chromsome rearrangements can produce cancer

the transer of a potention cancer causing gene to a new location, where it is activated by different regulatory sequences

when is cancer initated

when gentic chnages tale place that cause the genome to become unstable generating numerous chromosome abnormalties that can alter the expression of oncogenes and tumor supressor genes

mutagens

radiation (x rays and uv ray)and chemicals (cigarette smoke, nitrate and nitrate preservatives, benzoyl peroxide,

cancer cells are descendents of

colonal descendants from one mutant cell, where the cell accumulated specific mutations over a long period of time

metastasis process

cancer cells break away from original tissue, metasizing cells attach to wall of blood or lymph vessel secreting digestive enzymes to create an opening crossing the wall at the breach,

sporadic cancer

cancer cause by an accumulation of a number of mutations in somatic cells, beginning with a mutation in a single somatic cell and additional mutations accumulate

inherited cancer syndromes

inherited mutant genes cause a predisposition to cancer and are carried in a heterozygous state

APC

scaffold protein interacts with microtubules

BRCA 1

DNA repair, transcription factor

p53 abd RB

regulates cell division

retinoblastoma

malignant tumor of the eye in reitnoblasts,usually only in children