Genetics of Cancer Flashcards
proportion of individuals will develop cancer
males 1 in 2
females 1 in 3
cancer
a collection of >100 distinct disorders that share the common feature of uncontrolled cell growth.
cancer growth is caused by
mutations - changes in DNA that specifically affect genes that incite unlimited cell growth.
cancers are what kind of diseases?
genetic diseases
cancer development is based on two processes
continuous acquisition ofheritable genetic variation by random mutations.
natural selection which favors cells with mutations which gives them the ability to proliferate and survive better than normal cells.
cancer originates follow genetic changes in a _ cell.
single cell.
However, as the cancer cells grow, each cell may have different additional mutations so that the cancer cells differ.
two broad categories of cancer
familial (5-10%)
sporadic (mutations)
hereditary cancer signs
early onset
transmitted in an autosomal dominant pattern.
types of hereditary cancers
breast (10%)
colon >5%
prostate (10%)
largest etiologic afactors in cancer
genetics
alcohol
diet
tobacco
both sporaid and famililar cancers are caused by
gene mutations
types of tumor suppressor (TS) genes
gatekeepers
caretakers
oncogene
A mutant allele of a proto-oncogene, a class of normal cellular protein coding genes that promote growth and survial of cells.
Oncogenes stimulate proliferation and inhibit apoptosis.
sequence of proto-onco gene function
growth factors secreted -> growth factors bind to receptors -> cytoplasmic signal transduction proteins -> nuclear proteins: transcription factors -> cell growth genes.
mutations in signal transduction pathways
activate signal transduction and drive cells into the cell cycle.
c-kit, erb-B, RET, ras
mutations of cell cycle regulatory molecules
expedites the G1 - S phase transition as does loss of inhibitory proteins, making cells resistant to differentiation factors.
cyclin D1
mutation of transcription factors
actuvate a class of genes required for continued proliferation (jun, fos)
mutation of regulators of programmed cell death
bcl-2
overexpression results in prolonged cell survival and escape from apoptotic signals.
how many alleles are needed for oncogenes to be mutated
only one allele needs to be mutated.
oncogenes are
gain of function gene
ways in which proto-oncogenes can be converted into oncogenes
point mutation
chromosomal translocations
gene amplification
example of an oncogene
Ras
it affects transcription factors.
Ras
requires a growth factor be activated.
With mutations, Ras is active all the time and cellular growth is unrestrained.
in some cases, a proto-oncogene is activated by a
chromosomal translocation (e.g. CML)
chronic myelogenous leukemia
results in vast numbers of leukemic cells (granulocytes and megakaryocytes)
prrimary event causing myelogenous leukemia
enhanced tyrosine kinase activity
activation of proto-oncogene gene by chromosomal translocations
the translocation moves ABL (a tyrosine kinase) to the BCR gene. This causes ABL to always be activated and increases tyrosine kinase activity.
Compound which inhibits the BCR-ABL product
imatinib mesylate (gleevec)
function of tumor suppressor (TS) genes
they normally block or “put the brakes on” cellular growth.
are also cell adhesion molecules
involved in comtrol of cell cycle
repair mutations in DNA
mode of inheritance of mutations in TS genes
recessive.
Function of both alleles must be lost to be cancerous.
example of a TS gene
retinoblastoma
two hit model of carcinogenesis
two successive mutations (hits) are required to form some types of cancer.
gatekeeper
genes that control cell division
caretaker
genes that repair DNA damage and maintain genomic integrity.
gatekeeper genes encode
regulators of various cell cycle checkpoints
mediators of programmed cell death
types of retinoblastoma
sporadic 60% (unilateral)
familial: 40% (most bilateral)
mutations in retinoblastoma
first mutation: a point mutation is a point or some other small changes confined to the TS gene.
Second mutation loss of all or part of a chromosome.
RB1
controls cell proliferation.
RB1 gene function
bind and inactivate a group of cellular transcription factors (E2F) which are required for cell cycle progression.
hypophosphorylated RB1
inhibits transition from G1 to S
As protein (pRb) becomes more phosphorylated, it releases E2F and allows
cells to enter S phase
loss of RB protein
If RB gene is missing, E2F is not repressed and regulation of the cell cycle is disrupted and cells undergo more cell divisions.
Germline mutation (inherited diseases):
Germline mutation (inherited diseases): Inherit one in germ line (first hit inherited) and second hit in a somatic cell (second his acquired)
Somatic mutation (sporadic diseases):
Somatic mutation (sporadic diseases): Normal germ line, mutation in somatic cell (first hit acquired) and then second mutation in same clone (second hit is also acquired)
retinoblastoma second hits are
o Second hits are usually deletions
