New Material Final Exam Lecture 3/5: Cancer Genetics

what is cancer

a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body

• genetic disorder involving muts in cells

• not inherited but certain inherited muts can predispose a person to cancer

what do malignant tumors do

disrupts surrounding tissue

what is metastasis

cancer moves to new loactions

can muts in any gene lead to cancer

no → only genes that are integral in cell division (repairing dna damage, stopping cell cycle, etc) are typically associated w cancer but other ones can j b muts in proteins, etc

what is oncogenesis

how normal cells turn cancerous

• begins w loss of cell cycle control (makes tumour)

what is metastasis

tumor cells that undergo further changes that allow them to invade and disrupt other tissues

t/f: cancer cells have a lower rate of mut than normal cells

explain

false → have higher

• enzymatic systems that repair cells damage or mistakes during rep are often defective

• muts in genes involved in repair = more muts

• more muts = more pot muts in genes involved in repair/cell cycle control

  • positive feedback loop

    • more muts → higher rate of new muts → more muts, etc

what do mistakes in DNA replication and repair lead to as a result of uncontrolled cell division (besides tumours)

genomic instability → many cancer cells have major chrom abnormalities, including missing/extra chroms and large chrom rearrangements

• will end up not being able to do their desired fx bc so many muts

does a single mut in a gene involved in cell cycle control/dna repair result in cancer

no → multiple muts in those genes are req for a cell to become cancerous

how does the chance someone gets cancer change w age

increases

• supports idea cancer involves an accumulation of muts

do samples from tumors only have one active allele in X-linked genes

yes

X-inactivation → whole tumor is a result of one OG cell → if cancer occured/started in 2 diff types of cells then you could see both alleles representaed

what are cell cycle checkpoints and what do they involve

control mechanisms to ensure proper progression

• monitor major events in cell cycle (eg growth, dna replication, proper chrom segregation)

• involve diff CDK complexes (cyclin-dependent kinase complexes)

what are cyclins

proteins that appear at diff stages in the cell cycle → bind to CDK proteins and activate them

what do CDK complexes do

phosphorylate genes → this can help activate or deactivate them → regulates their activity

• modulated by cyclins

what are driver muts and what are the 2 ways they work

muts that promote cancer initiation and/or progression

• inactivate tumor suppressors or activate oncogenes

• have pot to inc net cell growth

  • eg muts in TP53, RB, BRCA

• cancer generally occurs when multiple driver muts are acquired

whatare passenger muts? explain

muts that do NOT contribute to cancer

• arise bc of inc muts due to driver muts

• make up majority of muts found in mature cancers

what are the two classes of genes that lead to loss of cell cycle control? are they activated or inactivated by mutations and do the mutant alleles act dominantly or recessively

1. tumor-supressor genes (loss of fx muts)

   • involved in cell cycle control or repairing dna

   • inactivated by muts

   • alleles act recessively (ie need both alleles to b activated by muts to have loss of fx and inc proliferation)

2. oncogenes (gain of fx muts)

• stimulate cell proliferation

• activated by muts

• mut alleles act dominantly (ie only need a mut in one wild type allele to simulate cell proliferation)

what are 2 examples of driver muts

tumour suppressor genes and oncogenes

what are RB, P53, and BRCA1/2 considered

tumour supressor genes

what is RB? what do muts in them result in

prod by a tumour suppressor gene

• normal proteins that delay entry into S-phase until cell is ready to divide

  • muts in RB gene causes retinoblastoma (most of the time)

    • one or both muts can be somatic BUT way more likely to cause retino if 1 is germ

what are P53? what do muts in them result in

normal protein fxs in the G1-S checkpoint

• mut gene in more than 50% of human cancers

• leads to many chrom abnormalities (uncontrolled cell division)

what are BRCA1 and BRCA2? what do muts in them result in

part of machinery for repairing double-stranded breaks in DNA

• muts in these genes lead to sig inc in risk for breast/ovarian cancer

• without functional Rb, S-phase can not be prevented

  • EF2 activates transcription of S phase genes w out any repressor to pause it → uncontrolled cell growth

what is rentinoblastoma

cancer of retina

• caused by muts in RB gene

• some families have a dominant genetic predisposition to certain types of cancer (eg retinoblastoma)

which individuals are more prone to retinoblastoma

people who interit one copy of the RB- (dysfunctional) allele

• considered a dom predisposition to cancer BUT cancer bc of tumor -repressors is a recessive trait on a cell level (2 mut alleles needed for cancer)

t/f: everyone who inherits an RB- allele gets cancer

false → only 75% penetrance

• still needs other copy to mutate before they get it

note: also has varying expressivity (ie can only be in one eye)

are muts in the Rb gene recessive or dominant

recessive → 1 copy of Rb can suppress E2F on its own

what are E2F proteins? how are they regulated

a family of transcription factors that control the expression of genes needed for a cell to enter and progress through S phase of the cell cycle.

Key role:

• When Rb (retinoblastoma protein) is bound to E2F → E2F is inactive, so S-phase genes stay off.

• When Rb gets phosphorylated by cyclin–CDK complexes → E2F is released and activated.

t/f: an individual w RB- gene has a higher likelihood of developing retinoblastoma in both eyes than those w 2 working

true → need functional mut in both eyes individually to mutate to get retinoblastoma

• person w out muts needs two muts in the SAME CELL in BOTH EYES to get it

• person w RB- only needs one mut in each eye for both to have

which phase does Rb act as a gatekeeper for

S phase

• it is a transcriptional repressor when unphosphorylated

how does Rb work

transcriptional repressor when unphosphorylated

• Rb is usually bound to E2F (blocks promoter)

• when cell is ready to go to S phase, Rb becomes phosphorylated (by cdk complex)

• unbinds from E2F protein and genes required to go to S phase are transcribed

which genes control the phosphorylation of Rb

(active) CDK phosphorylates Rb

• Rb no longer attaches to E2F

• genes for dna rep are expressed

• cell commits to S phase

t/f: tumour supressor genes usually need both alleles to be inactivated to lead to cancer

true

hereditary vs sporadic retinoblastoma

hededitary:

• all cells have one mut allele

• one cell aquires the second somatic mut

Sporatic

• one cell aquires 2 somatic muts

• diagnosed later in life

what does P53 do

protein that detects dna damage

what does protein p21 do

stops the S phase

• inactivates the CDK complex

• cell cycle arrest

what is TP53? explain how it works

• gene that codes for p53

  • p53 is a tumor suppressor protein that helps maintain genome integrity by preventing cells with DNA damage from dividing.

• How it works:

  1. DNA damage or stress → p53 levels rise.

  2. p53 can halt the cell cycle (by activating p21, which inhibits cyclin–CDK complexes) so the cell has time to repair DNA.

  3. If damage is too severe, p53 can trigger apoptosis (programmed cell death) or senescence.

• Normal role: Prevents cancer by ensuring only healthy, correctly replicated DNA is passed on.

• Cancer link: Mutations in TP53 are found in more than half of all human cancers. When p53 is lost or defective, cells can divide unchecked even with severe DNA damage.

If E2F and cyclins are the “go” signals for division, p53 is the emergency brake—and in cancer, that brake often fails.

tumour suppressor gene

• transcription factor (activator NOT repressor → activates P21 gene - inactivates CDK complex)

  • constitutively expressed but is rapidly degraded

    • doesn’t really work unless stabilized

• phosphorylation of p53 stabilizes it → it becomes an active transcription factor

  • p21 inactivates CDK complex

    • RB gate stays closed = cell cycle arrest

• if damage cannot be repaired, p53 initiates apoptosis

• p53 acts as brake for progression of the cell cycle

what phosphorylates p53? why does that phosphorylate it

cell damage/stress

• activates p53 → activates p21 → inhibits cdk complex → cell cycle arrest bc its damaged → gives time to repair OR if enough phos p53 accumulates, apoptosis

what happens w out functional Rb and p53

rapidly rep cells eventually acquire dna damage (naturally or mutagens)

• nothing to stop cell cycle to fix damage → muts occur and tumorigenesis (also called oncogenesis or carcinogenesis) begins

• loss of cell cycle control inc rate of new muts

• leads to cancers if enough muts accumulate

why don’t muts in a single gene involved in the cell cycle generally cause cancer

bc cell cycle has multiple diff checkpoints (backup systems)

why are we concerned with p53 muts and uncontrolled cell division if telomeres will eventually run out and the cells will die anyways

• inc chance muts controlling telomerase

• expression allow telomeres to be lengthened → cells basically become immortal

• muts like TP53 inc likelihood for muts in general, including other ket genes like telomerase gene

do the BRCA1 and BRCA2 genes have high or low penetrence

high penetrence → 90% for BCRA1 mutant alleles and 41% for BRCA2

what are BRCA1 and BRCA 2? what do muts in these result in

tumour suppressor genes

• gene products are parts of a surveillance system needed for repairing dna breaks

• when mutated, damaged dna may get replicated

  • heterozygotes are at higher risk for acquiring muts in remaining copy compared to individuals not born w mut

• promotes muts in other genes leading to cancer = phenotypic dominance

are mutant BRCA1 and 2 phenotypically dominant or recessive for cancer

recessive → when mutated, damaged dna may get replicated

• heterozygotes are at higher risk for acquiring muts in remaining copy compared to individuals not born w mut

• promotes muts in other genes leading to cancer = phenotypic dominance

what are proto-oncogenes

normal genes that mutate to form oncogenes

• a proto-oncogene is a gene w normal fx in a cell (usually related to cell growth/differentiation)

  • encode proteins needed for cell cycle progression

• gain of fx muts result in increased proliferation

• gain of fx muts can arise from insertion of a strong viral promoter adjicent to the proto-oncogene

what are oncogenes

mutated forms of proto-oncogenes → causes cell to reprod rapidly

• excessive proliferation inc chances of more muts which could lead to cancer

what is the gene that encodes for the ras protein an example of? explain why

a proto-oncogene

• codes for a family of proteins that act as molecular switches in cell growth and differentiation

• in normal cells, ras is activated by binding of growth factors to the cell

  • activation of ras leads to cell proliferation

• when ras genes are mutated (eg in cancer cells) ras is active even in absence of growth factors

are muts in ras gain or loss of fx muts

gain of fx muts

what studies helped lead to the discovery of specific proto-oncogenes? how

studying tumour-causing reteroviruses (oncoviruses)

• some viruses inc rate of cancer

• looking at genome of tumour-causing virus can reveal oncogenes

• looking at genomes of tumours induced by these viruses can also reveal oncogenes

• viral dna is relatively easy to find → identifying where in host genome it has integrated to cause tumours can help identify proto-oncogenes

are cancer causing viruses lytic dna viruses

no → do not promote cell lysis

instead they’re reteroviruses

what are reteroviruses? what do they do

RNA viruses

• most cancer causing viruses

• use an enzyme called reverse transcriptase → converts their RN genome into DNA

• that viral dna integrates into host genome

  • BUT they do not become viral particles and exit the genome and cell like lytic ones do

• once integrated into host genome, the viral genes are often transcriptionally active → strong/constitutive viral promoters

  • can be located anywhere in genome → can be located upstream of proto oncogenes (now making them onco)

    • oncogene gets transcribed along w viral genome and gets packaged into progeny virus particles which insert them into other hosts/cells

• this dna is generally permanently inserted into the host genome

are ongogenes dominant of recessive for cancer

dominant