Cancer Genetics

International Cancer Genome Consortium

Data from 100,000 cancer samples accessible to cancer researchers globally

cancer

• family of diseases

• each type caused by a unique combination of errors (ex. base pair substitutions, chromosome rearrangements (inter and/or intra), copy number variations, and more)

mutations divided into…

• drivers → contribute to cancer

• passengers → no effect

circos plots

type of circular graph used to visually represent complex relationships within datasets (ex. genomic rearrangements, copy number variations, ect)

how is cancer caused

uncontrolled cell division; thus many differences with normal cells are related to cell division

growth factors (normal cells vs. cancer cells)

• cancer cells can multiply without any growth factors bc they can make their own growth factors or have growth factor pathways that are stuck in the “on” position

• normal cells need growth factors in order for cell division to occur

what is lost in cancer and what does it do?

The controls that prevent overcrowding in tissues are lost.

• Controls include:

  • contact inhibition

  • automatic cessation of cell division

  • apoptosis (programed cell division)

Replicative immortality

• cancer cells show this

• can divide many more times than a normal cell of the body

  • human cells can only go through 40-60 rounds of division before they “grow old” and eventually die

Henrietta Lacks and the HeLa cell line

an African-American woman who was the unwitting source of cells from her cancerous tumor which were cultured by George Otto Gey to create the first known human immortal cell line (can divide indefinetely under the right conditions) for medical research. This is now known as the HeLa cell line

pap smear

cells collected by scraping the surface of the uterine cervix

HeLa cells contribution

expriments done on these cells have led to adnavcements such as polio and covid vaccines; treatments for cancer; aids and more; used in scientific studies around the world

senescence

process by which cells permanently stop dividing but don’t die

how do cells avoid senescence or cell death?

by maintaining their telomeres despite repeated cell divisions

• able to divide so much bc cancer cells express amplified telomerase which reverses the wearing down of chromosome ends that happen during each cell division

how does cancer kill?

by forming tumors

what is a tumor, how is it formed, and how does it kill

• a distinct mass of abnormal cells

• abnormal proliferation of cancer cells produces a tumor

• kills by crowding out normal cells

benign tumor

tumor stays localized

malignant cancers

invade other tissues and cause damage

how do malignant cancers invade other tissues and cause damage?

• pressing on other tissues

• malignant tumors may spread cancerous cells throughout body → metastasis

  • accounts for more than 90% of all data outcomes in cancer patients

metastasis

spread of cancer cells from the site of the original tumor to other areas of the body

other ways cancer cells are different that arent’t directly cell-cycle-related include and what do they help with

• help them grown, divide, and form tumors

• distinctive features of cancer cells include:

  • loss of differentiation - cancer cells lose shape

palladin

component of actin-containing microfilaments that control cell shape, adhesion, and contraction

c-Met

• receptor protein found on the surface of the cell

• aka. hepatocyte growth factor receptor (HGFR)

what does c-Met do? (cancer vs normal)

c-Met is phosphorylated (activated) by biding to its signal molecule, hepatocyte growth factor (HGF). It then activates several downstream signaling pathways. It is crucial for embryonic development and wound healing.

• In cancer, however, c-Met is overactive (deregulated) which causes cells to grow uncontrollably and leads to invasive growth (metastasis)

what do mutations in genes like c-met and Palladin do?

help cancer cells de-differentiate(loses specialized identity) and move about more freely than normal cells(metastasis/invasion)

vascular endothelial growth factor

helps the body to grow arteries into the tumor(angiogenesis) since cancer needs oxygen and nutrients to survive; also removes waste

genomic instability

cancer shows this; cells DNA becomes more prone to damage and mutation than normal

why dies genomic instability occur in cancer cells?

due to mutations in the genes that keep the genome stable (DNA repair genes) or genes involved in the cell cycle; if these genes are mutated other mutations can accumulate rapidly

Inherited cancer

when you inherit a mutated suppressor or a defective DNA repair gene; means your one step closer to accumulating necessary mutations for cancer to develop

what do mutations in DNA repair genes do?

doesn’t directly lead to cancer, but by failing to repair DNA properly it increases the mutation rates of all genes

example of a massive genomic rearrangement acquired in a single catastrophic event

in some cancers after a sudden catastrophic event the chromosome is shattered and reassembled in the wrong order leading to a massive genomic rearrangement

genes that contribute to metastasis include

abnormal plasma membrane proteins and incorrect glycosylation patterns that reduce stickiness of cells which allows them to separate, but also allows recognition by natural killer cells

tumor specific killer T cell (natural killer cell)

Special immune cell trained to recognize tumor cells; other t cells that are not specific for tumor antigens will ignore the tumor cell

tumor specific killer T cell (natural killer cell) process

• binds to the tumor cell using its T-cell receptor (TCR)

• releases toxic enzymes (proteases) into the tumor cell and activates P53

• triggers apoptosis

how are killer t cells produced

from blood stem cells that activate the master regulator E4BP4

process of metastasis

• cells grow as a benign tumor in the epithelium

• cells become invasive and enter capillarv

• cells adhere to blood vessel inside the organ you are spreading to

• cells escape from blood vessel to form micrometastasis

• colonize organ, forming full-blown metastasis

myoepithelium

in breasts and serve as an active defense against breast cancer metastasis

how do metastatic cancer cells travel when they leave tumors

in clusters not singles

knudson’s multistep model of cancer

since cells have many different mechanisms to restrict cell division, repair DNA damage, and prevent the development of cancer; cancer must develop in a multi-step process where multiple mechanisms must fail before a critical mass is reached and cell becomes cancerous

clonal evolution of tumors

tumor cells acquire more mutations that make them divide more quickly; allows them to become increasingly more aggressive in their proliferate properties

oncogenes

mutated, dominant-acting stimulatory genes that causes cancer(excessive cell survival and proliferation) arise from proto-oncogenes

proto-oncogenes

control cell division in stem cells so they replace old or damaged cells; after mutation becomes oncogene

How does a proto-oncogene become an oncogene?

through genetic changes that lead to an increase in either the amount of the proto-oncogenes protein product or an increase in the activity of the protein

• examples

  • translocation or transposition

  • gene amplification

  • point mutation

what do oncogenes mostly code for?

mostly code for proteins involved in signal transduction pathways (growth factors, their receptors, kinases etc.)

ras

• most frequently mutated oncogene in human cancers

what happens to ras in 30% cancers?

• amino acids 12 and 61 responsible form binding and splitting of GTP

• aa 12 or aa 61 are replaced in ras gene so that it is locked in the active state and never splits its GTP;

  • signals cell division even in the absence of growth factor

How ras works normally

• growth factor binds to the receptor, causing a conformational change and the addition of phosphate groups

• adapter molecules bind to the receptor and link to Ras; Ras binds GTP and is activated

• Activated Ras activates Raf, which activates a protein called MEK, which activates MAP kinase

• Activated MAP kinase moves into the nucleus and activates transcription factors

How ras works when mutated in cancer cells

same way but with no need for a growth factor due to Ras being continuously active

types of proto-oncogenes

cyclin and growth factor genes

• oncogenes frequently derive from these

what protein simulates the cell cycle

cyclin

what is the primary objective of cancer research?

to identify cancer driven genes that can be therapeutic targets

Ras proteins are activated when they

a) bind GTP

b) release GTP

c) bind GDP

d) undergo acetylation

a

tumor-suppressor genes

inhibitors (stop cell division, repair DNA, or trigger apoptosis is something is wrong)

tumor suppressor genes mutated

mutated recessive-acting (need both genes to be inactive for cancer to develop; one good copy is enough to function) inhibitory genes that are unactive and promote cell survival and proliferation

dominant mutation

gain-of-function; proto-oncogene → oncogene

recessive mutation

loss-of-function; tumor suppressor gene → mutated

gain of function

always “on”

loss of function

turned “off”

p53 protein

• “guardian of the genome”

• has many functions in the cell

• when activated by hyperproliferative signals, DNA damage, telomere shortening, or hypoxia; p53 causes cell-cycle arrest, senescence, or apoptosis)

how telomere shortening affects p53 (process)

1. Telomere shortening releases telomere binding proteins (TBPs) (free TBP increases each time)

2. Further shortening affects expression of telomere-shortening sensitive genes

3. Further shortening leads to DNA damage and mutations

how does hypoxia affect p53 and example

• activates p53

• example

  • colon metastasis in lung → hypoxia → p53 activation → apoptosis

what is p53 a transcription factor for and what does that mean?

p14, p16, p21, and p27 (turns on (activates) the expression of these genes in response to DNA damage)

how does p53 affect the cyclin-CDK complex?

inhibits the cyclin-CDK complex which is what drives the cell through the cell cycle phases; (cyclin is the product of the ras-signal transduction pathway)

What are ways to lose tumor-suppressor activity?

• loss-of-function mutations (assuming already loss-of-function mutation in maternal chromosome)

  • whole paternal chromosome lost

  • region containing normal gene(not mutated) deleted

  • loss-of-function mutation in paternal gene

  • gene activity silenced by epigenetic changes

Peto’s paradox

Cancer prevalence is not correlated with body size

• example

  • elephants have trillions more cells than humans and live a long time, yet they have lower cancer rates

epigenetic changes associated with cancer

• alterations to DNA methylation or chromatin structures

• reversible and not a mutation

• hypermethylation

• hypomethylation

Hypermethylation

decreased expression of tumor suppressor genes

Hypomethylation

increased expression of oncogenes

what is a possible way to regulate c-Met expression in tumors?

microRNAs

miRNA

inhibit gene expression and have reduced activity in tumor cells usually

Which type of mutation in telomerase could be associated with cancer cells?

a) mutations that produce an inactive form of telomerase

b) mutations that decrease the expression of telomerase

c) mutations that increase the expression of telomerase

d) all of the above

C

Hypermethylation is thought to contribute to cancer by:

a) inhibiting DNA replication

b) inhibiting the expression of tumor-suppressor genes

c) stimulating the translation of oncogenes

d) stimulating telomerase

b

how do carcinogens affect DNA mutations

damage them

viruses

associated with some cancers

retroviruses cause cancer by

• mutating and rearranging proto-oncogenes

• inserting strong promoters near proto-oncogenes

examples of animals transmitting cancer to each other

• devil face tumor disease between tasmanian devils

• canine transmissible venereal tumor (CTVT) between dogs