Lecture 19: Cancer Part 2

what do Hereditary diseases associated with

DNA-repair defects

what do Hereditary diseases associated with DNA-repair defects do

greatly increase the chances of cancer development

what do Sequenced cancer genomes show

large number and wide variety of somatic mutations

SV

structural variants

Indels

insertion and deletions

SNVs

single nucleotide variants

what do Cancer cells often develop

abnormal karyotypes

karyotypes

total set of chromosomes in a cell

what are the dramatically altered genomes cancer cells have Beyond accumulated mutations

Aneuploidy, Composite chromosomes

what do differentiated cells with sufficient oxygen perform

oxidative phosphorylation to generate energy from glucose

what do differentiated cells without oxygen perform

anaerobic glycolysis, less efficient

what process do cancer cells and proliferative tissue favor

aerobic glycolysis over oxidative phosphorylation

what are the benefits of aerobic glycolysis over oxidative phosphorylation

ATP generation is faster overall at the cost of burning more glucose, Glucose intermediates are used to synthesize biomass, anabolism

types of tumors

benign, malignant

Benign tumors

small and localized, composed of a single cell type that normally functions like the surrounding tissue

Malignant tumors

invade other tissues and seed formation of new tumors that continue to proliferate

Metastasis pathway step 1

metastatic cancer cells degrade the basement membrane

Metastasis pathway step 2

Cells migrate on extracellular matrix fibers to reach blood vessels

Metastasis pathway step 3

Degradation of the vessel wall and entry into the bloodstream (extravasation)

Metastasis pathway step 4

Seeding of cancer cells in distant tissues to form secondary metastatic tumor

how can Cancer can be driven by

loss-of-function mutations of tumor suppressors AND/OR gain-of-function mutations of oncogenes

what are GOF mutations in

signal receptors, signal-transducing proteins, transcription factors

what is GOF mutations involved in

promoting growth pathways

what are LOF mutations in

negative feedback mechanisms in growth pathways, proapoptotic proteins, DNA-repair proteins, cell-cycle control proteins

Proto-oncogenes

genes that function normally but have the potential for oncogenic mutations

RTK/Ras/MAPK pathways involved in cancer

highly mutated with pro-growth factor signaling proteins being proto-oncogenes, and negatively-regulating proteins being tumor suppressors

what can Oncogenic mutations in the Ras/MAPK pathway often lead to

constitutively active signal-transducing proteins

are is a common driver of cancer development

Ras activity mutations

Ras activity mutations

G12X mutations in Ras inhibit Ras GTPase activity, Loss-of-function mutations in the NF1 GAP protein

describe Gain-of-function mutations in oncogenes

autosomal dominant

describe loss-of-function mutations in tumor suppressors

recessive