Cancer Genetics

cancer

group of diseases characterized by cells that do not respond to the normal controls on cell division

• somatic mutations

• inherited suscetability

• tumors

localized

benign

invasive

malignant

cancer results from

somatic mutations

cancer-related genes

• control the cell cycle

• mutations in checkpoints can disrupt normal cell cycle controls

stimulatory signals from other cells

signals that tell a cell to progress in the cell cycle

cancer begins

mutation in a single cell

• leads to abnormal cell replication

• extra mutations in subsequent cells enhance proliferation further

cells evolve to grow faster and less impeded by controls

genes that regulate the cell cycle

1. stimulate growth and cell division

2. inhibit growth and cell division

stimulate growth and cell division

oncogenes/protooncogenes

• mutation = hyperactivity

• usually dominant → need 1 mutation

inhibit growth and cell division

tumor-suppressor genes

• inactive gene

• usually recessive → needs 2 mutations

oncogenes/protooncogenes

specific mutations can accelerate cell growth

• increase in cell growth mutations =

  • overexpress proteins

  • protein is stuck in ON position

oncogenes only need

1 dominant mutation

Myc Gene

mutation = duplication of gene

leads to hyperactivity and faster growth of cell

RAS

sticks signaling protein in an always ON position, causing excessive activity

tumor suppressor genes

normally limit cell growth

mutation = removes control → unhindered and faster cell growth

apoptosis

cell death → fail safe if something goes wrong

tumor-suppressor genes

needs both alleles to be mutated

• recessive acting mutation

familiar risk

already inherit one defective allele

• second allele needs to mutate to start road to cancer

RB-tumor suppressor gene

binds to E2F to prevent cell from going into S phase if doesn’t have proper cellular components for cell growth

• mutation of RB alleles = cell enters S phase even if not ready

• leads to tumors in eyes

unilateral retinoblastoma

tumor in 1 eye

sporadic = not inherited

bilateral retinoblastoma

tumor in 2 eyes

mutant = inherited

BRCA1/BRCA2

associated with breast and ovarian cancer

• tumor-suppressor gene = at G2/M checkpoint, arrests cell at checkpoint if DNA is damaged

if have mutated allele → risk of breast cancer is 80%

P53

associated with defects for 50% of all human cancers

• DNA damage → usually repairs damager or initiates apoptosis if not mutated

Li-Fraumeni syndrome

one inherited allele of p53 mutated, so only functional copy inherited

inheritance of early cancer in many different organs

APC

tumor supression controls pathway for cell to cell adhesion

• if mutated = hundreds of mini polyps which can become malignant

sporadic tumors

75% have APC mutated

70% of tumors

have P53 mutated

mutations cause

• uncontrolled cell growth

• genomic instability

• immortality

• angiogenesis

• metastasis

genomic instability

making more mutations and mistakes in the DNA during replication

immortality

telomerase activated

angiogenesis

recruiting blood vessels

metastasis

invasiveness = ability to move

produce faster growth

• delete or silence more tumor suppression genes

• enhance expression of oncogenes, angiogenesis, metastasis

• increased chromosomal abnormalities

  • aneuploidy, translocations, deletions

• changes in DNA methylation

  • decreased/increased methylation of CpG

• changes in miRNAs that regulate protooncogenes or turn off tumor suppressor genes

removing cell cycle checkpoints

causes genomic instability

colon cancer screening test

captures DNA from colon cells

looks for

• RAS mutations

• increased methylation

• detects blood

determining mutations in tumor genome

sequencing or SNP microarray

mapping of mutations across genome detect

lost, duplicated, mutated genes

driver mutations

drive fast growth

passenger mutations

consequence of high error rate → along for the ride

duplication mutations

cluster above in graph

deletion mutations

cluster below graph

environmental risks of cancer

• chemical exposure

• diet

• radiation exposure

• infectious agent

• medical treatments

chemical exposure

air pollution, food, environmental toxins, smoking

diet

carcinogens (plant and microbial toxins), fat

radiation exposure

sunlight, radon

infectious agents

viruses

• HPV

• SV40

• Hepatitis B

• Epstein-Barr virus

• Retrovirus

medical treatments

estrogen replacement therapy