22b: Intro to Neoplasia: Mutagens and Cancer genetics

What are mutagens?

any substance that mutates genes or causes chromosomal instability

Examples of mutagens

chemicals

radiation

viruses

inflammation

obesity

family heritability

How is inflammation a mutagen?

chronic inf has ongoing repair and proliferation

How is obesity a mutagen?

adipose released mediators cuasing inflammation and repair

When do mutations occur?

1. germline mutations: in womb

2. Somatic mutations: acquired in lifetime

What are proto-oncogenes?

normal genes that stimulate cell division

What is an oncogene? What does it cause

mutated proto-oncogene, causing cell to be stuck on + therefore constant cell division

What kind of mutation is needed for oncogene formation?

only one

dominant/GOF

What do tumor suppressor genes do?

stop cell cycle if there is a problem, checkpoint proteins

What does pRB (retinoblastoma protein) do? How?

ensures DNA is ready for duplication at the G1-s checkpoint

binds to E2F to stop cell division

What does p53 do? How?

ensures DNA is replicated correctly at the G2-m checkpoint

recognizes mutated DNA and either fixes it or stimulates apoptosis

What kind of mutation is used for tumor suppressor genes?

2, recessive/LOF

What is the most mutated oncogene?

Ras

What mutated oncogenes is in majority of melanomas?

GNAQ

What happens to RB1 when its is mutated? (on cellular level)

phosphorylated and can no longer bind E2F to stop cell division

What does a mutation to RB1 cause?

retinoblastoma

What is sporadic retinoblastoma?

both mutations acquired after birth

unilateral @2-4 years old

What is inherited retinoblastoma?

one mutation inherited + another acquired after birth

bilateral @2-6 months

What is the most common mutated tumor suppressor gene?

p53

What does BRCA1/2 do?

repairs DNA breaks and mutations

What does a BRCA 1/2 mutation do?

inhibits repair of DNA mutations, therefore BRCA1/2 can no longer repair cancerous mutations like Ras

What type of mutation is BRCA 1/2?

recessive, LOF

What does BCL-2 do?

inhibits apoptosis

What happens if BCL-2 is mutated?

turned on permanently, constantly inhibiting apoptosis, can't kill cancer cells

What type of mutation is BCL-2?

GOF/dominant

What enhances tumor growth? how?

angiogenesis

via VEGF + PDGF