Cancer genetics Flashcards
cancer resulting from mutation of tumor suppressor gene
mutation inactivates, loss of function.
both alleles must have mutation to cause cancer (either by recessive inheritance or dominant with 2nd hit).
examples of tumor suppressor gene mutations
mutations of Rb and TP53
retinoblastoma - pediatric cancer
proto-oncogenes
gene with the potential to cause cancer via somatic/acquired genetic mutation that leads to gain of function (always dominant at cellular level)
must be activated via genetic transformation
transformations that cause activation of proto-oncogenes into oncogenes
point mutation
gene amplification
ex: HER2
over-expression via translocated promoter or enhancer
translocation of gene fragment
2-hit hypothesis
one hit is hereditary, second is acquired (somatic)
loss of heterozygosity
after second hit occurs - no protection from 2nd genome
most frequent site of LOH across all types of cancers is p53
Neurofibromatosis
autosomal dominant RASopathy caused by mutation in NF1 - codes for GAP (GTPase activating protein) - mutation causes uncontrolled cell growth/division
2nd hit to create associated cafe-au-lait spots
why so different cancers occur among a family with Lynch Syndrome?
second hits are random and can occur at any tissues
Fanconi anemia
genetically heterogeneous autosomal recessive or sex-linked recessive disorder.
Sx: short stature, birth defects, bone marrow failure, cancer predisposition)
mutations in DNA repair genes (including BRCA1/2 - which contribute to breast cancers_
conditions that repair mutated gene via 2-hit process
Confetti ichthyosis - autosomal dominant skin disease, 2 hit areas become normal skin.
Ras oncogenes
GTPase is turned on permanently - MAP kinase pathway continuously on.
leads to colon cancer, point mutations.
ErbB oncogene
ErbB - codes for EGFR (epidermal growth factor receptor - an RTK), mutation leads to active receptor that cannot bind ligand
includes HERs
can be inhibited by tyrosine kinase inhibitor
RET oncogene
inherited (exception to rule that mutations in protooncogenes are rarely inherited)
causes MEN2 - multiple endocrine neoplasia
Cowden syndrome
autosomal dominant mutations in PTEN, a tumor suppressor gene that encodes a TP53-inducible phosphotase.
loss of inhibition of Akt signaling via dephosphorylation of PIP3 into PIP2
breast, endometrial, prostate cancer
Familial Adenomatous Polyposis
1% of colon cancers
causes excessive colon polls requiring prophylactic colectomy
caused by loss of APC gene, which codes for APC protein, a tumor suppressor
