1-26 Intro to Cancer Flashcards
cancer
is a genetic disease, second leading cause of death in US
clonal proliferation (subclones also), gives uncontrolled cell growth
benign turns malignant once crosses basement
membrane
genetically heterogenous cancer
neoplasia
“new growth” a clonal proliferation of cells exhibiting uncontrolled growth (tumor), some noeplasms are benign some are malignant
malignant neoplasm = cancer
carcinogens
cause DNA damage which leads to uncontrolled cell growth, act on specific pathways which control cell growth!!!
genetically heterogenous cancer
benign vs malignent
benign:
- well differentiated (resemble tissue of origin)
- usually slow rate of growth
- tumor grows as expansile nodules without infiltration of adjeacent tissue, remain circumscribed
- no metastasis
malignant:
1. may be well or poorly differntaited
2. usually rate rate of growth
3. poorly defined and infiltrate adjacent tissues
4. can metastasize
Dysplasia
disordered growth, usually associated with epithelium
has some features of neoplasia, dysregulated growth and accumulation of mutations
may progress to a malignant neoplasm, dysplasis does not pregress to benign neoplasms
metastasis
defining quality of malignant neoplasms
requires tumor to develop a repertoire of abilities
oncogene
oncogene is a gene that promotes autonomous cell growth in cancer cells, encodes oncoprotein
proto-oncogenes: are the unmutated cellular counterpart that gets mutated to turn into oncogene
can be activated by single nucleotide mutation ex: RAS missense mutation turns to constitutively active form
somatic hot-spot RAS mutations result in different cancer manifestations
tumor suppressor genes
encode proteins that prevent uncontrolled cell growth and division, participate in DNA repair, control DNA damage checkpoints
p53: inhibits cell cycle and induces DNA repair and/or apoptosis
- RB (retinoblastoma): prevents G1/S transition
usually need to lose both copies of the gene for loss of function
Oncogene activation by translocation
- position effect: upregulation of oncogene by position effect (ex: MYC regulated by IGH transcription enhancers to make burkitt’s lymphoma)
- translocation by fusion protein: philadelphia chromosome in CML
two hit hypothesis
- for tumor suppressors need to knock out both copies of the tumor suppressing gene
de novo: need to sporadically acquire both genes mutated
hereditary: inherit a damaged gene from parent, therefore only need to acquire 1 mutant, so cancer develops quicker potentially
molecular diagnostics of tumors/germlines
tumor testing: testing for somatic chances, ids tumor subtype, provides prognostic info, helps to id targeted therapies
germline testing: germline mutations, helps with prophylactic surveillance, provides information on cancer risk, non-tumor tissue is tested, usually testing blood or cheek cells
Multiple endocrine neoplasia type 2 (MEN2)
family hx: father and paternal aunt: pheochromocytoma
personal hx: no personal health history, 22 years old
referral: lump in neck
exam: mucosal neuromas of the lips and tongue
needle aspirate: possible carcinoma
tx: thyroidectomy
histology: medullary thyroid carcinoma
Genetic testing for mutaitonsi nthe RET gene for all famlies with medullary thryoid carcinoma, speceially at young age
if mutation is IDed, prophylactic thyroidectomy is recommended (90% of MEN2 pts develop thyroid carcinoma), at risk family should be tested, some lossoffx RET mutations are associated with Hirschsprung’s disease
Retinoblastoma
pt hx: 18 mo young child, white glow in pupil
exam: leukocoria with dialted pupil, not reacting to light
malignant transofmation of retinal cells, can be unilateral or bilat (more likely heritable then), heritable or de novo
lossoffx mutation (90%) or deletions, mean age of dx 1-2 years
test blood to ID germline inherited mutation, test tumor to ID de novo mutations
early dx is critical, possible secondary cancers are common, treatment dependent on size/extent
Li Fraumeni syndrome
pt hx: 15 year old metastatic osteosarcoma
family hx: early onset breast cancer on maternal side
molecular testing: pathogenic mutation in TP53 inherited from mother (tumor supressor mutation syndrome)
penetrance: is not absolute, 85% penetrant to develop tumor in life, 15% develop 1+ cancers, most commonly: sarcomas, breast, leukemia, brain tumor
classic criteria for genetic testing: multiple family history of tumors under age 45
compret criteria: LFS tumor under age 46, a famly tumor under age 56, other criteria more lax
Toronto protocol for surveillance: evaluation every 3-4 months, improves survival significantly, annual brain and whole body MRI and breast, colonoscopy, expensive but effective
Hereditary breast/ovarian syndrome
BRCA1/2, TP53, STK11, PTEN, ATM, CDH1, PALB2
BRCA1: more frequent of the two, loss of function mut, triple neg are more likely in BRCA1 mutant carriers, 2 Ashkenazi jews founder mutations
BRCA2: lossoffx mut, high risk of male breast cancer (6%) and 1 ashk jew founder mutation
indications for testing: under 45 yo, bilateral under 50, under 60 with triple negative, ovarian cancer, male breast cancer, pancreatic cancer, metastatic prostate cancer, ashjew patient with breast cancer
management of carriers: breast MRI at 25, mammogram 30, prophylactic mastectomy, prophylactic salpingiooophorectomy, transvag ultrasound, oral contraceptive
