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ONCOLOGY (Oncological *Mutations either in oncogenes or tumor-Supressing…
ONCOLOGY
Oncological *Mutations
either in oncogenes or tumor-Supressing genes
*Specific Tumor Mutated Genes
*2 hit Hypothesis with oncogenes
Notes
:
Knudson's 2 hit hypothesis says that of the 2 major types of inherited genetic cancer mutations, the proto-oncogenes only require 1 hit for the oncogenes to have a gain of function mutation
the tumor supressor genes, may have a one-hit inactivation of the gene
the 2nd hit leads to malignancy
note these are all autosomal dominant
ALK
ALK cancer = LARGE ALK with LARGE LUNGS and LYMPHOMAS
--> large cell lymphomas
--> non-small cell lung cancer
APC
APC = ALWAYS PASS (away) CANCER = PC - Pancreatic and Colorectal
--> tumor supressor gene APC in pancreatic and colorectal cancer
ALK
VHL gene = Von Hippel Lindau / Von trap
dominant kid
can't stand due to
kidney problems
...
plays the
HARP
--> RP kidney prolems
--> RCC and pheochromocytomas
*oncogene Mutations
*KRAS - MAPK gene mutation
"KRAS"
= Konstant Ras activation
--> GTP active form
"KRAS - MAPK = MA PK"
= Messenger ADENOCARCINOMA of Pancreas / KOLON
Clinical Cases
Clinical Case
Notes
:
note that
Clinical Case
Ras Mutations
Bras = GTP-bound oncoprotein
cell surface --> nucleus transporter
Notes
:
note that TP53 in the tumor-supressor gene family is mutated in almost all cancers
not as common as TP 53, but Ras GTP-bound transporter oncogene is the most common oncogene mutation
--> 20% of cancers have Ras mutation
Clinical Case
*RET gene mutation
"RET = RETTY your DOMINANT MEN 2 screen for BOTH"
"MEN2"
= MEdulla / EN2 = Endocrine organs x 2
--> adrenal medulla = pheochromocytoma
--> medulla of thyroid = either parathyroid or mucosal secreting
"2 screen for BOTH"
- if you find RET mutation you have to screen for both mutations
*RET gene = RETy MEN2 battle (first and second waves MEN 2 a/b)
*ALK gene mutation
adenocarcinoma of LUNGS
tyrosine Kinase receptor
*Tumor Suppressor Mutations
*MEN1 gene
*tp53 - LiFraumeni Syndrome = SBLA
Mortal Kombat on a Truck
--> dropping TP53
Clinical Cases
Clinical Case
Notes
:
note that
Clinical Case
p53 ts gene and Li-Fraumeni Syndrome
Notes
:
remember
"Li Frowns from tp53 BBS"
--> breast, brain, sarcomas
Clinical Case
*WILMS tumor = WT1 gene mutation
nephroblastoma
*Common hereditary cancer mutations
*Lynch Syndrome and HNPCC
Oncology
*Treatments
Checkpoint
Inhibitors
*Chemotherapy
Side Effects and Toxicities of Chemotherapy Agents
Alkylating Agents
Cisplatin
3 in ABCs of chemo toxicites
ottotoxicity, nephrotoxicity, peripheral neuropathy
Notes
:
Cisplatin has a very high rate of high frequency hearing loss
it has the symptoms ONE --> nephrotoxicity
--> ottotoxicity, nausea, emesis, nephrotoxicity
ABCs 123 of Chemo Toxicity:
1 A
= Anthrocyclines - I toxic ruby heart
--> dilated cardiomyopathy
2 B
= bleomycin - 2 hardenned lungs
--> pulmonary fibrosis
--> note also PF from AB = amiodarone + bleomycin, methotrexate, nitrofurantoin Abx
3 C
= cisplatin- 3 pairs of organs affected
--> 2 ears = ottotoxicity
--> 2 kidneys = nephrotoxicity
--> 2 lower limbs = peripheral neuropathy
Anthracyclines - "toxic Ruby Hearts"
end in "-rubicin" = toxic ruby heart
doxorubicin
Clinical Case
Clinical Case
Notes
:
note that
*Radiation Therapy
Apoptosis
both intrinsic and extrinsic Pathways
Extrinsic Apoptosis
Fas / FADD death domain / Caspases 8 & 10
Lymphocytic Fas Apoptosis
Auto-immune disease (RA and SLE)
leukemia and other cancers
Notes
the extrinsic pathway of apoptosis goes through the Fas receptor
think of
Fast suicide
Fas is bound by FasL ligand
--> 3 Fas receptors form a trisomer
trisomer becomes the FADD = Fas associated death domain
the FADD activates Caspases 8 and 10 that then initiate activer caspases 3 and 5
-- think of caspases 8 and 10 = "
hateful 8 suicide squad
"
note that the Fas / FADD / Caspases 8 and 10 are important for T lymphocytes to make sure they don't get out of control
they can self activate their own Fas extrinsic apoptosis and also to nearby T cells
Case example:
Intrinsic = mitochondrial Apoptosis
Cytochrome C release + ?
Apoptosis Overview: Intrinsic and Extrinsic Pathways
Apoptosis and Caspases
Notes
:
note that in both the pathways for apoptosis there are either initiator caspases or effector caspases
extrinsic initiator caspases = 8 10
the FADD activates Caspases 8 and 10 that then initiate activer caspases 3 and 5
Case example:
Caspases
Initiator Caspases7
--> 2 8 9 10
Effector Caspases7
--> 3 5
Benign Tumors
Neurofibromatosis (type 1)
Notes
:
note that Neurofibromatosis is a single gene autosomal dominant disorder
there are 2 types of NF
it has a mutation in the NF-1 gene = neurofibromatosis gene
remember that Neurofibromatosis has Cafe Au Lait spots on their skin, which also gives prime = 17 - CAFE SPOT = all the possible symptoms of NF:
C = cafe au lait spots
A = axillary freckling (this is much more in NF 1 vs. NF2)
F = fibromas (dermal often)
E = eye Lisch Nodules (hamartomas around the iris of the eye)
S = scoliosis and skeletal bowing
P = pseudoarthrosis
OT = Optic tumors (meningiomas, gliomas, astrocytomas, etc.)
prime 17 = NF comes from mutation of NF-1 gene on chromosome 17
Clinical Presentation
remember that
Neurofibromatosis has COFFEE CUPS on their back with SPILLED COFFEE
--> Cafe Au Lait spots = prime 17
CAFE SPOTs
C = cafe au lait spots
A = axillary freckling (this is much more in NF 1 vs. NF2)
F = fibromas (dermal often)
E = eye Lisch Nodules (hamartomas around the iris of the eye)
S = scoliosis and skeletal bowing
P = pseudoarthrosis
OT = Optic tumors (meningiomas, gliomas, astrocytomas, etc.)
prime 17 = NF comes from mutation of NF-1 gene on chromosome 17
Neurofibromatosis (type 2)
Neuro FM case 2
the fibromas in neuro FM are benign fleshy macule papules
they are from peripheral neuron myelin sheath
Schwann cells --> derived from neural crest GAMES (+ ad med)
Notes
:
note that Neuro FM has both flesh coloured papules that grow larger and larger and accumulate and are benign
note though that neuro FM can lead to malignancies in the brain
they also present with multiple cafe au lai spots
remember the mnemonic CAFE SPOTS for Neurofibromatosis
--> think of the fibromas as coffee cups on the trunk with spilled coffee
--> CAFE AU LAI with fibromas
Clinical Case
Pituitary Adenomas
benign tumors that present with bitemporal hemianopsia = vision loss / bluriness
--> optic chiasm compression
present with headaches
Prolactinoma
most common type of actively hormonal pituitary adenomas
prolactin causes galactorhea
prolactin inhibits GnRH from hypothal
--> hypogonadism in men and amenorrhea in women
Prolactinoma example
most common type of actively hormonal pituitary adenomas
prolactin causes galactorhea
prolactin inhibits GnRH from hypothal
--> hypogonadism in men and amenorrhea in women
Notes
:
note that hyperprolactinema causes galactorhea in women
prolactin also inhibits GnRH from hypothal
--> hypogonadism in men = decreased libido
--> amenorrhea in women
Case presentation:
Skin Cancer
Melanoma
Melanoma example
Clinical Case
Notes
:
note the
ABCDE of Melanoma lesions
A = assymetry
B = borders are irregular
C = colour is varient throughout --> red, brown, black
D = Diameter >=6 mm
E = Elvolving or changing
note that that melanocytes come from neural crest cells
Xeroderma Pigmentosum
see dermatology
Occular Neoplasms
Retinoblastoma
Clinical Case:
Notes
:
retinoblastoma is a cancer of the retinal cells of the eye
mutation in the RB1 = retinoblastoma gene on chromosome 13
--> good example of the two-hit hypothesis for gene mutations --> neoplasms
think RB1 --> baseball --> number #13 and the 2-hit hypothesis
2-hit hypothesis
1-hit - when you have germline defect in one pair of the RB1 gene on chromosome 13
--> this is called heterozygosity since you still have one good and intact gene
2-hit - if you develop a mutation in the second gene, then you will develop retinoblastoma
--> this is called loss of heterozygosity
Head And Neck Cancers
HNSSC's
(Head and Neck Small Cell Carcinomas)
Notes
:
note that any cancers of the head and neck are mostly all squamous cell carcinomas
most are caused by smoking and drinking and have primary sites in the oropharyngeal cavity
they can then spread and invade to local lymph nodes of the neck
*Bladder Cancer
gross PAINLESS hematuria in OLDER MEN
--> TBC = trasnitional Bladder CA
-->
UNTIL PROVEN OTHERWISE
smoking and workplace exposure to plastics or rubber are the biggest risk factors
Clinical Cases
Clinical Case
Clinical Case
Notes
:
note that
*Heart Cancer
primary tumors of the heart are rare
most common 80% = left atrial myxoma
Myxoma Histology
high vascular to myxomas since in the heart
hemorrhage
hemosiderin macrophages
--> like in Left HF
Clinical Cases
Clinical Case
Notes
:
note that
Clinical Case
*Cervical Cancer
most are caused by HPV infection
*HPV and Cervical Cancer
1s, 6s , 8s Strains
malignant HPV = strains 16, 18 and 31
--> sexual transmission
--> condoms
genital warts HPV = strains 6 and 11
--> skin to skin transmission
--> no protection
*Pancreatic Cancer
APC gene mutation
-->
"ALWAYS PASS (away) CANCER"
Any older person who presents
-->
SMOKER
--> painless jaundice and palpable GB
= pancreatic cancer until proven wrong by a scan
smoking is the biggest risk factor for pancreatic cancer
*Carcinogens
smoking is by far the biggest factor
*Kidney Cancer
over 90% are RCC
"cannonball metastases" from RCC in lung
*Multiple Myeloma
BAB the CRAB
M and M playing poker with BAB the CRAB and 2 GOBLINS = GOLD GOBLIN and APPLE GOBLIN
BAB the CRAB
antibodies of M and Ms POKER GAME = GOLD GOBLIN and APPLE GOBLIN
the river ELECTROPHORESIS of the first hand comes up as a SINGLE M PROTEIN SPIKE and the GOBLINS eat FRIED EGGS to pretend like they aren't nervous
M protein SPIKE in M&Ms
M&M goes ALL in with his STACKS of RBCs along with his ROULEAX ROLLEX and the GOBLINS return by throwing in the KEYS to their own BENZ JONES GOBLIN CAR
ROULEUX = stacked RBC CHIPS
BENZ JONES GOBLIN CAR = Bence jone Ig light chains
*Lipomas
sarcolipoma = the most common soft tissue tumour of adults
*sarcolipoma
sarcolipoma = the most common soft tissue tumour of adults
usually present in the pelvis area or the thighs are most common
--> note this is what Eamon had
*Li-Fraumeni Syndrome = LFS
"LOU FERIGNO syndrome"
caused by a p53 germline mutation
autosomal dominant
very high risk and penetrance for mutlple kinds of cancers
*Common tumor markers
*Cardiac tumors
myxoma most common
comes from the left atrium
Clinical Cases
Clinical Case
Clinical Case
Notes
:
note that
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