L56 57 Cancer Genetics

Question 1

chemical factors for cancer

Answer 1

carcinogens and mutagens

damage DNA by covalently binding and adding adducts

radiation can be carcinogenic (UV, X, gamma)
-pyrimidine dimers

80% human cancers caused by chemicals
-some require p450 to become ultimate carcinogens that attack nucleophilic groups

Initiators: cause actual damage

promotors: stimulate cell proliferations
- initiator must come first, then you need close together consistent promotors

Question 2

Viral Induction

Answer 2

15% of cancer

RNA virus: reverse transcripate
-integration, deregulation of celly cycle: inhibition of apoptosis, abnormal cell signaling

DNA Virus: down regulate tumor suppressor genes, TP53 and Rb

HPV:

• E6-destroys p53, no apoptosis or halt
• E7-Binds to Rb, liberates E2F (always on)

-recombinant HPV vaccine (quadrivalent) (4 protiens of viral coat)
-2HPV counterstrains that cuase warts and cause cervical cancer
e[stein barr-burkitts lymphoma

Question 3

protooncogenes

Answer 3

NORMAL GENES

• GF’s GF receptors, cell cycle control, tranfections,
• mutation-BECOME AN ONCOGENE
• GAIN IN FUNCTION

altered product:

• mutations in genre or promotor
• fusion creation
• multiple copies on same X

Question 4

Three wyas RTK can become overactive

Answer 4

all three increase Cyclin D-allowing cell to cross rest point

1. RTK mutation
   - trucatedL doesn’t need ligand
   - too many receptors: decreased conc of cofactor still activates
2. mutation ni signal transduction protein
   - RAS GTPase
   - RAS stim by RTK to release GDP and bind GDP, then hydrolyzes GTP to become inactive
   - mutation makes it always on (1/3 tumors)
3. Gene AmplificationL MYCL sent to quiescent cells to divide
   - involved in histone acetylation, motility, telemorase, red cell adhesion,
   - not mutated in tumors just elevated

Question 5

Burkitts Lymphoma

Answer 5

translocation from t(8:14)

MYC behind a very highly active promotor

IGG rpomotor

Question 6

Philidelphia chromosome

Answer 6

t(9:22) EBV ENHANCES TRANSLOCATION
-chronic myelogenous leukemia
ABL/BCR Fusion gene

Contitutively avctive Tyrosine Kinase

-normally depends on signal for activation

increased cell proliferation

Question 7

Genetic mutations of tumor suppressor genes

Answer 7

NormalL inhibnit proliferation in response to gene damage
-slow or halt cell cycle or APOPTOSIS

-both copies inactivated- CANCER

Rb and TP53

Rb mutated, does not bind to E2F

Question 8

P53 Tumor supressor

Answer 8

normal: p53 active and stabilized as a trans factor

p53 prevents neoplastic transformation in three ways
Quiescence
Senescence
Death

normally degraded by MDM2, damage happens, ATM expression causes release of P53 and it goes and binds to broken sites

Question 9

Retinoblastoma

Answer 9

inherited OR predisposed infance and age 2

result of a somatic mutation (AUT DOM TRANS)
Familial, family cluster, BILATERAL LIKELY
Sporadic , first mut, second with no fam history, UNILATERAL: RARE

Question 10

Knudsens 2 hit hypothesis

Answer 10

mutation of 2 copies of RB required to get RB
sporatic: one of single spont pool must get a second

familial: all cells have one, just one needs another

Question 11

Li Fraumani Syndrome

Answer 11

hereditary defects in P53

inher of one, predisposed to dev tumor

no single cancer type predominates, all over body

every branch in pedigree has cancer

Question 12

Neurofibromatosis Type I NFI

Answer 12

autosomal dominant

mutation/activation of both copies

benign tumor of schwann cells around the nerves of the APNS

skin hyperpigmentation, café au le spots 
lisch nodules (legions of iris)

Neurofiromin Protaien
-GTPase activating protein GAP facilitate deactivation of ras…raas always on

Question 13

Familial Adenomatous polyposis

Answer 13

mutant APC gene (adenomatous polyposis coli)

when one, the toher happens

1000s of colorectal polyps remove the colon

WNT path, control cell fate, adhesion, polarity

Question 14

WNT signaling

Answer 14

WNT: APC and betacatenin

WNT receptor is G coupled- sends for BC degredation
-transcription of growth genes inhibited

wnt presentL binds receptor and signals APC to let go of B cat and drives growth and transcription

tumor: B cat always in nucleus allowing trans, no apc, always on

colon crypt: stromal cells typically only secrete wnt at bottom and it dies out toward top

apc deficient, even the top of the crypt proliferates

Question 15

Accumulation of mutations speed up cancer in repair mechanisms

Answer 15

(60)MSH/MLH: SSDMMR : Hereditary non polyposis colon cancer
cannot repair….8-10 years down to 2-3 year for mutation gain

XP genes — Pyrimidine dimers NERL 1000x greater risk of developing cancer with Xeroderma pigmentosa
-RECESSIVE

BRCA1/2 LLL DNA repair of double stranded breaks, familial breaks cacner
from 12—80% ovary 15—40%

Question 16

miRNA and Aneuploidy

Answer 16

increase in oncogenes or decrease in tumor suppression

leukemias and lymphomas

disregulation of cancer associated genes by Aneuploidy - hallmark of cancer