Cancer Genetics, CML and Env. Influence on Dev't.

Question 1

Describe the key features of Retinoblastoma.

Features, Main Diagnostic, What’s observed if inherited?

Answer 1

Tumors in the eyes developed sporadically (late, bilateral) or inherited (earlier, unilateral).
Diagnostic Feature: deletion of chromosomal DNA with functional Rb gene
If proband inherited the disease, some of his family members will most likely develop one or more tumors in both eyes.
This is distinctive of “loss of heterozygosity” which occurs in people who inherit a bad Rb allele on Chr 13. Usually is BILATERAL and occurs later in life if inherited.

Question 2

P53 is classified as a _____ _____ gene that is intrinsically ________ but stabilized in _____ damage, where it triggers _________ if activated.

Answer 2

Gate keeper gene;
Unstable
DNA
Apoptosis

Question 3

Describe p14ARF and MDM2.

Answer 3

P14ARF - an alternate reading frame that binds MDM2 in order to free p53; pro-apoptotic; reduces cancer.
MDM2 - ubiquinates p53 for destruction by proteasome; anti-apoptotic; CANCER-related if over expressed.

Question 4

Caretaker Genes
(Examples and functions)

Answer 4

MLH - functions in mismatch repair; defect leads to HNPCC
ERCC1 - functions for GG-NER; defect leads to XP
BRCA-1/2 - functions in DSBR; defect leads to breast cancer

Question 5

Gatekeeper Genes
(Examples and functions)

Answer 5

Rb - inhibits G1/S transition by reducing E2F transcription

p53 - stops division and promotes apoptosis in DNA damage/stress.

Question 6

Describe bilateral tumors.

Answer 6

You already inherit 1 BAD ALLELE. These tumors occur if ONE event of an EXTRA BAD ALLELE is required to trigger a cancer such as (familial) Retinoblastoma.
Feature: Multiple tumors in the eye and multiple family members affected.

Question 7

Describe unilateral tumors.

Answer 7

Occurs if TWO EVENTS are required for (sporadic) tumor formation in Rb.
Feature: One Person gets a tumor in one of the eyes

Question 8

Loss of heterozygosity

Occurrence and causes

Answer 8

Occurs where the presence of one bad allele would eventually lead to the faster acquisition of another bad one.
Causes: loss and duplication, gene conversion, conversion of normal allele to heterochromatin, genetic recombination…
*In Rb, the 2nd bad allele comes faster but the onset of disease still occurs later in life.

Question 9

C-myc

Application and disease

Answer 9

Activated by over-production, gene amplification or translocation.
Disease: Burkitt Lymphoma occurs where c-myc is translocated near enhancers in B-cells which triggers B-lymphocyte tumors, XS antibodies.

Question 10

C-abl

Application and disease

Answer 10

Can self-activate by dimerization with no regulatory mechs needed. Usually maintained by a nearby regulator gene.
Disease: Chronic Myelogenous Leukemia - translocation between chromosome 9 and 22 = “Philadelphia Chromosome”, C-Abl is CONSTITUTIVELY ON; stuck in cytoplasm, highly mutable

Question 11

C-ras

Application and disease

Answer 11

Normally a G-protein that’s active with GTP; plays a role in cell signaling; SLOW intrinsic GTPase
Disease: Neurofibromatosis - NF1, a ras-GAP is mutated and therefore more RAS txn leads to more tumors in PNS

Question 12

Zika

Onset, Symptoms

Answer 12

A virus spread by mosquitoes in South America. Brain stops growing, fluid-filled ventricles enlarge, skull stops enlarging.
Symptoms of microcephaly, mental retardation.
Onset in 1st trimester of development. Mosquito transmits virus

Question 13

Rubella

Onset, Symptoms

Answer 13

Virus that causes congenital deafness, heart disease and eye deformity. Mental retardation can also occur.
Secondary features: microcephaly
Onset in 1st trimester of development.

Question 14

Folic Acid Deficiency

Onset, Symptoms

Answer 14

Mother not taking recommended 400 mg of folic acid daily can results in neural tube not closing at the end of 1 month.
Defects: anencephaly (flattened skull + microcephaly) or spina bifida (neural tube doesn’t close)

Question 15

Fetal Alcohol Syndrome

Symptoms, Onset, Recommendations

Answer 15

Symptoms: microopthalmia (small eyes), hyperactivity, microcephaly, facial abnormalities
Onset in 1st month of development
Cause: > 4-5 drinks/day
Recommendation: NO ALCOHOL when pregnant

Question 16

Thalidomide

Intention tx, Effect, Hero of the story

Answer 16

Intention: treat morning sickness; presumably “safe non-addictive sedative”
Effect: stoped development of blood vessels and neural tissues; undeveloped flipper-like limbs, neuropathy and dizziness in adults; aka “PHOCOMELIA”
Dr. Francis Kelsey from the FDA read early effects of defects from German articles and just said no (1960). She prevented a medical disaster in the US.

Question 17

Diethylstilbestrol (DES)

Description, Exposure, Effect

Answer 17

Non-steroidal estrogen in 1930s
Judged an animal carcinogen in the 1940s
Caused Vaginal cancer in female’s offspring (F2 generation) later in that offspring’s life; exposure in 1st trimester.
*Caused adenocarcinoma in the NEXT GENERATION, from mothers who took it.

Question 18

Fetal Origins of Adult Disease
Ex: Intrauterine Growth Retardation (IUGR)
(Exposure, Effects, Metabolism)

Answer 18

Mothers Exposed to chronic stress and corticoid stimulus in 3rd trimester (weeks 16-38) where the baby gains more weight.
Victims have increased risk of obesity, hypertension and cardiovascular diseases. Increased demand for calories
*There is no model accepted.

Question 19

Describe the risk mercury poses and what it’s used for in industry. What congenital disease occurs?
(Toxic agent, origin, symptoms)

Answer 19

Toxic to ALL ORGANISMS.
Used in antiseptics, biocide on crops, preservative of some vaccines, a diuretic (that can poison the kidney).
Disease: Minamata Disease - METHYL-MERCURY poisoning from fish such as tuna (bioaccumulates in marine predators); congenital defects, cannot move voluntarily

Question 20

What did the Seychelles Study show?

What fish is okay to eat and what fish should be avoided?

Answer 20

There is a negative regression between effects from methylmercury intake and a diet rich in fruits and veggies.
*Environments rich in protective nutrients staved off exposure to neuropathy.
Salmon is high in Omega-3’s and low in Hg
Avoid Tuna, Shark and Swordfish (common marine predators)

Question 21

What toxins are known to bio-accumulate up the food web?

Answer 21

PCBs (polychlorinated biphenyls) - poisons the ground for years, resists degradation, found in Great Lakes Fish
DDTs (common pesticide) - poisons insects
Methyl-mercury - found in tuna fish

Question 22

Describe the facts of Lead exposure.

Answer 22

> 5 micrograms of lead/dL in the blood is the threshold to neurological deficit.
Effects: lower IQ, higher risks of ADHD, emotional problems.

Question 23

Describe organophosphates.

Clinical case, half life, effects, politics

Answer 23

Flint Disaster - high levels of eroded lead from old pipes and organophosphates were found in children, short half life, neurological effects (disrupts neurotransmitters, esp. AcHE)
DAP metabolites were linked to SLOW REFLEXES.
The state knew about it and did not do anything to prevent this from occurring.f

Question 24

What are Reference concentrations and describe the convention.

Answer 24

Daily exposure for people without risk of bad effects.
Convention: 10-fold uncertainty factors across the board. [10-10-10] ~ Interspecies: intraspecies: sub-populations (i.e. Infants)

Question 25

What (6) ways can in uterine toxicity be shown?

Answer 25

1. Gestational age
2. Birth (congenital defect: Zika, Mercury, Thalidomide, Lead).
3. Infancy (delayed milestones)
4. Puberty
5. Adulthood (FOAD ~ Intrauterine growth Retardation).
6. F2 Generation (DES).