M3 L17: Genetic counseling, human genetics, and cancer genetics

Question 1

why does medical genetics involve the patient’s family more than other medical fields

Answer 1

1) family plays a role in patient’s care

2) patients’ diagnosis could have implications for the family since genetic diseases are heritable

Question 2

genetic diseases caused by mut in single genes

Answer 2

1) huntingtons
2) PKU

Question 3

genetic diseases caused by muts in one of many genes (genetic heterogeneity)

Answer 3

fanconi anemia (LOF mutation in one of 3 genes)

Question 4

example of a genetic disease influenced by the environment

Answer 4

PKU

Question 5

what are 4 types of hereditary diseases

Answer 5

1) mendelian
2) mitochondrial
3) chromosomal
4) multi-factorial

Question 6

how are mendelian conditions inherited

Answer 6

mut in single gene

dom/rec

can be autosomal or X linked

Question 7

how are mitochondrial muts inherited

Answer 7

mut in single gene but inherited maternally

variable penetrance/expressivity

usually more severe in males

Question 8

how are chromosomal muts inherited

Answer 8

add extra copy

usually spontaneous not inherited

influenced by maternal age

Question 9

how are multi factorial conditions inherited

Answer 9

inherit increased susceptibility for heart disease, cancer

Question 10

what is presymptomatic testing and a disease it’s used for

Answer 10

genotype adults before onset of symptoms

common for huntingtons

Question 11

challenges with presymptomatic testing and huntingtons

Answer 11

can help plan for future but traumatic if diagnosis is positive

ethical issues because diagnosis can indicate others are at risk for developing the disease too

Question 12

what are the two types of fetal screening

Answer 12

non invasive (no threat to fetus)

invasive (some risk to fetus)

Question 13

examples of non invasive fetal screens

Answer 13

1) maternal serum sampling: test blood and measure AFP, uE3, HCG (screening not diagnostic)

2) fetal cell sorting: draw mother’s blood and separate fetal cells –> extract fetal DNA (hard bc fragile and 1 billionth of the cells)

Question 14

examples of invasive fetal screens

Answer 14

1) amniocentesis: use needle to extract amniotic fluid and fetal cells

2) chronic villus sampling: pass tube transvaginally to get fetal cells from chorion

Question 15

what is preimplantation screening? common context?

Answer 15

remove a single cell from embryo during 8-16 cell stage –> genotype it

common for IVF

Question 16

What is the Guthrie test? who developed it

Answer 16

robert guthrie developed heel stick to screen for PKU - first widely used genetic screen for newborns

heel has few nerve endings - only use for diseases where QOL significantly improved if genotype is known/can be reliably diagnosed

place newborn blood with bacteria on media with phenylalanine analog (toxic) –> if bacteria grows, it means lots phenylalanine in blood

Question 17

What causes tay-sachs disease? why do carrier screening?

Answer 17

recessive lethal neuromuscular disorder: no functional hexosaminidase –> GM2 ganglioside builds up –> kills nerve cells

1/30 ashkenazi jewish people are carriers –> test to know risk before having kids

very poor QOL for individuals

Question 18

How can direct to consumer genetic tests be helpful? example?

Answer 18

test for genetic variants that are associated with certain phenotypes and increased risk for some conditions

ex) LOF of alpha-1 antitrypsin –> hyperactive protease in lungs and liver –> difficulty breathing/COPD

not a diagnostic test but can help you make informed lifestyle decisions (especially with a genetic counselor)

Question 19

3 goals of genetic counselor

Answer 19

communicate info, discuss options, help patient reach own decision

Question 20

what are the 4 variables to consider when assessing risk when having children

Answer 20

1) inheritance pattern
2) family structure
3) family genotype info
4) pop freq of the allele

Question 21

Why is cancer a disease of the genome?

Answer 21

cancer includes several diseases that are all caused by accumulated mutations in somatic cells –> causes cells to divide abnormally/rapidly

Question 22

cancer is the 2nd leading cause of death after _____? Which two cancers cause the most deaths?

Answer 22

heart disease

lung and breast

Question 23

what 2 types of muts are hallmarks of cancer and malignant tumors?

Answer 23

1) GOF in proto-oncogenes: promote cell cycle progression

2) LOF in tumor supressor genes: normally slow down the cell cycle

Question 24

what is angiogenesis

Answer 24

developing new blood vessels

Question 25

what is metastasis

Answer 25

cancer cells invading other tissues (local or breaking off --> start new tumor)

Question 26

what are driver and passenger mutations

Answer 26

drivers: mutations in cancer cells that lead to cancer progression passengers: mutations in cancer cells that do not lead to cancer progression

Question 27

what is the biggest risk factor for cancer

Answer 27

age

Question 28

is everyone equally susceptible to all sporadic cancers? What is the percentage of development?

Answer 28

yes 90%

Question 29

what is familial cancer

Answer 29

presence of a germline mutation increases susceptibility to a certain cancer

Question 30

examples of familial cancer

Answer 30

chronic myelogenous lukemia retinoblastoma li fraumeni syndrome breast/ovarian

Question 31

mechanism of chronic myelogenous leukemia (CML)

Answer 31

reciprical translocation btwn chrom 22 and 9 --> shortened 22 (philadelphia chrom) and fusion of C-ABL and BCR genes --> chimeric gene --> constitutively stimulate growth BCR normally transfers external growth signals to nucleus detection of phil chrom essentially diagnostic causes bone marrow to overproduce granulocytes

Question 32

what is sporadic retinoblastoma

Answer 32

both copies RB1 (autosomal gene) get mutated in cell that gives rise to retina VERY RARE FOR TWO INDEPENDENT MUTATIONS usually only one tumor in one eye

Question 33

mechanism for retinoblastoma

Answer 33

RB1 encodes protein pRB --> normally binds TF E2F, releases on certain cues mutated pRB can't bind E2F --> E2F upregulates genes involved in G1/S transition --> cells w/ RB1 muts continuously commit to division --> tumor

Question 34

what is hereditary retinoblastoma

Answer 34

zygote heterozygous for RB1 mut --> dev cancer if they get one sporadic mut one mut more likely to occur than two usually multiple tumors in both eyes

Question 35

what's the two hit hypoth? who developed it?

Answer 35

alfred knudson if cancer causing muts occur at some background rate, indiv who are heterozygous for mutations are at a higher risk for cancer than homo WT (only need one sporadic mut to have two hits)

Question 36

what's li fraumeni syndrome

Answer 36

inherited susceptibility to many types of cancer

Question 37

mechanism of li fraumeni syndrome

Answer 37

autosomal dominant mut in TP53 (tumor supressing gene) which encodes p53 "guardian of the genome" (TF that stops cells w/ damaged DNA from dividing via G1 arrest) nonfxn p53 --> damaged cells replicate and accumulate more muts --> cancer

Question 38

what percentage of breast/ovarian cancers are sporadic?

Answer 38

90-95%

Question 39

char of sporadic vs inherited susceptibility breast/ovarian cancers

Answer 39

sporadic: avg age onset is 60 yrs, unilateral familial: onset younger than 60, bilateral, contralateral (one side then other at later time), BCRA1 and 2 muts increase risk (both involved in DNA repair and follow 2 hit hypoth)

Question 40

what is cancer genomics

Answer 40

sequence cancer genomes to determine types of muts that lead to disease progression

Question 41

4 key takeaways from cancer genomics

Answer 41

no 2 tumors, even of the same type, have the exact same mutations some mutations common to many types of caner (p53) specific cancers usually have certain mutations (CML phil chrom and retinoblastoma RB1) epigenetic irregularities common (muts in chrom mod proteins/DNA methyltransferases)

Question 42

3 main types cancer treatments/pros and cons

Answer 42

radiation: can be mutagenic chemo: targets rapidly dividing cells; side effects; not equally effective for all cancers surgery: remove tumor; impossible with certain tissue types

Question 43

what is targeted cancer therapy? example?

Answer 43

can target mutant proteins with drugs if you know the causal mutation gleevec targets C-ABL-BCR fusion protein in CML --> stop protein and stop overproduction of granulocytes

Question 44

example of cancer gene therapy

Answer 44

CAR-T cells for acute lymphoblastic leukemia isolate T cells from patient --> modify antigen receptor to bind CD-19 (expressed by cancer cells) --> grow and inject into patient --> CAR-T cells kill cancer cells in blood also on target off tumor effects: b cells also have CD-19 --> CAR-T cells kill b cells --> body continuously makes more b cells --> stimulates CAR-T cells to divide/stay present

Question 45

Design an assay that would allow for the disease allele of the huntington gene to be identified using PCR.

Answer 45

Collect DNA from the patient, do PCR with primers that are complementary to the sequences up and downstream of the Huntington gene, do gel electrophoresis of the amplified patient’s DNA with a WT Huntington gene. If the WT gene travels farther, then the individual likely has the Huntington repeat sequences.

Question 46

Are direct-to-consumer genetic tests diagnostic? Why or why not?

Answer 46

No because they can only identify some genetic variants that might increase your risk for developing genetic diseases. They can help you make informed choices, especially going through the results with a genetic counselor.

Question 47

Describe one potential drawback of direct-to-consumer genetic testing in the absence of the support of a genetic counselor.

Answer 47

People might interpret the results incorrectly. They might not know what phenotypes the variants can cause, what steps they should take to decrease their risk, and they might worry that they are definitely going to develop a disease if they have a genetic variant. There may be other factors like other genes and environment that influence risk.

Question 47

Cancer can be thought of as natural selection playing out among somatic cells. Explain this idea.

Answer 47

Cancer refers to many diseases that have unregulated cell growth and division that impacts normal cell/tissue functioning. Cells that can grow and divide more than others are more successful in terms of fitness and natural selection, but this has negative effects on the patient.