M3 L17: Genetic counseling, human genetics, and cancer genetics Flashcards
why does medical genetics involve the patient’s family more than other medical fields
1) family plays a role in patient’s care
2) patients’ diagnosis could have implications for the family since genetic diseases are heritable
genetic diseases caused by mut in single genes
1) huntingtons
2) PKU
genetic diseases caused by muts in one of many genes (genetic heterogeneity)
fanconi anemia (LOF mutation in one of 3 genes)
example of a genetic disease influenced by the environment
PKU
what are 4 types of hereditary diseases
1) mendelian
2) mitochondrial
3) chromosomal
4) multi-factorial
how are mendelian conditions inherited
mut in single gene
dom/rec
can be autosomal or X linked
how are mitochondrial muts inherited
mut in single gene but inherited maternally
variable penetrance/expressivity
usually more severe in males
how are chromosomal muts inherited
add extra copy
usually spontaneous not inherited
influenced by maternal age
how are multi factorial conditions inherited
inherit increased susceptibility for heart disease, cancer
what is presymptomatic testing and a disease it’s used for
genotype adults before onset of symptoms
common for huntingtons
challenges with presymptomatic testing and huntingtons
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
what are the two types of fetal screening
non invasive (no threat to fetus)
invasive (some risk to fetus)
examples of non invasive fetal screens
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)
examples of invasive fetal screens
1) amniocentesis: use needle to extract amniotic fluid and fetal cells
2) chronic villus sampling: pass tube transvaginally to get fetal cells from chorion
what is preimplantation screening? common context?
remove a single cell from embryo during 8-16 cell stage –> genotype it
common for IVF
What is the Guthrie test? who developed it
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
What causes tay-sachs disease? why do carrier screening?
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
How can direct to consumer genetic tests be helpful? example?
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)
3 goals of genetic counselor
communicate info, discuss options, help patient reach own decision
what are the 4 variables to consider when assessing risk when having children
1) inheritance pattern
2) family structure
3) family genotype info
4) pop freq of the allele
Why is cancer a disease of the genome?
cancer includes several diseases that are all caused by accumulated mutations in somatic cells –> causes cells to divide abnormally/rapidly
cancer is the 2nd leading cause of death after _____? Which two cancers cause the most deaths?
heart disease
lung and breast
what 2 types of muts are hallmarks of cancer and malignant tumors?
1) GOF in proto-oncogenes: promote cell cycle progression
2) LOF in tumor supressor genes: normally slow down the cell cycle
what is angiogenesis
developing new blood vessels
what is metastasis
cancer cells invading other tissues (local or breaking off –> start new tumor)
what are driver and passenger mutations
drivers: mutations in cancer cells that lead to cancer progression
passengers: mutations in cancer cells that do not lead to cancer progression
what is the biggest risk factor for cancer
age
is everyone equally susceptible to all sporadic cancers? What is the percentage of development?
yes
90%
what is familial cancer
presence of a germline mutation increases susceptibility to a certain cancer
examples of familial cancer
chronic myelogenous lukemia
retinoblastoma
li fraumeni syndrome
breast/ovarian
mechanism of chronic myelogenous leukemia (CML)
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
what is sporadic retinoblastoma
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
mechanism for retinoblastoma
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
what is hereditary retinoblastoma
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
what’s the two hit hypoth? who developed it?
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)
what’s li fraumeni syndrome
inherited susceptibility to many types of cancer
mechanism of li fraumeni syndrome
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
what percentage of breast/ovarian cancers are sporadic?
90-95%
char of sporadic vs inherited susceptibility breast/ovarian cancers
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)
what is cancer genomics
sequence cancer genomes to determine types of muts that lead to disease progression
4 key takeaways from cancer genomics
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)
3 main types cancer treatments/pros and cons
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
what is targeted cancer therapy? example?
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
example of cancer gene therapy
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
Design an assay that would allow for the disease allele of the huntington gene to be identified using PCR.
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.
Are direct-to-consumer genetic tests diagnostic? Why or why not?
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.
Describe one potential drawback of direct-to-consumer genetic testing in the absence of the support of a genetic counselor.
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.
Cancer can be thought of as natural selection playing out among somatic cells. Explain this idea.
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.
