Genetics 21 - 30 Flashcards
Non-directiveness
Genetic counselors are not supposed to tell patients whether they should or should not undergo genetic testing. They should also avoid implicit and explicit judgments about what the parents should do if results are obtained
cfDNA
cell-free placental DNA
It’s found in fragments in the maternal blood, and for some aneuploidies cfDNA screening is more accurate than prior screenings
Problems with expansion/availbility of cfDNA testing to the general population
There are not enough genetic counselors to provide adequate counseling before & after testing and decisional support
PPV
Positive Predictive Value in cfDNA testing. Depends on the population incidence of the condition tested.
Risks of IVF
multiple pregnancies, ectopic pregnancy, cancellation, ovarian hyperstimulation syndrome, mechanical injury to other organs during egg retrieval, greater risk of premature delivery or c-section
How is pre-implantation genetic diagnosis (PGD) performed?
A single cell from the 8-cell stage is removed by puncturing the zona pellucida and aspirating a cell
PGD tests that can be performed
karyotyping, FISH, PCR to amplify specific genomic regions, and whole genome amplification followed by microarray or deep sequencing to look at copy number variation
What phase, according to the bogus study, must oocytes be in for no mosaicism to show up in embryos after a CRISPR/sperm injection?
M-phase
S-phase sperm + CRISPR injections showed an increase in WT/WT embryos produced, but did not eliminate mosaics.
Problem with the m-phase theory in CRISPR technology?
The maternal and paternal genomes are confined to separate compartments for at least a day post fertilization, so there is no way Cas9 is using the maternal genome as a template to repair the paternal
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
A rare, autosomal recessive genetic condition where a person has problems breaking down fatty acids for energy
Genetic basis for MCADD?
Mutation in the ACADM gene that codes for the medium-chain acyl-CoA dehydrogenase enzyme. this enzyme is essential for fatty acid oxidation, specifically medium-chain fatty acids
Signs and symptoms of MCADD?
Vomitting, lack of energy, low blood sugar.
Serious complications include seizures, breathing difficulties, liver problems, brain damage, coma, and sudden death.
Treatments for MCADD
Avoid periods of fasting, proper nutrition & exercise, avoid hypoglycemia
Constitutional (germline) =
inherited
Clonal expansion
cancers start from a somatic cell that accumulates favorable genetic and epigenetic mutations`
Two cancer models
- Stochastic Cancer Model
2. Cancer Stem Cell Model
Stochastic Cancer Model
Normal somatic cell with normal germline genotype. Mutations collect (image with green then red, yellow, purple) until there are a collection of mutations and the cell phenotype is less differentiated
Every malignant cell can re-seed a new tumor
Cancer Stem Cell Model
First mutation occurs in a somatic stem-type cell. It is more likely to evade therapy than evolved tumor cells and then repopulate the tumor.
Can’t ever guarantee that its gone so you undergo screenings to make sure its at bay
Only the original tumor stem cells can re-seed tumors
What complicates interpretation of DNA/chromosomes from tumors?
Mosaicism. Mix of different cell types
Cancer Immunotherapy
stimulate the patient’s own T cells to specifically attack tumor cells
Oncogenes
promote cell proliferation
just need one affected copy
Mutator genes
subtype of tumor suppressor genes
involved in DNA mismatch repair; “a gene that increases the mutation frequency of other genes”
Types of oncogene amplification
- double minute chromosomes (small chromosome fragments)
- homogeneously staining regions (HSRs); gene amplified in situ in original chromosome
- amplification below the cytogenetic level - ex. just four copies. Won’t see on FISH or karyotype but will on CGH array
Mechanisms of activation of oncogenes
- amplification
- activating point mutation
- chromosomal translocation (philadelphia chromosome)
- retroviral insertion (T cell leukemia example)
- hypomethylation of oncogene promoter
- aberrant mRNA splicing or mutations leading to use of alternative promoters/polyadenylation sites (different isoforms)
Are oncogene activations somatic or germline?
Typically somatic but can be germline (RET mutation leading to MEN1, MEN2).
Mechanism of gene inactivation in tumor suppressor genes
- deletion (loss of heterozygosity)
- other small genetic changes
- hypermethylation of promoter
tumor suppressor genes
encode transcripts/proteins that prevent cells from dividing too frequently or from surviving inappropriately (pumping the brakes)
Inheritance pattern of mutated tumor suppressor gene?
Autosomal dominant inheritance of cancer risk
note: mechanism is recessive at the tumor cell level
Neurofibromatosis 1 (NF1)
autosomal dominant condition, ~1/3500 worldwide
Mutation in NF1 tumor suppressor gene whose protein, neurofibromin, normally inhibits RAS
Fully penetrant, variable expressivity
CGH vs. SNP arrays in testing for deletions
CGH can detect a deletion and estimate length of the deletion while SNP array can characterize deletion but will also tell you which allele is lost
Familial Adenomatous Polyposis
typical tumor suppressor system; inherited APC gene mutation.
Colon polyps are results of independent 2nd hits to those cells
Hereditary non-polyposis colon cancer (HNPCC)
aka Lynch syndrome
HNPCC tumors show instability in length of some microsatellite alleles; novel alleles in the tumor are observed that are not part of the germline genotype (mutator phenotype)
mutator phenotype
achieved by the inactivation of so called mismatch repair (MMR) genes. These genes are important in maintaining the accurate repeat units of microsatellites
novel alleles are observed
Properties of malignant cells
immortal (never senesce)
can grow without being provided usual growth factors
avoid programmed cell death (apoptosis)
can induce blood vessel formation to feed tumor
ability to invade adjacent tissues, which can lead to ability to metastasize
What is the major risk factor for colon cancer?
Age
90% of “usual” cases are after age 50
When are screening tests performed?
Before a person has symptoms
if its after symptoms are present then you are conducting a diagnostic workup
In CRC, what is the first hit in adenoma to carcinoma?
APC tumor suppressor gene is inactivated
Subsequent hits are to K-Ras, 18q, TP53, etc
What percentage of people with FAP develop CRC by age 40?
100%
Treatment is prophylactic coloprotectomy by 20yo
What is a hallmark of Lynch Syndrome?
multiplicity of cancers
What are the clinical features of Lynch Syndrome?
predominately proximal colon cancers, flat polyps, progression from polyp to cancer in 2-3 years
What is Amsterdam/Bethesda criteria?
Method of diagnosis for Lynch Syndrome.
3 - 2 - 1
3 family members with Lynch synd cancers
2 first degree relatives
1 CRC before age 50
What is the only type of down syndrome known to have a hereditary link?
translocation
What laws protect genetic information?
HIPAA and state laws
What is the Genetic Information Non-Discrimination Act (GINA)?
A law that prohibits discrimination on the basis of genetic information, by health insurers and employers
What types of insurances do NOT fall under GINA protection?
Life insurance, disability insurance, and long term care insurance
What is not protected by GINA?
Analysis of proteins or metabolites that are related to a manifested disease that can be reasonably be detected by a trained healthcare professional
Sensitivity
Out of those people who have a disease, how many tested positive (a true positive rate)?
D / (C+D)
Specificity
Out of those people who do NOT have a disease, how many people tested negative (a true negative rate)?
A / (A+B)
What is a Receiver Operating Curve?
Plotting the sensitivity (y-axis) against the specificity (x-axis)
a perfect test would be a right angle
What traits will an ideal medical test have?
Sensitivity, specificity, a high positive predictive value (PPV), and inexpensive
What is a consequence of screening with low specificity?
Anxiety on the part of patient’s if they receive a false positive (and maybe they won’t follow up!)
What does it mean when genotype = phenotype?
100% penetrance
Relative risk
Ratio of two probabilities
Probability of disease in group 1 divided by the probability of disease in group 2
How do we find genes and pathways in a complex disease?
- linkage studies in families
- animal models
- GWAS (large population associations)
- isolated population studies
What can affect the relative risk for disease?
Less than 100% penetrance, multiple genes, and interactions with the environment
Why measure protein to diagnose a disease over just measuring the DNA
If there are many different mutations that can lead to disease BUT the disease has a characteristic LACK of a protein, then testing for the protein might make the most sense
