Genetics in Medicine exam 4

BIOL 429

cell cycle

ordered sequence of growth, DNA replication and cell division that a cell undergoes as it divides into two daughter cells. Life cycle of a cell

cell cycle control

mechanisms that regulate the sequence of events during cell division, ensuring proper DNA replication, separation of chromosomes and formation of two genetically identical daughter cells.

G1/S checkpoint

checkpoint that dictates if the cell should undergo mitosis and cell division

neoplasm

mass of cells with the property of uncontrolled cell division

tumorgenesis

formation of a tumor with cells showing uncontrolled proliferation

angiogenesis

formation of new blood vessels supplying blood to tumors.

benign

tumor has not invaded the nearby healthy tissue

malignant

tumor has invaded the nearby healthy tissue

metastasis

tumor cells break off from the main tumor and spread to distant parts of the body

carcinogens

mutagens that can leads to genetic change and cancer

cancer families

members with a higher possibility for having a certain cancer due to the inheritance of a pre-disposing allele

NextGen Sequencing

used to study genetic variation between organisms. Studies multifactorial diseases including cancer

Driver mutations

genes in which mutations are found frequently between tumor samples of the same type

passenger mutations

genes in which different random mutations are found in the same type of tumor samples

spontaneous mutations

replication errors occurring at a frequency of 1/ten billion for each base per cell division due to environmental exposures.

differentiation

process where unspecialized cells develop into specialized cells with distinct structure and functions

proliferation

rapid multiplication or increase in the number of cells

tumor suppressor gene

class of gene that controls cell division and will inhibit tumor formation

oncogene

genes when not properly expressed or regulated drive cancer formation

proto-oncogene

genes involved in the four basic regulators of cell growth (growth factors, growth factor receptors, signal transduction molecules, nuclear transcription factors)

two-hit hypothesis

patients who receive one mutated copy from their parents can more easily get a mutation in the second copy due to random mutation. when both copies become mutated, tumor formation occurs.

transformed cells

cells with unregulated cell growth and division

genetic instability

widespread mutations, chromosomal breaks and aneuploidy indicative of tumor formation. Active oncogenes, deactivate tumor suppressors.

senescence

cell reaches point where it cannot divide and will eventually die because telomeres get too short

Cyclin

proteins associated with the cycle of cell division which initiate certain processes of mitosis

CDK

Binds to cyclin to drive the progression through the checkpoints of the cell cycle. It can phosphorylate target proteins and drive cell cycle forward

p21

inhibits CDK/cyclin binding. cell cycle inhibitor. regulates cell growth and prevents uncontrolled cell division

TP53

tumor suppressor gene that regulates cell growth and prevents the development of tumors. monitors DNA damage and triggers mechanisms to repair damage.

pRB (encoded by the RB1 gene)

RB1 gene encodes pRB which is a key tumor suppressor protein that regulates the cell cycle progression and prevents uncontrolled cells growth. Key protein in the G1/S checkpoint that prevents cells from progressing if DNA damage and other abnormalities are detected

ERBB

mediates signals from the extracellular environment to the cell nucleus that influences cell growth, differentiation, migration, and survival. over expression or mutations can lead to cancer.

RAS

proteins crucial for cell signaling that can become oncogenic when they are mutated which leads to uncontrolled cell growth, and evasion of death signals.

jun/fos/myc

play crucial roles in cancer development and progression. These proteins transcription factors that are deregulated in cancer cell which contribute to uncontrolled cell growth and proliferation

telomerase

enzyme that uses RNA template to produce telomere DNA that adds DNA sequences to the ends of chromosomes which counteract the shortening that occurs in cell division. Telomeres then never shorten enough to cause the cell to die

APC

tumor suppressor that plays crucial role in regulating cell growth, adhesion, and migration in the Wnt signaling pathway. controls levels of b-catenin. mutations lead to cell growth and tumor formation.

B-catenin

multifunctional protein involved in cell-cell adhesion and gene transcription. crucial mediator of the Wnt/b-catenein signaling pathway. Abnormal activation can drive cancer development.

what kind of disorder is cancer

single gene disorder or multifactorial cancer

most common disorder that causes cancer

cancer is more common as a multifactorial disorder

what type of disorder can pedigrees be used for

single gene disorders

why are multifactorial cancers complex

they are complex because they rise from an interplay of multiple genetic, environmental, and lifestyle factors rather than a single cause. This makes it extremely difficult to pinpoint to a single cause and predict the development and progression of the disease.

can cancer evolve

yes cancer can evolve

why can cancer evolve

cancer can evolve because it is a process of natural selection where cancers with advantageous mutation survive and proliferate which leads to changes in the tumors characteristics.

how do proliferation and differentiation relate to cancer

in normal cells, proliferation and differentiation are balanced. in cancer cells, little to no differentiation occurs but cancer cells undergo major proliferation

order of the cell cycle

G1-S-G2-M

M

mitosis and cell division

G1

cell performs function, most cells sit in this stage

S

synthesis, duplicate DNA

G2

duplicates organelles

how is the cell cycle important in controlling proliferation

ensures orderly replication and division of cells. Makes sure cell only progresses through cycle when conditions are favorable.

key cell cycle checkpoint

G1/S checkpoint is the key checkpoint because it determines if the cell should undergo mitosis and cell division.

proteins that control G1/S checkpoint

P53 binds to a protein that encodes for p21. p21 blocks binding of CDK/cyclin complex. This causes pRB to be not-phosphorylated which binds to E2F and blocks its activity. when CDK/cyclin is active it binds to pRB and phosphorylates it which causes E2F to be active to enter cell nucleus and act as transcription factor to drive cell through G1/S checkpoint.

two events that must occur for tumorgenesis to happen

additional growth signals are produced, signals that inhibit growth and promote differentiation are inhibited.

why is cancer not just one disorder

different types of cancer can arise in different organs and tissues. each type of cancer has their own characteristics and causes.

which kind of tumor is considered cancer

malignant

how are tumors classified

tumors are classified through their tissues or origin

why are tumors monoclonal

because they arise from a single ancestral cell

primary basis of tumorgenesis

primary basic of any tumor formation are genetic changes that occur in somatic cells. these changes allow for an exit of cell cycle control

mutation that is induced by a carcinogen

carcinogens induce mutations by exposure to external agents that cause DNA damage

mutation that is spontaneous

mutation caused by a random mutation that causes error in DNA mechanisms. responsible for 95% of tumor formations.

why is NextGen sequencing a powerful tool in cancer study and treatment

it allows for the analysis of genetic information in cancer cells which enables for faster and more accurate diagnosis, better personalized treatment plans and better understanding of cancer development and progression.

how do driver mutations arise

through single base changes, small insertions or deletions, chromosomal rearrangement, chromosomal duplications

how do passenger mutations arise

random genetic changes in DNA that dont directly contribute to disease progressions

what classes of mutation are tumor supressors

loss-of-function mutations and null mutations

what classes of mutation are oncogenes

gain-of-function mutations

are pediatric or adult tumors more quiescent

pediatric tumors are more dormant

what processes are disrupted by driver mutations

cell growth, cell division, DNA replication

are the processed disrupted by driver mutations tumor suppressors or oncogenes

both

what is the difference between tumor suppressors and oncogenes

tumor suppressors regulate cell growth, suppress tumors and promote apoptosis

oncogenes promote uncontrolled cell growth and division

does the two-hit hypothesis apply to tumor suppressors or oncogenes

tumor suppressors

what is the constitutional mutation

the mutation that is inhertited

what is the additional mutation

the one that is randomly mutated

function of CDK/cyclin complexes in cell cycle control

CDK/cyclin complex drives the progression through the cell cycle checkpoints

how does a proto-oncogene become an oncogene

via a mutation, gene amplification or chromosome rearrangement that leads to increased activity of a gene product. oncogenes are activated through mechanisms that result in increased ecpression or activity

how does gene amplification work

gene amplification works by having an increased number of proto-oncogenes within the DNA. This leads to increased expression of a protein that leads to a mutation.

how can viral infection result in tumor formation

the genome of a virus is reverse transcribed before it is integrated into the host. If it is integrated near an oncogene it will leads to the oncogene being expressed.

treatment

management and care of a patient for either a disease or a disorder

cure

to remove the cause of the disease or disorder and restore previous health

active treatment

directed to immediately cure

casual treatment

treatment directed towards the symptoms

environmental treatment

removal of environmental cues to treat symptoms

enzyme/molecular replacement therapy

expression of a specific enzyme in a metabolic pathway is reduced

RNA based therapy

SiRNA can be used to degrade mutant RNA

surgical treatment

removing a deformity

monoclonal antibody therapy

injects monoclonal antibodues to bind target and lessens inflammatory diseases

gene therpy

method that allows for replacement of a specific gene

allelic hetergeneity

when multiple different mutations at the same gene locus cause the same or similar phenotype

genetic heterogeneity

when different genetic mutations or variants cause the same or similar phenotype

dietary restriction therapy

treating the symptoms by changing dietary habits

diversion therapy

activation of alternative metabolic pathways to lessen the concentration of dangerous metabolite in the patient

inhibition therapy

block one of the enzymes in a metabolic pathway

depletion therapy

remove a compound that when it builds up to hight levels can be toxic

three classes of genetic disorders

multifactorial, single gene, chromosomal

why are multifactorial disorders most easily treated

often have environmental cues that lead to their development and those environmental cues can be removed to reduce symptoms

why are chromosomal disorder most difficult to treat

they results from a loss or gain of chromosomal material so treatment at best just handles the symptoms

what is more likely used for genetic disorders, treatment or a cure

treatments because genetic disorders are often widespread and difficult to correct. DNA is very complex so it is very challenging to correct underlying issues

why is genetic counseling a key part of the process of treating a genetic disorder

because treatment will be a life-long endeavor, and the patient must be informed of this. It also aids family members who will be helping with caregiving. it also informs family members about their chances of inheriting the disease and inform patient of risks of passing it to offspring.

which treatments are more passive (target symptoms)

surgical, environmental

which treatment are more active (target underlying cause)

enzyme replacement, gene therapy, RNA based treatment, monoclonal antibody

what are the three reasons why a genetic disorder may not be treated

1. the gene is not identified or disease pathogenesis is not understood. this makes it very difficult to diagnose, treat, or prevent condition.

2. Pre-diagnostic fetal damage. when harm is done to the developing fetus before a definitive diagnosis of the problem can be made

3. severe phenotypes are less willing to respond to treatment because the symptoms are too sever to treat

what is considered a successful treatment of a genetic disorder

a treatment can be considered successful when it improves the patients quality of life. for some this can be to just reduce the symptoms and potentially prevent disease progression, and for other it could be to cure the condition

how do allelic and genetic heterogeneity affect treatment of a genetic disorder

they make treatment very difficult because it they complicate diagnosis, prediction of disease progression and selection of appropriate therapies