Chapter 22: medical genetics and cancer

• precision medicine

• in  _____, a person’s genotype determines their treatment

concordance

the degree to which pairs of individuals (identical. or fraternal twins) exhibit the same trait

100%

for diseases caused by a single gene, concordance among identical twins should be ____

•Identical or monozygotic (MZ)

•Fraternal or dizygotic (DZ) twin

identical twins are aka ____ and fraternal are aka ___

a single gene

When a human disorder is caused by a mutation in _____, the pattern of inheritance is called simple Mendelian inheritance and it can be deduced by analyzing human pedigrees

• •Frequently, an affected offspring has two unaffected parents

• •When two unaffected heterozygotes have children, the percentage of affected children is (on average) 25%

• •Two affected individuals will have 100% affected children

• •The trait occurs with the same frequency in both sexes

4 common features of autosomal recessive:

autosomal recessive

Disorders that involve defective enzymes typically have a ___mode of inheritance

autosomal recessive

Tay-Sachs disease is an example of ___mode of inheritance

1. An affected offspring usually has one or both affected parents

2. An affected individual, with only one affected parent, is expected to produce (on average) 50% affected offspring

3. Two affected heterozygotes will have (on average) 25% unaffected offspring

4. For most dominant disease-casing alleles, the homozygote is more severely affected with the disorder

5. The trait occurs with the same frequency in both sexes

• Five common features of autosomal dominant inheritance

Autosomal Dominant Inheritance

Huntington disease shows ____ inheritance pattern

•Haploinsufficiency

• The heterozygote has 50% of the normal protein

• •This is not sufficient for a normal phenotype

explain dominant disorder aniridia

•Gain-of-function mutations:

• •Mutation changes a protein, so it gains a new function

explain dominant disorder huntington disease

•Dominant-negative mutations:

• •The altered gene product acts antagonistically to the normal product

explain dominant disorder Marfan syndrome

• Males are much more likely to exhibit the trait

  • •They possess only one X-chromosome unlike females who possess two X-chromosomes

• •Mothers of affected males often have brothers or fathers who are affected

• •Daughters of affected males produce, on average, 50% affected sons

• •Three common features of X- linked recessive traits

X-Linked Recessive Disease

hemophilia has what inheritance pattern?

x-linked recessive

Duchenne muscular dystrophy has what inheritance pattern?

1. Only females exhibit the trait if it is lethal in males

2. Affected mothers have a 50% chance of passing the trait to daughters

• They also have 50% chance of passing the gene onto sons but many times these disorders are lethal in sons, so they are not observed in the pedigree.

two common features of x-linked dominant inheritance

X-Linked Dominant

inheritance pattern of Vitamin D-resistant rickets?

Genome-Wide Association Studies (GWAS)

the examination of a genome-wide set of genetic variants among different individuals to see if any variant is associated with a disease or other trait

• single nucleotide polymorphisms (SNPs)

Genome-Wide Association Studies (GWAS) usually tries to find an association between one or more _______and a disease or other trait

false —> •SNP may be closely linked to a particular disease-causing allele due to the founder effect and hence not involved in a cause-and-effect relationship

T/F: Association of SNP with disease implies a cause-and-effect relationship

• •Altering gene expression

• •Change the function of the coded protein

• •If a cause-and-effect relationship does exist between an SNP and a disease-causing allele in GWAS, SNP may have a variety of effects resulting in: (2 items)

• Genetic testing

_____ refers to the use of tests to discover if an individual has a genetic abnormality

• •Genetic screening

______ refers to population-wide genetic testing

• Biochemical

• immunological

2 types of genetic tests for abnormalities done at a protein level:

DNA sequencing

karyotyping

2 types of genetic tests for abnormalities done at a DNA/chromosomal level:

biochemical

the ____ test for genetic abnormalities involves The enzymatic activity of a protein being assayed in vitro.

immunilogical

the ____ test for genetic abnormalities involves The presence of a protein being detected using antibodies that specifically recognize that protein. Western blotting is an example of this type of technique (see Chapter 20).

DNA sequencing

the ___ test for genetic abnormalities is described below:

If the gene associated with a disease has already been identified and sequenced, that gene can be amplified from a sample of cells using PCR and then subjected to DNA sequencing, as described in Chapter 20.

Karyotyping

the ___ test for genetic abnormalities is described below:

The chromosomes from a sample of cells can be stained and then analyzed microscopically for abnormalities in chromosome structure and number (see Figure 2.2). → identify gross differences (translocation/missing chromosome)

• E.g. Tay-Sachs disease in ashkenazi Jews

• Genetic testing has also been conducted on specific populations in which a genetic disease is prevalent

• for example…

1. Noninvasive Prenatal Testing

what genetic test before birth is this?

• Analyze the cell-free DNA (cfDNA) present in the blood of the pregnant mother

• •cfDNA is usually identical to the DNA of the fetus

• •Can be conducted as early as week 10 of pregnancy

1. Amniocentesis

what genetic test before birth is this?

• •Fetal cells are obtained from the amniotic fluid

• •Grown for 1-2 weeks to increase cell numbers

• •Karyotyping performed on cells to observe chromosome number and structure

1. Chorionic villus sampling

what genetic test before birth is this?

• •Fetal cells are obtained from the chorion (fetal part of the placenta) and karytotyping is performed

• •Can be performed earlier during pregnancy than amniocentesis

• •However, it poses a slightly greater risk of miscarriage

1. Preimplantation genetic diagnosis

• •Available for in vitro fertilization

• •Testing of embryo before implantation

• 1-2 cells removed in the 8-cell stage and tested

• Cancer

_____ is a disease characterized by uncontrolled cell division 

true!

T/F: cancers are clonal in origin

Characteristics of cancer

1. Most cancers originate from a single cell

2. Cancer is a multistep process

3. Cancer growth is malignant

Characteristics of cancer

1. Most cancers originate from _______

2. Cancer is a ____ process

3. Cancer growth is ____

benign

cancer begins as a ___ non-invasive growth

• Invasive

• •_______ cancer cells invade surrounding healthy tissues

• Metastatic

• •_______ – Moves to a different site in body and causes secondary tumors

• an inherited predisposition

• are not

• •5 to 10% of cancers are due to _______ 90 to 95% are _____

80%

• at least ___% of cancers are related to exposure to mutagens

• carcinogen

• •An environmental agent that causes cancer

• •Oncogenes (GAS PEDAL)

•Mutant gene that is overexpressed and overactive; Contributes to cancerous growth

• •Tumor suppressor genes (BRAKES)

• •Gene that prevents cancers

proto-oncogene

•Normal, nonmutated gene with the potential to become an oncogene is a ______

• Gain-of-function

• _______mutations produce an oncogene

true

T/F A single copy of the oncogene promotes cancerous growth

• •Amount of protein is increased

• •Change in the structure of the protein to make it overly active

• •Protein expressed in a cell type where it is not normally expressed

• Gain-of-function mutation that produces an oncogene usually has one of three effects

  • •Amount of ____ is increased

  • •Change in the ______

  • •Protein expressed _____

• •S – DNA replication

• •M – mitosis and cytokinesis

mitosis and cytokinises take place in the ___ phase of the cell cycle and DNA replication takes place in the __ phase

growth factors

•Commitment to cell division is regulated in part by polypeptide hormones known as ______

•Epidermal growth factor (EGF)

________ is a growth hormone that stimulates skin cells to divide

• Oncogenes

• •_______ commonly encode proteins that function in cell signaling pathways related to cell division

GTP

when Ras protien is bound to ___ it is in it’s active form and returns to it's inactive form once it hydrolyzes this molecule

true

T/F: the ras gene is a proto-oncogene that can become oncogene

missense

• •______ mutations in ras genes are found in a large number of different cancers

• more of the GTP-bound active form of the protein, keeping the signaling pathway turned on and stimulates the cell to divide

• •Some mutations decrease the ability of the Ras protein to hydrolyze GTP which results in….

permanently activated

•Missense mutations in the ras gene can change the structure of the Ras protein to make it ______

the Philadelphia chromosome

•Chronic myelogenous leukemia (CML) is correlated with the presence of _______

translocation

• The shortened (philadelphia) chromosome 22 occurs due to a _______ between chromosomes 9 and 22

bcr/abl fusion protein in white blood cells which causes Chronic myelogenous leukemia (CML)

in the philadelphia chromosome, the translocation results in …

• 15

• •Up to ___% of all human cancers are associated with viruses

Hardy-Zuckerman-4 feline sarcoma virus RETROVIRUS

Causes sarcomas in cats

Rous sarcoma virus (RSV) RETROVIRUS

Causes sarcomas in chickens

Hepatitis B

Causes liver cancer in several species, including humans

Papillomavirus

Causes benign tumors and malignant carcinomas in several species, including humans; causes cervical cancer in humans

Herpesvirus

Causes carcinoma in frogs and T-cell lymphoma in chickens. A human herpesvirus, Epstein-Barr virus, is a causative agent in Burkitt lymphoma, which occurs primarily in immunosuppressed individuals such as AIDS patients.

false! BOTH COPIES NEED. TOBE INACTIVATED

T/F: only one copy of the tumor-suppressor gene needs to be inactivated to promote cancerous growth

• retinoblastoma —> •Causes a tumor in the retina of the eye

• The first human tumor-suppressor gene identified was the ______ gene

1. Inherited

2. Non inherited

• •There are two types of retinoblastoma

• 1.  ______, which occurs in the first few years of life

• 2.______, which occurs later in life

• •Retinoblastoma requires “two” mutations to occur

  • either 1 inherited mutation + 1 non-inherited mutation

  • 1 non-inherited mutation + 1 non-inherited mutation

the “two-hit” model for retinoblastoma states that…

false! it is rare and occurs much later in life

T/F: the non-inherited form of retinoblastoma is pretty common

• activates genes required for cell cycle progression

• transcription factor

what does E2F do?

•  Rb inhibits E2F’s activity and prevents the cell from progressing through cell cycle in an unregulated manner

what happens when Rb bind E2F?

• a cell can always progress through the cell cycle

• •If no functional Rb protein is present,…

false! 50%

T/F: •About 30% of all human cancers are associated with defects in the p53 gene

• to determine if a cell has incurred DNA damage

• •A primary role for the p53 protein is…

• •Activate genes that promote DNA repair

• •Activate genes that arrest cell division and repress genes that are required for cell division

• •Activate genes that promote apoptosis – programmed cell death

• •If p53 finds DNA damage on a cell it will promote cellular pathways that

  • •Activate genes that promote____

  • •Activate genes that ,,,

  • •Activate genes that promote ___

• Apoptosis

• ______ is a process that involves cell shrinkage, chromatin condensation and DNA degradation resulting ultimately in programmed cell death

caspases (cell executioners)

apoptosis is facilitated by proteases known as _____

• vesicles

• phagocytized

• In apoptosis, the cell is broken down into small ______ 

• Eventually _____ by cells of the immune system

negatively

Rb ___ regulates cell division

• •Negatively regulate cell division:

• •Maintain genome integrity:

• •Tumor-suppressor genes fall into two general categories

•Genome maintenance

•Checkpoint proteins

2 ways of maintaining genome integrity:

1. _________Cellular mechanisms that either prevent mutations from occurring or prevent mutant cells from dividing or surviving

2. _________ detect genetic abnormalities and prevent cell division (DNA repair enzymes)

checkpoint

DNA repair enzymes are examples of ___ proteins

1. A mutation in the tumor-suppressor gene itself

2. Aneuploidy

The function of tumor-suppressor genes can be lost in two main ways:

Chromosome loss may contribute to the progression of cancer if the lost chromosome carries one or more tumor-suppressor genes

how can aneuploidy silence tumor-suppressor genes?

• •The promoter could be inactivated

• •An early stop codon could be introduced in the coding sequence

how can a mutation in the tumor-suppressor gene silence it? (2 possibilities)

Mutations that cause tumors to be resistant to chemotherapy

• •Malignancy can accumulate genetic changes that make it more difficult to treat like…

• •Missing chromosomes – may have tumor suppressor genes so they are lost

• •Duplicated chromosomes – may have proto-oncogenes so they get expressed

• 2 Chromosomal abnormalities are associated with cancer

• predisposition

• •About 5% to 10% of all cancers involve germ-line mutations; People who have inherited such mutations have a ______ to develop cancer

• tumor-suppressor gene

Inheritance of Cancers in Pedigrees

• •Most inherited cancers involve a defect in a ______

• •The individual is heterozygous, with one normal and one inactive allele

dominant

•At the level of a human pedigree, a predisposition for cancer is inherited in a _____ fashion

• recessive

• •At the cellular level, however, the development of cancer is ______

• •DNA methylation

• •Covalent modification of histones

• •Chromatin remodeling

• •Several types of (epigenetic) chromatin modifications are found to be abnormal in cancer cells like… (3)

1. chromatin-modifying proteins

2. chromatin-modifying proteins

• •Abnormal chromatin modifications in cancer mostly occur due to:

• 1. Mutations in genes that encode _______

• 2. Environmental agents that alter the functions of ______

• lead to inhibition of chromatin-modifying proteins

• or

•  lead to increased function of chromatin-modifying proteins

Mutations in Genes that Encode Chromatin-Modifying Proteins may… or …

correlation coefficient

a statistically significant correlation between epigenetic changes and a particular type of cancer is called …

correlation coefficient

a ____ can determine if two variables, like methylation and severity of cancer are related